Pilot study of a heptavalent vaccine-keyhole limpet hemocyanin conjugate plus QS21 in patients with epithelial ovarian, fallopian tube, or peritoneal cancer.

PURPOSE: To characterize the safety and immunogenicity of a heptavalent antigen-keyhole limpet hemocyanin (KLH) plus QS21 vaccine construct in patients with epithelial ovarian, fallopian tube, or peritoneal cancer in second or greater complete clinical remission. EXPERIMENTAL DESIGN: Eleven patients in this pilot trial received a heptavalent vaccine s.c. containing GM2 (10 microg), Globo-H (10 microg), Lewis Y (10 microg), Tn(c) (3 microg), STn(c) (3 microg), TF(c) (3 microg), and Tn-MUC1 (3 microg) individually conjugated to KLH and mixed with adjuvant QS21(100 microg). Vaccinations were administered at weeks 1, 2, 3, 7, and 15. Periodic blood and urine samples were obtained to monitor safety (complete blood count, comprehensive panel, amylase, thyroid-stimulating hormone, and urinalysis) and antibody production (ELISA, fluorescence-activated cell sorting, and complement-dependent cytotoxicity). RESULTS: Eleven patients were included in the safety analysis; 9 of 11 patients remained on study for at least 2 weeks past fourth vaccination and were included in the immunologic analysis (two withdrew, disease progression). The vaccine was well tolerated. Self-limited and mild fatigue (maximum grade 2 in two patients), fever, myalgia, and localized injection site reactions were most frequent. No clinically relevant hematologic abnormalities were noted. No clinical or laboratory evidence of autoimmunity was seen. Serologic responses by ELISA were largely IgM against each antigen with the exception of Tn-MUC1 where both IgM and IgG responses were induced. Antibody responses were generally undetectable before immunization. After immunization, median IgM titers were as follows: Tn-MUC1, 1:640 (IgG 1:80); Tn, 1:160; TF, 1:640; Globo-H, 1:40; and STn, 1:80. Only one response was seen against Lewis Y; two were against GM2. Eight of nine patients developed responses against at least three antigens. Antibody titers peaked at weeks 4 to 8 in all patients. Fluorescence-activated cell sorting and complement-dependent cytotoxicity analysis showed substantially increased reactivity against MCF7 cells in seven of nine patients, with some increase seen in all patients. CONCLUSIONS: This heptavalent-KLH conjugate plus QS21 vaccine safely induced antibody responses against five of seven antigens. Investigation in an adequately powered efficacy trial is warranted.     

Ductal Carcinoma-In-Situ: Long-Term Results of Breast-Conserving Therapy

Background: The role of breast-conserving therapy (BCT) in the management of ductal carcinoma-in-situ (DCIS) is controversial because of reported high recurrence rates. We reviewed our experience to determine whether the rate and pattern of locoregional recurrence after BCT were similar in patients with DCIS and patients with early-stage (T1) invasive breast tumors and whether local recurrence affected survival.Methods: Between 1973 and 1994, 87 patients with DCIS alone, 22 patients with DCIS with microinvasion (DCIS-M), and 646 patients with invasive breast cancer 2 cm or smaller in diameter were treated with BCT (wide local excision with radiotherapy) at The University of Texas M. D. Anderson Cancer Center. Survival was calculated by the Kaplan-Meier method. The median follow-up times were 11 years for patients with DCIS alone, 12 years for patients with DCIS-M, and 8 years for patients with invasive breast cancer.Results: Eleven (13%) of 87 patients with DCIS and 5 (23%) of 22 patients with DCIS-M had developed locoregional recurrences at follow-up. Two patients with DCIS with locoregional recurrence died of breast cancer. Of the 646 patients with invasive breast cancer, 56 (9%) had a locoregional recurrence, and 16 (2%) died of breast cancer. The median time to locoregional recurrence was significantly longer in patients with DCIS or DCIS-M (9–10 years) than patients with invasive tumors (5 years).Conclusions: DCIS is a favorable disease with an excellent long-term survival. The locoregional recurrence rate in patients with DCIS treated with BCT is similar to that in patients with early-stage invasive breast cancer treated with BCT, but time to locoregional recurrence is significantly longer in patients with DCIS. In patients with DCIS treated with BCT, intense surveillance for locoregional recurrence needs to be maintained for the patients lifetime.Presented at the 53rd Annual Meeting of the Society of Surgical Oncology, New Orleans, Louisiana, March 16–19, 2000.     

Diagnosis of deep septic thrombophlebitis in cancer patients by fluorine-18 fluorodeoxyglucose positron emission tomography scanning: a preliminary report.

PURPOSE: To determine the role of the fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scan in the diagnosis and management of deep septic thrombophlebitis (STP). PATIENTS AND METHODS: We conducted a prospective observational evaluation of FDG-PET in patients with cancer and suspected STP. Retrospective evaluation of patients with cancer and deep venous thrombosis (DVT) who underwent FDG-PET and extremity duplex scan (DS) was also performed. RESULTS: Strong venous uptake was observed in FDG-PET of nine STP episodes versus 0 of 27 DVT episodes (P <.001). FDG-PET identified central vein STP in five patients, whereas DS and venography were negative in five and two of these patients, respectively. FDG-PET diagnosis of STP resulted in therapeutic changes in all patients. In four patients, follow-up FDG-PET confirmed resolution. CONCLUSION: In cancer patients, FDG-PET identifies STP even in areas not optimally visualized by DS or venography, distinguishes STP from DVT, and leads to significant therapeutic changes.     

Stent-based gene therapy

Delivery of gene therapy to inhibit intimal hyperplasia has been proposed to prevent postangioplasty restenosis. We sought to apply gene therapy by using a stent-based technique. There are several hurdles that must be overcome before gene-stent therapy can be applied successfully in clinical trials. These include increasing the efficiency of gene delivery through atherosclerotic plaque; increasing intramural retention times; preventing the inflammatory reaction that stents coated with biodegradable polymers can elicit; overcoming the risk of systemic gene delivery; and accessing the adventitia via percutaneous approach. We evaluated a gene-stent delivery mechanism based on microporous metal microneedles developed with nanotechnology in an attempt to overcome some of these problems. A novel approach to the transfection of genes by microfabricated technology was evaluated in smooth muscle cells in culture. We demonstrated that microneedles can deliver gene therapy to smooth muscle cells in culture and can produce controlled penetration of the IEL and intima. We conclude that taller microneedles need to be developed to reach the media in diseased human arteries and that this technology has the potential to be incorporated in a stent to deliver gene therapy in atherosclerotic plaque.     

The effect of ethnicity on immediate reconstruction rates after mastectomy for breast cancer

BACKGROUND: Multiple factors may influence whether patients undergo immediate breast reconstruction along with mastectomy for breast cancer. The authors investigated whether ethnicity was an independent predictor of immediate breast reconstruction. METHODS: The authors identified 1004 patients who underwent mastectomy for breast cancer during the period 2001-2002. The rates of immediate reconstruction among different ethnicities were evaluated using the chi-square test. Logistic regression was used to adjust for covariates, including age and disease stage. Medical records were analyzed to identify factors that influenced each patient's decision for or against immediate breast reconstruction. RESULTS: Three hundred seventy-six women (37.5%) underwent immediate breast reconstruction: This included 20.2% of African-American women, compared with 40.0% of white women, 42.0% of Hispanic women, 42.2% of Asian women, and 10.0% of Middle Eastern women (P < 0.001). The unadjusted odds ratio (OR) for immediate reconstruction for African-Americans versus whites was 0.38 (95% confidence interval [95% CI], 0.23-0.63; P < 0.001). After multivariate analysis, this disparity persisted, with an adjusted OR of 0.34 (95% CI, 0.18-0.62; P = 0.001). Asian women had lower rates of immediate reconstruction compared with white women (adjusted OR, 0.50; 95% CI, 0.24-1.04; P = 0.06). Hispanic women did not have immediate reconstruction rates that differed significantly from white women. Middle Eastern women had lower rates of immediate reconstruction compared with white women (adjusted OR, 0.08; 95% CI, 0.02-0.38; P = 0.002), but they had a corresponding increase in the rate of delayed reconstruction. In a stepwise analysis of the decision pathway to immediate reconstruction, it was found that African-American women were less likely to be offered referrals for reconstruction, were less likely to accept offered referrals, were less likely to be offered reconstruction, and were less likely to elect reconstruction if it was offered. CONCLUSIONS: African-American women underwent immediate breast reconstruction at significantly lower rates compared with white women, Hispanic women, and Asian women. After adjusting for covariates, including age and disease stage, African-American women and Asian women had lower rates of reconstruction compared with white women. The factors that contribute to these differences warrant further study.     

Trastuzumab, paclitaxel, cisplatin, and radiation for adenocarcinoma of the esophagus: a phase I study

Purpose: To conduct a phase I study incorporating trastuzumab with paclitaxel, cisplatin, and radiation for adenocarcinoma of the esophagus. Methods and Materials: Patients with adenocarcinoma of the esophagus without distant organ metastases were eligible. All patients received cisplatin 25 mg/m² and paclitaxel 50 mg/m² weekly for 6 weeks with radiation 50.4 Gy. HER-2/neu-positive patients (2 + /3 + by immunohistochemistry) received weekly trastuzumab at dose levels of 1, 1.5, or 2 mg/kg weekly for 5 weeks after an initial bolus of 2, 3, or 4 mg/kg, respectively. HER-2/neu-negative patients received the same chemoradiation without trastuzumab as a control for toxicity. Dose-limiting toxicities were defined as grade 3 esophageal, cardiac, or pulmonary toxicity. Results: Twelve of 36 screened patients (33%) overexpressed HER-2/neu by immunohistochemistry (seven 3 + and five 2 + ). Eight of 12 patients with HER-2/neu overexpression by IHC had an increase in the number of HER-2/neu genes, six from amplification of the HER-2/neu gene and two were hypderdiploid for chromosome 17. Thirty patients were enrolled (12 HER-2/neu-positive and 18 HER-2/neu-negative controls). No increase in toxicity was seen with the addition of trastuzumab. One of 12 patients in the trastuzumab arm and 8 of 17 in the control arm had grade 3 esophagitis (p ≤ .026). Mean left ventricular ejection fraction for the trastuzumab group was 57% before treatment and 56% after treatment. Conclusion: HER-2/neu is overexpressed in approximately one-third of esophageal adenocarcinomas. Trastuzumab can be added at full dose to cisplatin, paclitaxel, and radiation. Future studies of trastuzumab in esophageal adenocarcinoma are indicated.     

Cerebral abscess caused by Cladosporium bantianum infection--case report

A 26-year-old woman currently treated for systemic lupus erythematosus with steroid therapy presented with sudden onset of right hemiplegia. Computed tomography of the brain showed a large frontoparietal ring-enhanced lesion with perifocal edema. Stereotactic aspiration of the lesion revealed Cladosporium bantianum. The size of the abscess did not reduce in spite of optimum antifungal treatment. The abscess was subsequently excised through a frontoparietal craniotomy. At follow up after 24 months, there was no recurrence of the abscess. Cerebral Cladosporium bantianum infection is usually refractory to antifungal agents and the prognosis is very poor. This patient had the longest survival period in a case of Cladosporium brain abscess so far reported.     

The ultrastructure of tomatine adjuvant

The tomatine adjuvant, consisting of tomatine, n-octyl-beta-D-glucopyranoside, phosphatidylethanolamine, cholesterol, and ovalbumin, has recently been shown to potentiate the immunogenicity of protein antigen and elicit cytotoxic T-lymphocyte responses in immunized animals. The physicochemical properties of tomatine adjuvant have not been characterized. The aim of this study was to examine the microstructure of this complex formulation, as directly related to its physicochemical properties. To elucidate the micromorphology of this system, the tomatine adjuvant was separated by isopycnic ultracentrifugation, followed by freeze fracturing and examination by transmission and scanning electron microscopy. The adjuvant mixture was shown to be composed of several micro- and nano-structures. The major fraction obtained from isopycnic separation was shown to consist of flaky needle-like microcrystals, approximately 80-160 nm in width and 2-4 microm in length. The tomatine crystals alone in 0.9% NaCl, on the other hand, were shown to be elongated hollow tubular crystals of hundreds of nanometers up to a few microns in length, along which n-octyl-beta-glucopyranoside was speculated to serve as a seeding microtemplate for gel crystallization of protein complexes. Indented marks within the gel phase were observed in the freeze fractured replicas of the adjuvant, suggesting that protein complexes may have been crystallized or precipitated within the gels. Several other forms of micro- and nano-structures were also observed, showing multiple-dispersion features with gel characteristics. The presence of gel crystalline and multiple-dispersed phases is postulated to contribute to the sustained immunopotentiation effect of tomatine adjuvant.     

Breast-conservation therapy in early-stage breast cancer patients with a positive family history

Background Our goal was to evaluate the role of breast-conservation therapy in early-stage breast cancer patients with a family history (FH) of breast cancer. Methods Between 1970 and 1994, 1324 female patients with breast cancer were treated with breast-conservation therapy at our institution. From these, we identified 985 patients with stage 0–II breast cancer and who had available information on FH status. FH was considered positive in any patient who had a relative who had been previously diagnosed with breast cancer. Disease-specific survival was calculated from the date of initial diagnosis using the Kaplan-Meier method. Results The stage distribution for the 985 patients was as follows: 0 in 65 (7%), I in 500 (51%), and II in 420 (43%). The median age was 50 years (range, 21–88), with a median follow-up time of 8.8 years (range, .25–29). The median tumor size was 1.5 cm. FH was positive in 31%. There were no significant differences in locoregional recurrence, distant recurrence, disease-specific survival, or incidence of contralateral breast cancer in patients with a positive FH versus patients with a negative FH. Conclusions Breast-conservation therapy is not contraindicated in early-stage breast cancer patients with a positive FH.