Phase I evaluation of TNFerade biologic plus chemoradiotherapy before esophagectomy for locally advanced resectable esophageal cancer.

BACKGROUND: Neoadjuvant chemoradiotherapy followed by surgery is the primary treatment option for patients with locally advanced esophageal cancer. This multicenter phase I trial examined intratumoral injection of TNFerade biologic, an adenoviral vector that expresses the human tumor necrosis factor-α gene, with chemoradiotherapy in locally advanced esophageal cancer. OBJECTIVES: To assess pathologic complete response (pCR), time to disease progression, progression-free survival, survival, and safety and tolerance in patients treated with preoperative chemoradiation combined with endoscopy or EUS-guided intratumoral injection of TNFerade biologic. DESIGN/INTERVENTION: Five weekly injections of TNFerade biologic, dose-escalated logarithmically from 4 × 10(8) to 4 × 10(11) particle units (PU), were given in combination with cisplatin 75 mg/m(2) and intravenous 5-fluorouracil 1000 mg/m(2)/d for 96 hours on days 1 and 29, and concurrent radiation therapy to 45 Gy. Surgery was performed 9 to 15 weeks after treatment. SETTING: U.S. multicenter study. PATIENTS: Patients with stage II and III esophageal cancer were enrolled. MAIN OUTCOME MEASUREMENTS: Primary outcome measures were safety, feasibility, tolerability, and rate of pCR. Secondary outcome measures were overall survival (OS) and disease-free survival. RESULTS: Twenty-four patients with a median age of 61 years were enrolled; 88% of the patients were men, 21% were stage II, and 79% were stage III. Six (29%) had a pCR, observed among 21 patients (20 who underwent esophagectomy and 1 at autopsy). Dose-limiting toxicities were not observed. The most frequent potentially related adverse events were fatigue (54%), fever (38%), nausea (29%), vomiting (21%), esophagitis (21%), and chills (21%). At the top dose of 4 × 10(11) PU, thromboembolic events developed in 5 of 8 patients. The median OS was 47.8 months. The 3- and 5-year OS rates and disease-free survival rates were 54% and 41% and 38% and 38%, respectively. LIMITATIONS: We included primarily adenocarcinoma. CONCLUSIONS: Preoperative TNFerade, in combination with chemoradiotherapy, is active and safe at doses up to 4 × 10(10) PU and is associated with long survival. This regimen warrants additional studies.

Chilliness: a vasomotor symptom in Japan.

OBJECTIVE: To examine the differences between biomedical and Japanese women's concepts of vasomotor symptoms and the relationships between the symptom of chilliness (hiesho) and menopause status, other vasomotor symptoms, and environmental factors such as soy isoflavone intake and exposure in Japan. DESIGN: Participants were healthy Japanese women, aged 45 to 55, living in Kyoto and Fukushima prefectures, divided into menopausal groups based on menstrual patterns. Women recalled 82 general health symptoms during the previous 2 weeks and collected finger-prick dried blood spots and matched 24-hour dietary records, which were analyzed, respectively, for isoflavone concentration by high-performance liquid chromatography coulometric electrode array detection and for soy isoflavone intake using a Japanese phytochemical database. RESULTS: An examination of konenki (Japanese for climacteric) symptoms suggests that chilliness (hiesho), which was reported by 29.3% of participants compared with a range of 3.0% to 22.1% for hot flushes, constitutes an important vasomotor symptom. Chilliness prevalence differed significantly between premenopausal and other menopausal status groups, with positive correlations with other estrogen-influenced sexual-vasomotor symptoms and negative correlations with isoflavone concentrations. Negative correlations with soy isoflavone intake were also found for sweating, although not for nobose and hoteri (two Japanese terms for hot flush). CONCLUSIONS: Chilliness seems to be a more important vasomotor symptom than hot flushes and sweats in Japanese women and may reflect differing thermoregulatory physiology, possibly influenced by dietary soy.

6-Methylprednisolone does not impair anti-thymocyte globulin (ATG) immunosuppressive activity in non-human primates.

BACKGROUND: Induction treatments with anti-thymocyte globulin (ATG) in solid organ transplantation may enhance the efficacy of maintenance immunosuppressive therapy. Since ATG can trigger Fas (CD95) mediated T cell apoptosis, a process antagonized in vitro by corticosteroids, an important issue is whether corticosteroids could interfere with T cell depleting and immunosuppressive activities of ATG. METHODS: MHC mismatched skin allografts were performed on cynomolgus and rhesus monkeys treated with ATG (20 mg/kg) associated or not with 6-methylprednisolone (10 mg/kg). RESULTS: There was no difference between the two immunosuppressive regimens as regards the intensity and duration of peripheral T lymphocyte depletion and the appearance of anti-ATG antibodies. Skin graft survival was increased in monkeys treated with 6-methylprednisolone as compared with ATG alone. CONCLUSIONS: In vivo, corticosteroids do not interfere with ATG ability to induce massive T cell depletion and to delay skin allograft rejection in non-human primates.