Proton beam therapy for hepatocellular carcinoma: a retrospective review of 162 patients.

PURPOSE: We present results of patients with hepatocellular carcinoma (HCC) treated with proton beam therapy. EXPERIMENTAL DESIGN: We reviewed 162 patients having 192 HCCs treated from November 1985 to July 1998 by proton beam therapy with or without transarterial embolization and percutaneous ethanol injection. The patients in the present series were considered unsuitable for surgery for various reasons, including hepatic dysfunction, multiple tumors, recurrence after surgical resection, and concomitant illnesses. The median total dose of proton irradiation was 72 Gy in 16 fractions over 29 days. RESULTS: The overall survival rate for all of the 162 patients was 23.5% at 5 years. The local control rate at 5 years was 86.9% for all 192 tumors among the 162 patients. The degree of impairment of hepatic functions attributable to coexisting liver cirrhosis and the number of tumors in the liver significantly affected patient survival. For 50 patients having least impaired hepatic functions and a solitary tumor, the survival rate at 5 years was 53.5%. The patients had very few acute reactions to treatments and a few late sequelae during and after the treatments. CONCLUSIONS: Proton beam therapy for patients with HCC is effective, safe, well tolerable, and repeatable. It is the useful treatment mode for either cure or palliation for patients with HCC irrespective of tumor size, tumor location in the liver, insufficient feeding of the tumor with arteries, presence of vascular invasion, impaired hepatic functions, and coexisting intercurrent diseases.     

Continuous exposure to dibromoacetic acid delays pubertal development and compromises sperm quality in the rat.

Previously our work on the haloacid by-products of drinking water disinfection focused on adult exposures. Herein we evaluate the consequence of continuous exposure to dibromoacetic acid (DBA) via drinking water through reproductive development into adulthood. An initial study in which offspring were exposed from gestation day (GD) 15 through adulthood revealed significant delays in preputial separation and vaginal opening, dose-related decreases in the fertility of cauda epididymal sperm, and dose-related diminutions in the sperm membrane protein SP22. Subsequent studies consisted of groups in which exposure ceased on postnatal day 21 (PND 21) versus adulthood. For each exposure, animals were evaluated after puberty (PND 56) as well as at adulthood (PND 120). Exposure to 4, 40, or 400 ppm DBA from GD 15 through PND 21 failed to result in any significant reproductive alterations. By contrast, continuous exposure until adulthood resulted in dose-related alterations consistent with those observed in the dose-finding study. Preputial separation and vaginal opening were delayed 4 and 3 days in males and females exposed to 400 ppm (76.3 mg/kg) DBA. This was associated with increased responsiveness of both the testis and ovary to hCG ex vivo; hCG-stimulated testosterone production by testicular parenchyma on PND 56 was increased at 4 ppm (0.6 mg/kg) DBA and higher. Finally, the quality of proximal cauda epididymal sperm was compromised by continuous exposure to DBA. The sperm membrane proteome was altered in a dose-related manner with SP22, and one of its charged variants, diminished at 40 ppm (3.6 mg/kg) DBA and higher. As more sensitive endpoints are evaluated, lower effect levels can be attributed to haloacid exposure. We are now extending our evaluations to epidemiology studies designed to evaluate sperm quality in men exposed to varying levels of disinfection by-products.     

Property of thimerosal-induced decrease in cellular content of glutathione in rat thymocytes: a flow cytometric study with 5-chloromethylfluorescein diacetate.

There is a concern on the part of public health community that adverse health consequences by thimerosal, a preservative in vaccines for infants, may occur among infants during immunization schedule. Therefore, the effect of thimerosal on cellular content of glutathione was examined on thymocytes obtained from 4-week-old rats using a flow cytometer and 5-chloromethylfluorescein diacetate. Thimerosal at concentrations ranging from 1 to 10 microM reduced the cellular content of glutathione in a concentration-dependent manner, and the complete depletion of cellular glutathione was observed when the cells were treated with 30 microM thimerosal. L-Cysteine significantly attenuated the actions of thimerosal to reduce the glutathione content and to increase the intracellular Ca2+ concentration. Prolonged incubation (24 h) with 1-3 microM thimerosal induced the apoptosis. The cytotoxic action of thimerosal was greatly augmented when the cells suffered oxidative stress induced by H2O2. It may be unlikely that thimerosal exerts potent cytotoxic action under the in vivo condition because the blood concentration of thimerosal after receiving vaccines does not seem to reach micromolar range and nonprotein thiols at micromolar concentrations are present in the blood.     

Total abdominal hysterectomy after radiation therapy for cervical cancer: use of omental graft for fistula prevention

Abdominal hysterectomy after treatment of cervical cancer by radiation therapy is associated with a significant rate of postoperative vesicovaginal fistulas. In this series, five patients with invasive cancer of the cervix treated by radiation therapy developed new cervical or uterine neoplasms 1 to 27 years after treatment. All underwent abdominal hysterectomy without postoperative fistula formation. Success is attributed to cautious surgical technique and to the use of the omental pedicle graft to bring new vascularity to the vaginal apex and bladder base. The technique of forming an omental pedicle graft is described.     

Tri-n-butyltin delays the cell death induced by hydrogen peroxide in rat thymocytes

Tri-n-butyltin (TBT), one of environmental pollutants accumulated in mollusks, at nanomolar concentrations decreases cellular content of glutathione (GSH), suggesting that TBT increases cell vulnerability to oxidative stress because GSH has a role in catabolizing hydrogen peroxide (H(2)O(2)). In order to examine this possibility, the effect of tri-n-butyltin chloride (TBTCl) on rat thymocytes suffering from oxidative stress induced by H(2)O(2) was examined using a flow cytometer with four fluorescent probes; ethidium bromide, 2',7'-dichlorofluorescin diacetate, 5-chloromethylfluorescein diacetate and annexin-V-FITC. TBTCl at concentrations ranging from 100 nM to 1 μM attenuated H(2)O(2)-induced decrease in cell viability in a dose-dependent manner. It was unlikely that TBTCl reduced H(2)O(2)-induced oxidative stress because TBTCl failed to affect H(2)O(2)-induced oxidation of intracellular molecule (2',7'-dichlorofluorescin) and H(2)O(2)-induced decrease in cellular content of GSH. Results suggest that TBTCl may inhibit the pathway of cell death induced by H(2)O(2) or that TBTCl may induce a protective substance against the oxidative stress produced by H(2)O(2).     

Atypical cystic lobule of the breast: An early stage of low-grade ductal carcinomain-situ

The authors describe the characteristics of atypical cystic lobules (ACLs), which represent a step in the formation of low-grade ductal carcinoma in-situ. The authors define ACLs as a proliferation of luminal cells showing low-grade cytological atypia without architectural atypia. ACLs were compared with conventional hyperplasia, low-grade ductal carcinoma in-situ, and lobular neoplasia. 1) In about 40% of the cases, atypical cystic lobules merged with fully established micropapillary/cribriform ductal carcinoma in-situ. 2) Immunohistochemical staining for hormone receptors, keratin nineteen, and cyclin D1 revealed that atypical cystic lobules demonstrate a consistent immunophenotype, which differs from that of normal lobules and benign lesions and matches the one of low-grade ductal carcinoma in-situ. 3) ACLs are sometimes calcified. Osteopontin-positive histiocytes infiltrated all Kossa-positive (type II microcalcification) cribriform and comedo-type carcinomas and ACLs. The similarities in cytological and immunohistochemical features, the close proximity of the two types of proliferation, and the similarities with respect to calcification suggest that atypical cystic lobules represent an early stage in the formation of certain types of low-grade ductal carcinoma in-situ.     

Preclinical and first‐in‐human phase I studies of KW‐2450, an oral tyrosine kinase inhibitor with insulin‐like growth factor receptor‐1/insulin receptor selectivity

Numerous solid tumors overexpress or have excessively activated insulin‐like growth factor receptor‐1 (IGF‐1R). We summarize preclinical studies and the first‐in‐human study of KW‐2450, an oral tyrosine kinase inhibitor with IGF‐1R and insulin receptor (IR) inhibitory activity. Preclinical activity of KW‐2450 was evaluated in various in vitro and in vivo models. It was then evaluated in a phase I clinical trial in 13 patients with advanced solid tumors (NCT00921336). In vitro, KW‐2450 inhibited human IGF‐1R and IR kinases (IC₅₀ 7.39 and 5.64 nmol/L, respectively) and the growth of various human malignant cell lines. KW‐2450 40 mg/kg showed modest growth inhibitory activity and inhibited IGF‐1‐induced signal transduction in the murine HT‐29/GFP colon carcinoma xenograft model. The maximum tolerated dose of KW‐2450 was 37.5 mg once daily continuously; dose‐limiting toxicity occurred in two of six patients at 50 mg/day (both grade 3 hyperglycemia) and in one of seven patients at 37.5 mg/day (grade 3 rash). Four of 10 evaluable patients showed stable disease. Single‐agent KW‐2450 was associated with modest antitumor activity in heavily pretreated patients with solid tumors and is being further investigated in combination therapy with lapatinib/letrozole in patients with human epidermal growth factor receptor 2‐postive metastatic breast cancer.