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.     

A case of primary malignant lymphoma of the duodenum successfully treated with dose escalating chemotherapy

A 65-year-old woman with diabetes mellitus was hospitalized for heart failure and anemia in August 2001, and recovered with conservative treatment. An endoscopic examination revealed an ulcerative mass located in the duodenal bulb to the 2nd portion. Abdominal CT scan demonstrated tumor involvement in the pancreas head. The diagnosis of a diffuse large B-cell lymphoma, clinical stage IIE, was made by endoscopic biopsy. Although surgical resection of the localized intestinal tumor would have been a common choice for initial treatment, polychemotherapy was selected; the patient had diabetes mellitus and preferred polychemotherapy to surgical operation. Because of bulky intestinal mass, transmural disease and sensitive histological type, standard-dose chemotherapy was considered to include a high risk of intestinal perforation. We performed dose-escalating chemotherapy: A half dose of THP-COP (pirarubicin, cyclophosphamide, vincristine) was given at the start in October 2001, 60% THP-COP as the next cycle, 80% THP-COP as the 3rd cycle and thereafter. Without serious complications of the intestine, she received a total of 6 cycles of chemotherapy and subsequent involved field radiation. There has been no evidence of recurrence of disease 14 months from the start of chemotherapy. When conditions make surgical treatment difficult, dose-escalating chemotherapy in a treatment cycle may be considered as an alternative.     

Therapeutic advances in BIG3‐PHB2 inhibition targeting the crosstalk between estrogen and growth factors in breast cancer

Our previous studies demonstrated that specific inhibition of the BIG3‐PHB2 complex, which is a critical modulator in estrogen (E2) signaling, using ERAP, a dominant negative peptide inhibitor, leads to suppression of E2‐dependent estrogen receptor (ER) alpha activation through the reactivation of the tumor suppressive activity of PHB2. Here, we report that ERAP has significant suppressive effects against synergistic activation caused by the crosstalk between E2 and growth factors associated with intrinsic or acquired resistance to anti‐estrogen tamoxifen in breast cancer cells. Intrinsic PHB2 released from BIG3 by ERAP effectively disrupted each interaction of membrane‐associated ERα and insulin‐like growth factor 1 receptor beta (IGF‐1Rβ), EGFR, PI3K or human epidermal growth factor 2 (HER2) in the presence of E2 and the growth factors IGF or EGF, followed by inhibited the activation of IGF‐1Rβ, EGFR or HER2, and reduced Akt, MAPK and ERα phosphorylation levels, resulting in significant suppression of proliferation of ERα‐positive breast cancer cells in vitro and in vivo. More importantly, combined treatment with ERAP and tamoxifen led to a synergistic suppression of signaling that was activated by crosstalk between E2 and growth factors or HER2 amplification. Taken together, our findings suggest that the specific inhibition of BIG3‐PHB2 is a novel potential therapeutic approach for the treatment of tamoxifen‐resistant breast cancers activated by the crosstalk between E2 and growth factor signaling, especially in premenopausal women.     

Castleman disease and mimickers: Clinicopathological findings of atypical lymphoproliferative disorders associated with autoimmune disease

Atypical lymphoproliferative disorders (LPDs) related with autoimmune disease (AID) show marked clinicopathological diversity, which are defined as three distinct clinicopathological subtypes such as those resembling Castleman disease (CD), atypical paracortical hyperplasia with lymphoid follicles (APHLF), and atypical lymphoplasmacytic and immunoblastic proliferation (ALPIB). We studied excisional biopsy specimens from 31 patients with atypical LPDs associated with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren syndrome (SjS). The lesions in these 31 cases were classified into 6 (19.4%) cases resembling CD, 14 (45.2%) cases of APHLF, and 11 (35.5%) cases of ALPIB. Five cases (83.3%) resembling CD were in the active stage with systemic symptoms and multicentric lymphadenopathy. Thirteen cases (92.9%) of APHLF showed systemic symptoms, multicentric lymphadenopathy and abnormal laboratory findings. Histologic findings for cases resembling CD were rare in patients with RA and SjS. In AID patients, histologic findings for cases resembling CD or APHLF findings correlated with disease activity and multicentric lymphadenopathy. Six cases (54.5%) of ALPIB were in the active phase with systemic symptoms and multicentric lymphadenopathy. ALPIB tended to be unrelated to AID activity, especially in the majority of patients with no abnormal laboratory findings. Atypical LPDs associated with AID is a group of diseases that may be overdiagnosed and overtreated. The diagnosis of atypical LPDs associated with AID requires an understanding of the histological findings as well as a comprehensive assessment of the presence of systemic symptoms, the distribution of lymphadenopathy, and abnormal laboratory findings.     

Role of chymase on growth of cultured canine Tenon's capsule fibroblasts and scarring in a canine conjunctival flap model

Chymase is a chymotrypsin-like serine protease contained in the secretory granules of mast cells. Recently, we reported that chymase activity and the number of chymase-positive mast cells in conjunctival tissues were significantly increased during the wound healing process in a hamster model of glaucoma surgery. However, it has been unclear the role of chymase on conjunctival scarring. In the present study, we evaluated the effect of dog chymase on cell proliferation of fibroblasts established from canine Tenon's capsule and the effect of a chymase inhibitor on scarring in a canine conjunctival flap model. After a fibroblast cell culture was established from canine Tenon's capsules, the fibroblasts were incubated in the presence of dog chymase (5-20 ng ml(-1)). Cell proliferation was evaluated by bromodeoxyuridine incorporation. In a canine conjunctival flap model, a sponge treated with a chymase inhibitor, Suc-Val-Pro-Phe(P)(OPh)(2), or placebo was placed in between the conjunctiva and sclera and the conjunctival incision was closed. One week after the surgery, adhesion degree was assessed, and chymase activities in the conjunctival lesion and in the areas of the conjunctiva and sclera were measured. In cultured canine Tenon's capsule fibroblasts, dog chymase significantly increased cell proliferation, and this chymase-dependent proliferation was completely suppressed by the chymase inhibitor. In the canine surgical model, chymase activity in placebo-treated eyes was significantly increased compared to control eyes, while it was significantly decreased by treatment with the chymase inhibitor. Scores for adhesion degree in the chymase inhibitor-treated eyes were significantly decreased in comparison with those in placebo-treated eyes. The conjunctival area in the chymase inhibitor-treated eyes was also suppressed to 52.6% compared with that in placebo-treated treated eyes. In conclusion, chymase stimulates proliferation of fibroblasts derived from canine Tenon's capsule and chymase may play an important role in scarring after glaucoma surgery.     

Two Distinct Cases of Adult-onset Kawasaki Disease

Kawasaki disease (KD) is a systemic vasculitis syndrome that mostly affects children under 4 years old. Among the reported KD cases, only 1% were over 10 years old. We herein report 2 cases of adult-onset KD (AKD) in 19- and 17-year-old boys diagnosed with a persistent fever and cervical lymphadenitis. Both patients showed cardiac complications, such as coronary artery dilation and myocarditis. Repeated intravenous immunoglobulin therapy was effective in the 19-year-old, while plasma exchange therapy was needed for the 17-year-old, with no sequelae noted at discharge. KD should be considered as a differential diagnosis for persistent fever in adults.     

C-Reactive Protein as a Prognostic Variable That Reflects Uncontrolled Up-Regulation of the IL-1-IL-6 Network System in Colorectal Carcinoma

Up-regulation of the IL-1-IL-6 network stimulates systemic expression of C-reactive protein (CRP). This cytokine network system plays a pivotal role in inducing angiogenic growth factors in intestinal mucosa. Serum CRP level and tissue concentrations of cytokines in colorectal cancer patients were determined and an in vitro model was employed to determine the time course of induction of IL-6 in Caco-2 cells. Increased serum CRP was associated with recurrent disease and shorter survival time. Intense surgical stress and the presence of an acute phase reactant were independently associated with overexpression of IL-6 in the tumor. Enhanced IL-6 protein expression in Caco-2 cells induced by the initial treatment with IL-1beta or lipopolysaccharide could be abrogated by additional presupplementation of IL-1ra. The presence of an acute phase reactant reflects uncontrolled up-regulation of the local IL-1-IL-6 network system in the tumor, which may enhance the survival and proliferation of remnant cancer cells after tumor resection.