Characteristics of Japanese patients with eosinophilic fasciitis: A brief multicenter study.

Eosinophilic fasciitis is a relatively rare cutaneous fibrotic condition affecting the deep fascia of the extremities, with or without peripheral blood eosinophilia. To examine the characteristics of Japanese patients with eosinophilic fasciitis, we conducted a brief, multicenter, retrospective survey at seven university hospitals. In total, 31 patients were identified as having eosinophilic fasciitis, among whom 30 patients fulfilled the Japanese diagnostic criteria. The male : female ratio was 2.3:1, and the mean age was 47.7 years. Three of the patients were under 20 years old. The possible triggering factors included muscle training, sports, walking or sitting for a long time, physical work, insect bite and drug. Co-occurrence of morphea was observed in nine cases (29%), and malignancies were associated in three (two hematological malignancies and one internal malignancy). Immunological abnormalities in the serum showed positive antinuclear antibody, positive rheumatoid factor, increased aldolase levels and increased immunoglobulin G levels. The patients were treated with either monotherapy or combination therapy by oral prednisolone (20-80 mg/day), methotrexate (6-10 mg/week), cyclosporin (100-150 mg/day), mizoribine, infliximab and phototherapy. Methylprednisolone pulse therapy was performed in six cases. By contrast, spontaneous improvement due to resting only was observed in two cases, and skin hardening was improved by withdrawal of the anticancer drug in one case. This study suggests several characteristics of Japanese patients with eosinophilic fasciitis, namely male predominance, rare pediatric occurrence, immunological abnormalities and coexistence with morphea. Systemic prednisolone is the first-line therapy, but pulse therapy is occasionally required for severe cases. The triggering events of physical stress are not so frequent as have previously been reported, and various factors or even unknown factors may be associated with the induction of eosinophilic fasciitis.

Zinc deficiency exacerbates pressure ulcers by increasing oxidative stress and ATP in the skin.

BACKGROUND: Zinc deficiency is believed to be a predisposing factor for the development and intractable healing of pressure ulcers (PUs); however, the mechanisms of this association have not been elucidated. OBJECTIVE: Objective was to elucidate the mechanisms of the formation of severe and prolonged PUs under the zinc deficiency condition. METHODS: We assessed PUs formation after cutaneous ischemia-reperfusion (I/R) injury in mice fed with a zinc-adequate (ZA) or a zinc-deficient (ZD) diet from 2 weeks before I/R injury. Wound size, vascular damage, apoptotic cells, adenosine triphosphate (ATP) amount, and the number of Langerhans cells (LCs) in I/R area were analyzed. We evaluated the extent of oxidative stress in I/R area in OKD48 mice through bioluminescence detection. RESULTS: We found that dietary zinc deficiency caused the formation of severe and prolonged PUs in mice. Zinc deficiency increased the vascular disorder, oxidative stress, and apoptosis induced by cutaneous I/R injury. I/R injury-induced oxidative stress signals were significantly higher in ZD OKD48 mice than in ZA OKD48 mice. Additionally, zinc deficiency reduced the number of LCs and increased the amount of ATP in cutaneous I/R-injured skin. Oral supplementation of zinc improved zinc deficiency-associated PUs. CONCLUSION: Zinc deficiency might increase cutaneous I/R injury-induced vascular damages, oxidative stress, and apoptosis, as well as ATP amount in I/R area due to the loss of LCs. These mechanisms might partly account for zinc deficiency-induced formation of severe and prolonged PUs. Oral supplementation of zinc might be a reasonable therapeutic choice for patients with PUs and zinc deficiency.

Diagnostic criteria, severity classification and guidelines of localized scleroderma.

We established diagnostic criteria and severity classification of localized scleroderma because there is no established diagnostic criteria or widely accepted severity classification of the disease. Also, there has been no clinical guideline for localized scleroderma, so we established its clinical guideline ahead of all over the world. In particular, the clinical guideline was established by clinical questions based on evidence-based medicine according to the New Minds Clinical Practice Guideline Creation Manual (version 1.0). We aimed to make the guideline easy to use and reliable based on the newest evidence, and to present guidance as specific as possible for various clinical problems in treatment of localized scleroderma.

Diagnostic criteria, severity classification and guidelines of lichen sclerosus et atrophicus.

We established diagnostic criteria and severity classification of lichen sclerosus et atrophicus, because there is no established diagnostic criteria or widely accepted severity classification of the disease. Also, there is no clinical guideline for lichen sclerosus et atrophicus in Japan, so we proposed its clinical guideline. The clinical guidelines were formulated by clinical questions and recommendations on the basis of evidence-based medicine according to the New Minds Clinical Practice Guideline Creation Manual (version 1.0). We aimed to make the guidelines easy to use and reliable including the newest evidence, and to present guidance for various clinical problems in treatment of lichen sclerosus et atrophicus.

Diagnostic criteria, severity classification and guidelines of eosinophilic fasciitis.

We established diagnostic criteria and severity classification of eosinophilic fasciitis because there is no established diagnostic criteria or widely accepted severity classification of the disease. Also, there has been no clinical guideline for eosinophilic fasciitis, so we established its clinical guideline ahead of all over the world. In particular, the clinical guideline was established by clinical questions based on evidence-based medicine according to the New Minds Clinical Practice Guideline Creation Manual (version 1.0). We aimed to make the guideline easy to use and reliable based on the newest evidence, and to present guidance as specific as possible for various clinical problems in treatment of eosinophilic fasciitis.

Topical betamethasone butyrate propionate exacerbates pressure ulcers after cutaneous ischemia-reperfusion injury.

Ischaemia-reperfusion (I/R) is involved in the development of various organ diseases. There has been increasing evidence that cutaneous I/R injury is associated with the pathogenesis of pressure ulcers (PUs), especially at the early stage presenting as non-blanchable erythema. However, there is no evidence-based treatment for early-stage PUs. Our objective was to assess the effects of topical steroid on the development of PUs after cutaneous I/R injury in mice. Cutaneous I/R was performed by trapping the dorsal skin between two magnetic plates for 12 h, followed by plate removal. Topical application of betamethasone butyrate propionate (BBP) in I/R areas significantly increased the size of PUs after I/R. The number of thromboses was increased, and CD31(+) vessels were decreased in the I/R area treated with topical BBP. The number of oxidative stress-associated DNA-damaged cells and apoptotic cells in the I/R area was increased by topical BBP treatment. In addition, the mRNA level of NADPH oxidase 4 (Nox4), the essential enzyme that produces reactive oxygen species, was significantly increased and that of NF-E2-related factor 2 (Nrf2), a transcription factor that regulates the expression of antioxidant proteins, was inhibited in the I/R area treated by BBP. The number of CD68(+) macrophages and the level of transforming growth factor-beta in lesional skin were also decreased by BBP. These results suggest that a topical steroid might accelerate the formation of PUs induced by cutaneous I/R injury by aggravating oxidative stress-induced tissue damage. Topical steroids might not be recommended for the treatment of acute-phase decubitus ulcers.

[A case of perianal squamous cell carcinoma attaining a complete response over five years with chemoradiotherapy].

We report a case with perianal squamous cell carcinoma, which showed a complete response more than five years after chemoradiotherapy. A 69-year-old-man was introduced to our hospital for the diagnosis of squamous cell carcinoma [T3 (8.0 × 8.0 cm) N0M0, Stage II]. The patient was treated by chemoradiotherapy, which consisted of 5-FU 750 mg/m²/ day (continuous intravenously) on days 1-5 and 29-33, and mitomycin C 10 mg/m² on days 1 and 29 and radiation at 2 Gy/day for 5 days per week (total dose 60 Gy). The patient tolerated this treatment with no severe adverse effects. Tumor disappeared completely 1 month after this treatment with no adjuvant therapy. The patient has been alive with no sign of recurrence for 6 years.

Clinical usefulness of a supplementary cyclosporin administration with a topical application of maxacalcitol ointment for patients with moderate psoriasis vulgaris.

In this study, we aimed at confirming the clinical usefulness of a supplementary additional cyclosporin microemulsion preconcentrate (CyA MEPC) administration in 15 patients with psoriasis vulgaris whose disease activity had been unchanged or exacerbated with topical maxacalcitol treatment. Each patient took a supplementary CyA MEPC administration, 2.5 mg/kg per day in addition to maxacalcitol ointment therapy. When the Psoriasis Area and Severity Index (PASI) score revealed over a 75% decrease against the initial value, the administration of CyA MEPC was tapered off, and a topical application of maxacalcitol ointment was continued for the maintenance phase. All patients could obtain improvement within 12 weeks. In 12 patients whose PASI score reduced over 75%, CyA MEPC was tapered off. Of those, five patients remained in remission by maxacalcitol ointment for over 12 months and three patients for 6 months. In conclusion, this preliminary study may suggest that supplementary therapy of short-term CyA MEPC administration in combination with topical vitamin D3 treatment may be worth trying for patients with moderate psoriasis vulgaris.

Myelotoxicity of preoperative chemoradiotherapy is a significant determinant of poor prognosis in patients with T4 esophageal cancer.

PURPOSE: Currently, preoperative chemoradiotherapy followed by surgery is the only promising strategy for patients with T4 esophageal cancer. This study retrospectively analyzed the prognostic factors in patients with curatively resected cancer after chemoradiotherapy. PATIENTS AND METHODS: Between September 1989 and December 2003, 42 patients with T4 esophageal cancer received preoperative chemoradiotherapy (CRT) followed by curative surgery. Chemotherapy consisted of 5-fluorouracil/cisplatin (FP) or 5-fluorouracil/adriamycin/cisplatin (FAP). A total dose of 40 Gy of radiation was delivered concurrently. Surgery was scheduled 4 weeks after the completion of CRT. The treatment response was categorized using general criteria. Toxicities of the CRT were assessed according to National Cancer Institute of Common Toxicity Criteria (NCI-CTC). Univariate and multivariate analyses were performed to identify significant prognostic clinicopathological factors. RESULTS: The overall survival rate was 38.4% at 5 years. The toxic grade for leukopenia (grade 0-2/3-4) and pathological effect (grade 3/1-2) were significantly different by univariate analysis (P = 0.03 and 0.05, respectively). Multivariate analysis identified the toxic grade for leukopenia as the only significant and independent determinant of prognosis (P = 0.05). CONCLUSION: In patients with T4 esophageal cancer who receive CRT followed by curatively resection, myelogenic chemotoxicity is a significant prognostic factor.

Liver perfusion chemotherapy for selected patients at a high-risk of liver metastasis after resection of duodenal and ampullary cancers.

OBJECTIVE: To evaluate the prognostic benefit of postoperative liver perfusion chemotherapy (LPC) in patients who undergo curative resection of duodenal and ampullary cancers. SUMMARY BACKGROUND DATA: Both nodal involvement and pancreatic invasion are poor prognostic indicators after curative resection of ampullary or duodenal cancers due to high incidences of liver metastasis. Therefore, we have performed postoperative LPC on a number of such "high-risk" patients. METHODS: During the period of 1990 to 2005, 72 consecutive patients successfully underwent curative (R0) resection of duodenal or ampullary carcinomas at our institution, The Osaka Medical Center for Cancer and Cardiovascular Diseases. Of these 72 patients, 38 were found to have positive nodal involvement and/or pancreatic invasion based on an intraoperative inspection, and of these, 28 were deemed to be suitable candidates for intraoperative catheterization: 1 catheter was placed into the gastroduodenal artery; another into the portal vein (group A). Postoperatively, they received an infusion of 5-fluorouracil (5-FU: 125 mg/d) via each of the 2 catheters for a period of 28 continuous days. The remaining 44 patients (group B) did not receive any other adjuvant therapy. The survival rates and patterns of disease failure were compared between these 2 groups and their subgroups. RESULTS: All 72 patients survived the operation, and all 28 patients in group A completed their courses of LPC without showing any significant adverse signs. Postoperative histopathology was later performed to get a more accurate picture regarding the degree of nodal involvement and/or pancreatic invasion: In group A, 21 patients (group A1) proved positive for nodal and/or pancreatic invasion whereas 7 patients (group A2) proved negative; and in group B, 16 patients proved positive (group B1) whereas 28 proved negative (group B2). Although group A displayed higher incidences of nodal involvement and pancreatic invasion, the 5-year survival rates for the 2 groups varied only slightly. The 5-year survival rate was 70% in group A1, 85% in group A2, 35% in group B1, and 92% in group B2, respectively. The difference between B1 and B2 and the difference between A1 and B1 were statistically significant, and these differences were conclusively found to be attributable to the different incidences of liver metastasis. CONCLUSION: Through this research, both nodal involvement and pancreatic invasion were confirmed to be reliable predictors of liver metastasis after curative resection of ampullary and duodenal cancers. Since LPC was proven to be effective in preventing the postoperative development of liver metastasis, it should be more actively performed for patients with a high-risk of liver metastasis.

[A case of refractory inguinal lymphorrhea cured by lipiodol lymphangiography].

We report a case of inguinal lymphorrhea cured by Lipiodol lymphangiography. The patient was a 80-year-old female who underwent an abdomino-perineal resection with lateral pelvic lymph node dissection and inguinal lymph node extraction for anal canal cancer. Histologically, the tumor was a poorly differentiated adenocarcinoma and considered to be stage IV (a2, n3 (+), P0, H3, M (-), cur C) in the Japanese classification of colorectal cancer. We recognized a lot of lymph node metastases in dissected lateral pelvic lymph node and inguinal lymph node. By hepatic arterial infusion using 5-FU (1250 mg/body weekly), the liver metastases had a complete response after 15 courses. She noticed a left inguinal lymph node swelling and an elevation of serum CEA level (79.5 ng/mL) was observed. There was no evidence of recurrence except left inguinal lymph nodes. She underwent a left inguinal lymph node dissection. Serous discharge from a surgical site persisted despite of conservative therapy such as compression. She received lymphangiography using 8 mL of Lipiodol from left dorsum of foot. We found three lymph ducts heading to left groin and observed a lot of Lipiodol leakage from ducts. We determined not only the site of leakage but we also confirmed a gradual decrease and a complete stop of lypmphorrhea in 7 days after lymphangiography. Slight lymph edema of left lower extremity appeared but gradually relieved. Lymphangiography using Lipiodol helps determine the site of leakage and may be an effective therapeutic modality for treating refractory lymphorrhea.

Feasibility and efficacy of combination therapy with preoperative and postoperative chemoradiation, extended pancreatectomy, and postoperative liver perfusion chemotherapy for locally advanced cancers of the pancreatic head.

BACKGROUND: The outcome after resection of advanced pancreatic cancers is extremely poor because of the high incidence of the postoperative development of liver metastasis and local recurrence. We performed a combination of chemoradiation and liver perfusion chemotherapy and extended pancreatectomy. METHODS: Nineteen patients with T3 pancreatic head cancers were enrolled. A total of 24 Gy in 12 fractions of 10-MV x-rays with a concurrent intravenous infusion of 5-fluorouracil (5-FU; 3 g/12 days) was administered to the pancreatic head area. An extended pancreaticoduodenectomy was performed, and catheters were placed into the gastroduodenal artery and the superior mesenteric vein. During the first 28 postoperative days, 5-FU was continuously infused via the hepatic artery and portal vein (3.5 g/28 days x 2). Finally, 36 Gy in 18 fractions with 5-FU (3 g/6 days) was applied to the pancreatic bed. RESULTS: After preoperative chemoradiation, four patients did not undergo surgical resection because of distant metastases. Fifteen patients underwent pancreaticoduodenectomy, liver perfusion chemotherapy, and postoperative chemoradiation. No patient developed grade 3 toxicity as a result of preoperative chemoradiation, but one patient (7%) developed grade 3 leukopenia during the postoperative treatments. The morbidity rate was 20% (3 of 15 patients), and the mortality rate was 0%. The overall 3-year survival rate was 53%. The 3-year disease-free survival rate was 66% in patients who pathologically responded well (>50%), versus 0% in patients with poor responses (P = .04). CONCLUSIONS: A combination of preoperative and postoperative chemoradiation plus postoperative liver perfusion chemotherapy with an extended pancreatectomy is feasible, and the long-term outcomes are also promising.

Unusual atrophic change after repeated arterial therapy for hepatocellular carcinoma: report of a case.

We report the case of a 45-year-old man with advanced hepatocellular carcinoma (HCC) who was able to undergo radical surgery after repeated transarterial therapy. Transarterial chemoembolization was repeated three times, and thereafter, transarterial infusion chemotherapy using Lipiodol was performed on the right hepatic artery. Because notable atrophy of the right lobe and compensated hypertrophy of the left lobe were detected after this therapy, an extended right lobectomy could be performed. Histologically, the HCC showed complete necrosis. The remarkable atrophic change of the right lobe was thought to be due to an obstruction of the right portal veins by the spread of inflammation around the bile duct necrosis, in addition to the narrowing of the hepatic artery. A thorough understanding of this phenomenon and the development of methods to clinically apply it in the treatment of cancer patients may thus lead to an increase in the percentage of resectable cases of advanced HCC.

Ultraviolet-B phototherapy is successful in Japanese patients with early-stage mycosis fungoides.

UVB phototherapy is widely used for the treatment of psoriasis and atopic dermatitis, however, only limited reports evaluate its usefulness in the treatment of mycosis fungoides. We introduced UVB phototherapy to five patients with early-stage mycosis fungoides. All of them were classified as stage IB (erythematous stage), and none had obtained a satisfactory response to other therapies. After initial treatment with UVB phototherapy, all the patients obtained significant improvement in their skin lesions leaving pigmentary changes. After this satisfactory response was achieved, the same dose of UVB was administrated as a maintenance therapy with longer intervals between exposures. Histopathological examination of three patients revealed decreased numbers of inflammatory cells in both the epidermis and the dermis after the treatment. Immunohistochemical study showed that CD1a+/HLA-DR+ dendritic cells were present throughout the lesional epidermis before the treatment. In contrast, after the treatment, the dendritic cells in the epidermis were CD1a+/HLA-DR-. Although it remains unclear why only the expression of HLA-DR antigen was eliminated after treatment, we presume that this loss of HLA-DR antigen expression by epidermal Langerhans cells was, in part, responsible for the improvement of skin lesions. This preliminary study suggests that UVB phototherapy is an effective treatment for patients with early-stage mycosis fungoides.

Effect of activated human mast cells and mast cell-derived mediators on proliferation, type I collagen production and glycosaminoglycans synthesis by human dermal fibroblasts.

Although an increased number of mast cells in fibrotic tissues such as scleroderma, keloid or healing wound has been highlighted, it is still unclear whether or not mast cells are fibrogenic. The aim of the present study is to determine whether functionally active human mast cells can provide human dermal fibroblasts directly with fibrogenic properties. In order to examine the effects of IgE-mediated mast cell activation on fibroblast proliferation and synthesis of type I collagen, we utilized an in vitro defined system in which cultured human mast cells were co-cultured with human dermal fibroblasts. We also employed a three-dimensional fibroblast culture system using supplementation of L-ascorbic acid as an assay system to investigate the effects of mast cell-derived mediators on synthesis of glycosaminoglycans by human fibroblast. Fibroblast proliferation was actively stimulated with IgE-activated mast cells. However, this stimulatory effect was canceled in co-cultures with a higher number of IgE-activated mast cells. In the presence of a higher number of activated mast cells, the fibroblast cell layer was destroyed, in contrast to an intact cell layer in the presence of same number of the mast cells without activation. Type I collagen synthesis was unchanged in fibroblasts co-cultured with mast cells. The total amount of main disaccharide units, particularly DELTADi-HA, was increased when fibroblasts were exposed to histamine. Thus, we conclude that other factors, in addition to mast cells, are important in the development of human tissue fibrosis or sclerosis.