Induction of cytotoxic T cells as a novel independent survival factor in malignant melanoma with percutaneous peptide immunization.

BACKGROUND: Malignant melanoma (MM) often shows multiple chemo-resistance, leading to poor prognosis of the patients. Therapeutic anti-cancer vaccination may be a feasible way to prolong the survival of patients. We have demonstrated that application of antigenic peptides via the tape-stripped, horny layer-removed skin, known as percutaneous peptide immunization (PPI), induces tumor cell-specific cytotoxic T lymphocytes (CTLs) in rodents and humans. OBJECTIVE: To evaluate clinical significance of PPI in advanced MM patients. METHODS: We performed PPI in 59 patients undergoing advanced MM with Melan-A, tyrosinase, MAGE-2, MAGE-3 and gp-100 peptides based on HLA typing in individuals. The induction of CTLs was assessed by the tetramer or pentamer flow cytometry in 35 patients. Patients showing positive CTL responses to all antigens were defined as complete responder (n=18), and those showing negative responses to at least one applied antigen were classified as incomplete responder (n=17). The primary endpoint of the study was overall survival (OS). For statistical analysis, log-rank test, univariate and multivariate Cox proportional hazard model were used. RESULTS: OS of the complete responders was longer than that of the incomplete responders (median survival time: 55.8 vs 20.3 months, log rank P=0.089). A hazard ratio for the complete responders relative to the incomplete responders was 0.23 (95% confidence interval: 0.06-0.93, P=0.039) in a multivariate Cox proportional hazard model. CONCLUSION: The induction of CTLs was a novel independent survival factor, and the induction of peptide-specific CTLs by PPI contributes to the prolonged survival and represents an impact on therapeutic approaches in MM. Unique trial number: UMIN000005706.

Applicability of radiocolloids, blue dyes and fluorescent indocyanine green to sentinel node biopsy in melanoma.

Patients with primary cutaneous melanoma underwent sentinel node (SN) mapping and biopsy at 25 facilities in Japan by the combination of radiocolloid with gamma probe and dye. Technetium-99m ((99m)Tc)-tin colloid, (99m)Tc-phytate, 2% patent blue violet (PBV) and 0.4% indigo carmine were used as tracers. In some hospitals, 0.5% fluorescent indocyanine green, which allows visualization of the SN with an infrared camera, was concomitantly used and examined. A total of 673 patients were enrolled, and 562 cases were eligible. The detection rates of SN were 95.5% (147/154) with the combination of tin colloid and PBV, 98.9% (368/372) with the combination of phytate and PBV, and 97.2% (35/36) with the combination of tin colloid or phytate and indigo carmine. SN was not detected in 12 cases by the combination method, and the primary tumor was in the head and neck in six of those 12 cases. In eight of 526 cases (1.5%), SN was detected by PBV but not by radiocolloid. There were 13 cases (2.5%) in which SN was detected by radiocolloid but not by PBV. In 18 of 36 cases (50%), SN was detected by radiocolloid but not by indigo carmine. Concomitantly used fluorescent indocyanine green detected SN in all of 67 cases. Interference with transcutaneous oximetry by PVB was observed in some cases, although it caused no clinical trouble. Allergic reactions were not reported with any of the tracers. (99m)Tc-tin colloid, (99m)Tc-phytate, PBV and indocyanine green are useful tracers for SN mapping.

Histological differentiation, histogenesis and prognosis of cutaneous angiosarcoma.

BACKGROUND: Cutaneous angiosarcoma (CAS) is a rare, extremely malignant vascular tumor. The optimum treatment for patients with CAS has not been defined because of its exremely rarity. As prognostic factors in patients with CAS, tumor less than 5 cm in size has a better prognosis. Although tumor differentiation in other sarcoma is an important prognostic factor, tumor differentiation in CAS is not a prognostic factor. CAS is thought as a collection of hemangiosarcoma, lymphangiosarcoma, tumors which cannot be classified as of vascular and lymphatic origin, or mixed tumor of both. Histogenesis of CAS have not been clarified yet. We tried to classify histogenesis by immunohistochemistry and evaluate the prognosis among histogeneses. METHODS: Using immunohistochemistry, we classified histogenesis of CAS in 20 patients who visited Osaka City University Hospital between 1998 and 2008. RESULTS: From the results of immunohistochemical staining with CD34 and D2-40, histogenesis of CAS can be divided into vascular type (CD34 positive D2-40 negative), mixed type (CD34 positive D2-40 positive), and lymphatic type (CD34 negative D2-40 positive). Vascular type was found in 2 cases, mixed type in 5 cases, and lymphatic type in 13 cases. Survival rates were not significantly affected by histogenesis, however, survival rate of mixed type was better than those of others. CONCLUSIONS: CAS can be divided into vascular type, mixed type, and lymphatic type based on immunohistochemistry. Because of a small group, we did not suggest that histogenesis of CAS was related with prognosis. We speculate that antiangiogenic agents might be important in the treatment based on histogeneses in CAS. In the future, further accumulation of chemotherapeutic cases might upgrade histogenesis classification as an important prognostic factor in the treatment of CAS.

Survival analysis of malignant melanoma in Japan--multivariate analysis of prognostic factors.

BACKGROUND: The prognostic factors of cutaneous melanoma reported in Japan were different from those in US and Europe in evaluating the prognostic values of the biopsy types, sex, anatomic location and so on. The aim of this study was to identify the prognostic factors for survival in cutaneous melanoma in Japan by performing univariate and multivariate analyses. METHODS: We studied a total of 103 patients with cutaneous melanoma, treated in Osaka City University Hospital during the period 1991-2003. Eleven factors were evaluated by uni- and multivariate analyses. Kaplan-Meier analyses were performed to estimate and compare five-year survival rates. After checking for independence, prognostic factors were then evaluated applying a Cox proportional hazards model in localized melanoma patients and in all invasive melanoma patients. RESULTS: On univariate analysis, anatomic location, ulceration, tumor thickness, Clark's level, lymph node metastasis, distant metastasis and TNM staging were significantly related to five-year survival rates. Clark's level and TNM staging were excluded after checking for independence. Multivariate analysis revealed that significant prognostic factors were tumor thickness and anatomic location in localized melanoma patients, and distant metastasis, tumor thickness, sex and anatomic location in all invasive melanoma patients. CONCLUSIONS: Thinner tumors, female gender and location on the extremity are favorable prognostic features in malignant melanoma. Tumor thickness whose best cut-off point is 4 or 5 mm is the most important prognostic factor in predicting survival in the melanoma patient. These results were similar to those in U.S. and Europe.

Dermatofibrosarcoma protuberans with atrophic appearance at early stage of the tumor.

We report a case of dermatofibrosarcoma protuberans (DFSP) which had looked like an atrophic plaque on the face for 20 years and been diagnosed as morphea. At the late stage after subsequent development of a nodule, histopathological examinations including immunohistochemical stainings revealed the final diagnosis of DFSP. While DFSP is given typical "protuberant" morphology, our case indicates that DFSP sometimes appears as a non-protuberant lesion. Some reported variants of non-protuberant DFSP are suspected to be preceding features at the early stage of DFSP before the protuberant feature occurs. We should take this preprotuberant stage of DFSP into consideration of different diagnoses with non-protuberant lesions. Histopathological examination and immunohistochemical stainings are necessary for an accurate and early diagnosis of DFSP.

A case of ileoileal intussusception caused by metastatic pedunculated tumor of cutaneous angiosarcoma.

Cutaneous angiosarcoma is a rare aggressive vascular tumor that occurs in elderly patients and is usually located on the head and face. Metastases often develop in the cervical lymph nodes, lungs, bone, liver and spleen. There have been no reports of ileoileal intussusception due to metastatic tumor from cutaneous angiosarcoma. We reported a case of cutaneous angiosarcoma in a 67-year-old Japanese male accompanied with ileoileal intussusception due to metastatic angiosarcoma. We assume that the metastatic tumor in the small intestine was metastasized hematogeneously from cutaneous angiosarcoma, resulting in the formation of nodules and the rapid growth of a pedunculated tumor as a forerunner of the ileoileal intessusception.

Codeine phosphate-induced hypersensitivity syndrome.

OBJECTIVE: To report a case of drug-induced hypersensitivity syndrome related to codeine phosphate. CASE SUMMARY: A 19-year-old Japanese man was prescribed codeine phosphate 10 mg 3 times daily and several other drugs for cold symptoms. About 20 days later, an erythematous, maculopapular rash appeared and progressed to erythroderma; a spiking fever also developed. He had splenomegaly and generalized lymphadenopathy on admission. Laboratory examinations showed atypical lymphocytosis, eosinophilia, and increased liver enzyme values. The platelet count slowly decreased after admission. The increased numbers of megakaryocytes in bone marrow and platelet-associated immunoglobulin (Ig) G antibodies in serum were compatible with a diagnosis of immune thrombocytopenic purpura. A significant increase in IgG antibodies to human herpesvirus 6 (HHV6) and transient viremia were helpful in diagnosing hypersensitivity syndrome. The results of patch tests were positive for codeine phosphate. An objective causality assessment revealed that an adverse drug event was probable. DISCUSSION: Codeine is an opioid analgesic. Severe adverse cutaneous reactions rarely occur. As of March 3, 2004, our case is, to our knowledge, the first report of hypersensitivity syndrome attributed to codeine phosphate. Drug-induced hypersensitivity syndrome is an acute, potentially life-threatening, idiosyncratic adverse reaction caused mainly by aromatic anticonvulsants. It is characterized by the triad of fever, skin rash, and internal organ involvement. Reactivation of HHV6 is involved in the pathogenesis of this syndrome and may have also caused the immune thrombocytopenic purpura in our patient. CONCLUSIONS: Codeine phosphate may rarely be associated with hypersensitivity syndrome. Clinicians should be aware that the potentially fatal syndrome can be caused by various drugs.