picibanil and Melanoma

The microbial immunostimulant OK-432 has been studied intensively in preclinical systems and has shown promise as an anticancer agent in trials that have been conducted over the past 20 years in Japan. To date, no systematic dose response evaluation of this agent has defined its dose-limiting toxicity or immunobiological activity. A phase IA study has been conducted in 25 patients with metastatic cancer at the University of Pittsburgh Cancer Institute Melanoma Center, establishing 30 KE as the maximal tolerable dosage, on the basis of cutaneous reactions. Subsequently, 48 patients with resected high-risk melanoma participated in a phase IB study of OK-432. This study has evaluated the immunomodulatory activity of OK-432 at five dosages ranging from 1 KE to 20 KE, administered ID twice weekly for 3 months. A formal analysis of the treated population in comparison to the randomized control group has been conducted, and profound immunological effects have been defined in the group of patients treated with OK-432. Patients who participated in this trial had a significant depression of OK-432-inducible cytokine production (interleukin-1 beta, interferon gamma, and tumor necrosis factor alpha) at baseline. Treatment with OK-432 reversed this deficit for interferon gamma (IFN gamma) production in a dose-dependent manner, and mitigated the inhibition for interleukin-1 (IL-1) across all dosage groups. The impact of OK-432 upon other immunological functions of the treated cohorts is more variable, with durable suppression of mononuclear cell superoxide production, and in vitro cytotoxicity to tumor. Immunological characteristics of the entire cohort demonstrate a strong and significant correlation of elevated blood CD16+ cell counts and natural killer activity with early tumor progression and death due to melanoma. Favorable prognosis is associated with monocyte capacity to produce tumor necrosis factor (TNF), and polymorphonuclear leukocyte formylmethionyl-leucylphenylalanine-inducible superoxide release. This study reveals several new immunological correlates of tumor progression and lethal outcome in resected high-risk melanoma. It demonstrates that the depressed IL-1, TNF, and IFN gamma release associated with melanoma may be mitigated by treatment with OK-432. This study has defined treatment and dose response patterns of immunomodulation associated with one of the most complex immunological agents yet evaluated in phase IB trials, in a well-defined population

Topics: Adjuvants, Immunologic; Antineoplastic Agents; Cytotoxicity, Immunologic; Female; Humans; Male; Melanoma; Picibanil

Prognosis was obviously poor in PPSM-treated stage Ib cases, compared with extra PPSM-treated counterparts (P less than 0.01). Out of the PPSM-treated stage Ib cases, those where prophylactic lymph node dissection was performed ran a prognosis similar to the extra PPSM-treated stage Ib cases: it is advisable therefore to perform the prophylactic lymph node dissection actively in the PPSM-treated stage Ib cases. A response rate of 28.6% was achieved with PAV therapy in stage IV cases, with metastases to the skin, subcutaneous tissue, lymph nodes and bone responding to the therapy. PAV therapy, when applied in operable cases, brought about excellent 5-year survival rates as 100% high as in stage Ia, 92.9% in stage Ib, 53.1% in stage II, and 66.9% in stage Ib + II cases. In a randomized, controlled study of bestatin in stage Ib and II cases over about 4 years has revealed that both the disease-free rate and the survival rate were significantly high in the bestatin-treated group, compared with the control group.

Topics: Adult; Aged; Female; Humans; Leucine; Lymph Node Excision; Male; Melanoma; Middle Aged; Neoplasm Staging; Picibanil; Prognosis; Sex Factors; Skin Neoplasms

Topics: Biological Products; Clinical Trials as Topic; Dacarbazine; Drug Therapy, Combination; Female; Humans; Immunity, Cellular; Immunotherapy; Male; Melanoma; Nimustine; Nitrosourea Compounds; Picibanil; Vincristine

Topics: Aged; Anti-Infective Agents, Local; Antineoplastic Agents; Cytoreduction Surgical Procedures; Ethanol; Groin; Humans; Lymph Node Excision; Lymphatic Metastasis; Male; Melanoma; Pelvis; Picibanil; Skin Neoplasms

A patient with malignant melanoma of the oral cavity who lived for a long period despite developing liver metastasis is presented. An 81-year-old female was referred to our hospital because of a pigmented tumor of the lower gingiva. Under the clinical diagnosis of malignant melanoma, she underwent bilateral functional neck dissection and marginal mandiblectomy. Histological diagnosis of the operation material was malignant melanoma with regional lymph node metastasis. In spite of loco-regional control, liver metastasis developed at 7 months after the surgery. She then underwent combination chemotherapies with dimethyl triazeno imidazole carboxamide (DTIC), nimustine hydrochloride (ACNU) and vincristin (DAV therapy), or cisplatin, DTIC, ACNU and tamoxifen (DAC-tam), but no marked response was obtained. Considering the advanced age of the patient, immunotherapy with a biological response modifier, OK432, alone was started. After administration of OK432, the metastatic tumor gradually decreased, and she is alive without any clinical symptoms of tumor at 46 months after the detection of liver metastasis, although it is still present on ultrasonic and CT examinations.

Topics: Aged, 80 and over; Antineoplastic Agents; Female; Humans; Liver Neoplasms; Lymphatic Metastasis; Melanoma; Mouth Neoplasms; Picibanil; Treatment Outcome

Many authors have reported that oral melanoma patients showed much worse prognosis than those with cutaneous melanoma. We investigated treatment method and prognosis of patients with oral malignant melanoma.. Twenty-one patients with oral melanoma treated at our hospital were investigated, with special reference to the influence of preoperative surgical procedures such as biopsy, incision, or tooth extraction on the prognosis.. All patients underwent surgery followed by immuno-chemotherapy with dimethyl triazeno imidazole carboxamide (DTIC), ninustine hydrochloride (ACNU), vincristine (VCR), and biologic response modifier OK-432. Local control was obtained in 20 of 21 patients. Lymph node metastasis appeared in 13 patients, but neck failure was not detected in any patients. Distant metastasis occurred in 9 patients in spite of loco-regional control. Five-year survival rate of 12 patients with no preoperative surgical procedure was 91.7%, while that of the 9 patients who had undergone surgical procedures before treatment was 25.9% (P < .05).. Oral melanoma patients can obtain a prognosis as good as that for cutaneous melanoma patients, when the above-mentioned therapy is used without any preoperative surgical procedures.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Contraindications; Dacarbazine; Female; Humans; Immunotherapy; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Mouth Neoplasms; Neoplasm Metastasis; Nimustine; Picibanil; Prognosis; Risk Factors; Tooth Extraction; Vincristine

Focal ground-glass opacity (GGO) on computed tomography has been reported in several disorders including inflammatory disease and primary neoplastic lesion of the lung. We report a case of malignant melanoma of the nasal cavity metastatic to the lungs in which multiple pulmonary nodules showed GGO. Lung biopsy specimen demonstrated melanoma cells proliferating in a lepidic fashion along the thickened alveolar wall simulating bronchioloalveolar carcinoma. Metastatic lung tumor showing GGO is uncommon.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Chemotherapy, Adjuvant; Dacarbazine; Diagnosis, Differential; Female; Humans; Lung Neoplasms; Melanocytes; Melanoma; Middle Aged; Nasal Cavity; Nose Neoplasms; Picibanil; Tegafur; Tomography, X-Ray Computed; Uracil

We report a very rare case of double cancer involving palatal malignant melanoma and gastrointestinal stromal tumor (GIST), a rare tumor of the gastrointestinal tract originating from a primitive mesenchymal cell. After chemotherapy, radiation therapy, and treatment with interferon and OK-432, the GIST was resected and the melanoma disappeared. The patient has had no evidence of recurrent tumor, and the patient's clinical course has been uneventful for 1 year. This is probably the first report of synchronous double cancer involving oral malignant melanoma and GIST.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Gastrointestinal Stromal Tumors; Humans; Interferon-beta; Melanoma; Neoplasms, Multiple Primary; Palatal Neoplasms; Picibanil; Stomach Neoplasms

In the present study we investigated the effect of OK-432, a streptococcus preparation, on the contact-mediated inhibition of human NK activity by primary cultures of monolayer cells. Either peripheral blood lymphocytes (PBL) or large granular lymphocytes (LGL) were incubated (2 x 10(6) cells/ml, total volume 2 ml) on confluent monolayer cells (uvea-derived fibroblasts, uvea-derived melanoma cells, or renal carcinoma cells) for 18 h in 24-well plates, washed twice, and tested for cytotoxicity against K562, a human myelogenous leukemia cell line, in a 4 h 51Cr-release assay. After contact with monolayer cells, NK activity of both PBL and LGL was significantly reduced. When these effector cells were preincubated with 0.1 U/ml of OK-432 for 18 h and then tested for the sensitivity to contact-mediated inhibition, the inhibition was significantly reduced. The pretreatment of monolayer cells with OK-432 or the addition of OK-432 into the coculture wells (of effector cells and monolayer cells) also significantly reduced the contact-mediated inhibition. Moreover, OK-432 (0.1 U/ml) reestablished the inhibited NK activity of PBL. These results suggest that OK-432 might enable NK cells to escape from the contact-mediated inhibition by monolayer cells and thus provide an additional potential mechanism for the observed clinical effectiveness of OK-432 reported by many groups.

Topics: Adenosine Triphosphate; Carcinoma, Renal Cell; Cell Communication; Cells, Cultured; Cytotoxicity, Immunologic; Fibroblasts; Humans; Immunologic Factors; Kidney Neoplasms; Killer Cells, Natural; Melanoma; Picibanil; Streptococcus pyogenes; Tumor Cells, Cultured; Uvea; Uveal Neoplasms

This paper introduces the current status of melanoma treatment with various biologic response modifiers (BRMs) in Japan, with an emphasis on the clinical results of Interferon therapies. The authors also refer briefly to the current situation of interleukin-2 (IL-2) and tumor necrosis factor (TNF) in Japan. Many BRMs have been used in treatment of melanoma, e.g., IFN, IL-2, TNFs, BCG, MY-1 (DNA extracted from BCG), WPG (CWs of Bifidobacterium infantis, ATCC 15697), OK-432 (Picibanil, Streptococcus pyogenes preparation), bestatin, and forphenicinol. Some of these have completed clinical trials, while others are still undergoing clinical testing. Among IFN-alpha, beta, and gamma, intralesional administration of natural IFN-beta was found to be more effective than IFN-alpha for metastatic skin melanoma, the survival time of patients being prolonged by the administration of IFN-beta. IFN-gamma appeared to have lower efficacy than IFN-alpha and beta. The frequency of BRM application to melanoma treatment will increase. The authors foresee that combinations with radio- and/or other chemotherapy will be more common than the single use of a BRM, especially in the case of IFN.

Topics: Biological Factors; Biological Products; Cell Wall Skeleton; Cytokines; DNA, Bacterial; Glycine; Humans; Interferon Type I; Interferon-gamma; Interferons; Interleukin-2; Leucine; Male; Melanoma; Middle Aged; Mucoproteins; Mycolic Acids; Picibanil; Recombinant Proteins; Skin Neoplasms; Tumor Necrosis Factor-alpha

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dacarbazine; Female; Humans; Melanoma; Middle Aged; Nimustine; Nitrosourea Compounds; Picibanil; Vaginal Neoplasms; Vincristine; Vulvar Neoplasms

There is significant evidence that the macrophage plays a critical role in the host's defense against neoplasia. Tumor-necrosis factor was recognized by Carswell et al. during a study of the antitumor activity of serum from mice infected with BCG and subsequently injected with endotoxin. The same procedure was applied to rabbits in order to obtain serum containing tumor-necrosis factor (TNF). Sera from these mice and rabbits contained a factor that induced hemorrhagic necrosis of certain mouse sarcomas in vivo and had cytotoxic effects on mouse and human tumor cells in vitro. Sera from mice and rabbits singly treated with BCG or endotoxin did not have these properties. Other agents such as C. parvum, OK-432, lentinan or zymosan, that cause hyperplasia of reticuloendothelial system and increase sensitivity to endotoxin lethality, could substitute for BCG in priming for TNF release. However, the use of P. acnes as a priming agent was the most effective and lipopolysaccharide from gram-negative bacteria appeared to be unique in its ability to elicit TNF release. TNF is a protein with a molecular weight, ranging from 40,000 to 60,000 that has both tumor necrotizing activity in vitro and tumor killing activity in vitro. It is relatively stable to heating at up 70 degrees C. This result indicated that both in vitro and in vitro activities of mouse and rabbit TNF are a property of one and the same molecule. TNF is thought to be produced by macrophage and is distinguished from the other know macrophage products in serum containing TNF. TNF is cytotoxic to several but not all tumor cell lines. Its most interesting feature is that it reportedly dose not affect any non-transformed cell types, implying that it somehow recognizes transformed cells.

Topics: Animals; Cytotoxicity, Immunologic; Female; Glycoproteins; Growth Inhibitors; Humans; Lung Neoplasms; Macrophages; Melanoma; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Weight; Mycobacterium bovis; Neoplasms, Experimental; Picibanil; Rabbits; Sarcoma, Experimental; Tumor Necrosis Factor-alpha

Skin metastasis of malignant melanoma has been difficult to control by chemoimmunotherapy. We report a case of melanoma with marked reduction of multiple skin and lung metastasis and an improved cell-mediated immunity using combined DAV (DTIC, ACNU, Vincristine) and OK-432 chemoimmunotherapy in association with doses of indomethacin administered over a long period (250 mg/day, 6 months) to relieve the cancerous pain.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Humans; Indomethacin; Lung Neoplasms; Male; Melanoma; Nimustine; Nitrosourea Compounds; Pain, Intractable; Picibanil; Skin Neoplasms; Suppositories; Vincristine

A 60-year old woman with metastatic malignant melanoma who was well responded to a combination chemotherapy including DTIC was reported. She was noted a lentigo in the left first toe and histological examination revealed malignant melanoma in October 1978. Amputation of the left lower leg and dissection of the left inguinal lymph nodes had been done. OK-432 was injected as postoperative immunotherapy. She was readmitted to our hospital with the symptoms of pain and numbness of the left arm. Physical examination revealed a palpable mass in the left supraclavicular region. Incisional biopsy of the supraclavicular mass revealed metastatic malignant melanoma. She received a combination of 100mg DTIC i.v. for 5 days, 100 mg ACNU i.v. for one day and 1 mg VCR i.v. for one day (DAV chemotherapy) postoperatively. Subcutaneous injection of OK-432 with the dose of 5 KE per week was continued. Major side effects of DAV chemotherapy were nausea and transient leukocytopenia. No serious side effects were observed. On completion of the first course of DAV chemotherapy, abnormal shadow of the left apex was completely disappeared and on completion of the third course of DAV chemotherapy, high density area was markedly decreased in the cervical CT. She gained symptomatic reliefs and was discharged in August 1983. The combination chemotherapy including DTIC appeared to be effective in the treatment of metastatic malignant melanoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Drug Administration Schedule; Female; Humans; Melanoma; Middle Aged; Neoplasm Metastasis; Nimustine; Nitrosourea Compounds; Picibanil; Vincristine

We used concomitant therapy that consisted of cryosurgery and injection of OK 432 (a hemolytic streptococcal preparation) in the treatment of a giant malignant melanoma that primarily arose from the hard palate to the alveolar process in a 69-year-old man. The tumor consequently disappeared completely. One and a half years later, there are no signs of relapse.

Topics: Aged; Alveolar Process; Biological Products; Cryosurgery; Humans; Male; Melanoma; Palatal Neoplasms; Picibanil

This study, based on a cooperative group project involving 4 major medical institutes in Japan, presents the second survey of malignant melanoma patients (198 cases) where an attempt is made to systemically evaluate the survival rates of these patients with respect to the tumor thickness and location of primary lesions, and the response to chemoimmunotherapy. More than 50% of total collected cases showed the primary lesions on the limbs. The most common type and site of involvement is the acral lentiginous melanomas involving the plantar areas (more than 30). The survival rates affecting the limbs were better than those affecting the non-limb areas. However, the comparison of the survival rates did not reveal any difference between those cases affecting the plantar and non-plantar areas. The difference in the prognosis of melanoma patients appeared to be related to the tumor thickness. By historical comparison, the DAV (DTIC, ACNU, VCR) treated group exhibited a better survival rate than the non-DAV treated group. Furthermore, the DAV group with immunoadjuvant therapy (mainly OK-432) showed a better prognosis than the DAV group without any immunoadjuvant therapy.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Child; Dacarbazine; Female; Foot; Hand; Humans; Japan; Male; Melanoma; Middle Aged; Nimustine; Nitrosourea Compounds; Picibanil; Proteoglycans; Skin Neoplasms; Vincristine

Topics: Adenocarcinoma; Biological Products; Female; Humans; Melanoma; Ovarian Neoplasms; Picibanil

A 59-year-old woman with recurrent malignant melanoma of the vulva has well responded to a combination of immunotherapy and chemotherapy. As an immunotherapy, 10KE OK-432 were injected into the tumor twice a week. Chemotherapeutic regimen consisted of intravenous push of 1 mg vincristine on day 1,100 mg dacarbazine from day 1 through 5 and 50 mg nitrosourea (ACNU) on day 5. This treatment was repeated with 4 week intervals. Before treatment, the patient had a 3 X 3 X 5 cm subcutaneous mass on the left vaginal wall near the introitus. Fifty percent objective reduction of the tumor was achieved 6 weeks after commencement of intralegional immunotherapy and chemotherapy, and the tumor almost disappeared 8 months later. At this time, the treatment was changed to a supportive immunotherapy with intramuscular injection of 1KE OK-432 twice a week. But the tumor began to enlarge 2 months later and the patient is now being treated with the same combination therapy. Major side effects were febrile episodes on the day of intratumor injection of OK-432 and nausea, vomiting during the interval of chemotherapy. Anemia was the main hematologic side effect, but leukocytopenia and thrombocytopenia were not severe. The combination of intratumor injection of OK-432 and chemotherapy seems to be effective for the treatment of malignant melanoma.

Topics: Adjuvants, Immunologic; Antineoplastic Agents; Biological Products; Cyclophosphamide; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Injections; Melanoma; Middle Aged; Mitomycin; Mitomycins; Picibanil; Vincristine; Vulvar Neoplasms

A 33-year-old woman with malignant melanoma well responded to a chemotherapy including DTIC, ACNU, and VCR, and intralegional injection of OK-432. Four years prior to admission, a lentigo of 5 mm diameter at her left frontal chest was found, but, histological examination resulted in no distinctly malignant findings. In November 1979, multiple subcutaneous tumors appeared over posterior surface of the chest and left axillar region, which were gradually increasing in number and size, then she was admitted to our hospital in June, 1980. Biopsy of subcutaneous tumors revealed a malignant melanoma and its metastasis to skin. Immunochemotherapy was started immediately based upon this diagnoses. The patient received 100mg DTIC i.v. for 4 days, 100mg ACNU i.v. for one day and 1 mg VCR i.v. for one day. OK-432 was locally injected into some tumors as an immunotherapy. On completion of the third course of chemotherapy, all subcutaneous tumors were decreased in size, especially the tumors injected with OK-432. However, patient didn't respond to a repeated chemotherapy, thereafter malignant melanoma was metasized to uterus and peritoneum in May, 1981, and she died in September, 1981. Major side effects of this chemotherapy were nausea and mild transient leukocytopenia. The combination of chemotherapy including DTIC and local injection of OK-432 appeared to be effective for malignant melanoma.

Topics: Adult; Biological Products; Dacarbazine; Drug Therapy, Combination; Female; Humans; Melanoma; Nimustine; Nitrosourea Compounds; Picibanil; Skin Neoplasms; Vincristine

Topics: Adjuvants, Immunologic; Adult; Antineoplastic Agents; Brain Neoplasms; Dacarbazine; Drug Therapy, Combination; Female; Humans; Male; Melanoma; Nimustine; Nitrosourea Compounds; Picibanil; Skin Neoplasms; Vincristine

This study, based on a co-operative group project involving 4 major medical institutes in Japan presents the first survey of malignant melanoma (MM) patients (157 cases) where an attempt was made to systemically evaluate the distribution of primary MM, and the response to DAV-chemoimmunotherapy. The distribution of primary MM in Japan is unique in a sense that the MM involving the lower extremities occupied more than 50% of the total male and female cases. The commonest type and site of involvement is the acrolentiginous MM involving the plantar area (30%). The regimen of our group included the combination of DTIC, VCR and ACNU, a new nitrosourea with or without immunoadjuvants OK-432, PSK, or NK-421). By a historical comparison, the DAV-treated group showed a better prognosis in the survival rates of overall (Stages I-IV) and disseminated (Stages III-IV) patients than those of the non-DAV group. However, the effect of combined immunoadjuvants was not statistically significant, though OK-432 showed a significant inhibition of lymphopenia which always occurred during DAV therapy.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Drug Therapy, Combination; Female; Humans; Leucine; Male; Melanoma; Middle Aged; Nimustine; Nitrosourea Compounds; Picibanil; Proteoglycans; Skin Neoplasms; Vincristine