Pathological responses to low-dose irradiation and Pepleomycin in Oral squamous cell carcinoma are predictive of Locoregional control.

BACKGROUND: The prognosis of advanced oral cancer remains dismal. While multimodal therapy is beneficial, maintaining the quality of life of long-term survivors is important. Therefore, risk-adapted treatment regimens need to be designed. We herein investigated whether pathological responses in oral cancer patients treated with preoperative chemoradiotherapy predict locoregional recurrence. METHODS: We retrospectively reviewed the data of 51 oral cancer patients who received preoperative radiotherapy and concurrent pepleomycin, followed by curative surgery at our institution between January 2009 and June 2018. Each patient received preoperative external beam irradiation to the primary tumor and lymphatics (2 Gy per day for approximately 3 weeks) concurrent with pepleomycin (2.5 mg/day). Surgery was performed approximately 3-4 weeks after the completion of preoperative chemoradiotherapy. Pathological responses were defined based on the grading system of Oboshi and Shimosato. RESULTS: Eight, 22, 16, and 5 patients had Oboshi and Shimosato grades 2a, 2b, 3, and 4, respectively. Favorable pathological responses (grades 3 and 4) were observed in 41.2% of patients (21 out of 51 patients). The pathological response and number of pathological lymph node metastases were identified as significant prognostic factors for locoregional control in the univariate analysis. Three-year locoregional control rates were 100 and 56.6% in patients with favorable and unfavorable pathological responses, respectively. CONCLUSIONS: The present study demonstrated that pathological tumor responses to preoperative chemoradiotherapy are a useful predictive factor for locoregional control.

Upregulation of respiratory burst of polymorphonuclear leukocytes by a bleomycin derivative, peplomycin.

The influence of peplomycin (PLM) on the respiratory burst of peripheral blood polymorphonuclear leukocytes (PMN) was investigated. Short-term (5 min) treatment of human PMN with 0.1mu g/ml to 100mu g/ml of PLM increased phorbol myristate acetate (PMA)- and formyl-methionyl-leucyl-phenylalanine (FMLP)-induced luminol-dependent chemiluminescence. PMN, as well as alveolar macrophages from rabbits treated with 0.5 to 1.0 mg/kg of peplomycin per day for 5 days, generated more superoxide (O2-) than the cells from untreated rabbits. In both PLM-treated and untreated PMN, chemiluminescence induced by FMLP and PMA was decreased to less than 50% of the control by staurosporine, superoxide dismutase (SOD) and catalase. However, the peak intensity in PLM-untreated PMN was decreased to about 30% of the control by genistein, while this agent induced a slight decrease in peak intensity in the PLM-treated PMN. Inositol triphosphate and diacyl glycerol levels were not clearly increased by PLM, but an increase of intracellular Ca++ and a shift of protein kinase C (PKC) to the membrane occurred in PMN within 1 min after PLM treatment. Western blotting revealed that the tyrosine phosphorylation of a 115 kDa protein was upregulated by 5 to 50mu g/ml of PLM. While, PLM suppressed SOD activity in alveolar macrophages and PMN. These results seem to indicate that PLM increases the respiratory burst of PMN and macrophages both by way of direct PKC activation and by the upregulation of protein tyrosine phosphorylation. This increased reactive oxygen generation, together with the suppression of SOD activity seems to be tissue-impairing.

A new animal model of continuous catheterization for investigating mechanisms of arteritis associated with chemotherapy.

Although superselective continuous intra-arterial infusion has advantages for cancer therapy, intra-arterial chemotherapy is often interrupted by arterial damage due to arteritis. Therefore, an animal model must be developed to elucidate the mechanism of arteritis associated with continuous anti-cancer drug infusion. We developed a new rat model with which to investigate the causal mechanism(s) of vascular damage associated with continuous catheterization chemotherapy. Chemotherapeutic agents (fluorouracil (5-FU) or peplomycin (PEP)) were continuously administered for 7 days into the abdominal aorta of male Sprague-Dawley rats through a catheter fixed in situ. We found that the incidence of apoptotic endothelial cells of the aorta was higher nearer the tip of the catheter. The incidence of apoptosis was higher in the group treated with 5-FU than with PEP. This animal model will be useful to improve arterial damage among patients undergoing chemotherapy using continuous catheterization.

Drug eruption due to peplomycin: an unusual form of Stevens-Johnson syndrome with pustules.

A rare case of Stevens-Johnson syndrome (SJS) due to peplomycin in a 48-year-old man is described. The patient had squamous cell carcinoma on the scalp and underwent preoperative neoadjuvant chemotherapy with peplomycin. On the fifth day of the chemotherapy, he developed a fever and multiple dusky violaceous erythematous areas and pustules on his trunk, thighs, and palms. Erosive erythema and erosions also developed on his soles, scrotum, and oral mucosa. A biopsy specimen taken from the eruption on the thigh revealed marked liquefaction degeneration of the basal layer of the epidermis. Laboratory examinations demonstrated aggravation of liver function. Additionally, the patient developed conjunctivitis and corneal erosions. Although he had some subcorneal pustules, we diagnosed the case as an unusual form of SJS because of severe mucous membrane involvement. Oral prednisolone was administered, and the symptoms subsided. Then the patient underwent wide local excision. One month after surgery, we performed patch tests and a lymphocyte stimulation test with negative results. Then we re-administered peplomycin starting with 1/20 of a daily dose and gradually increasing the dose each day. After administration of the regular daily dose, the patient had a relapse of fever, eruptions, stomatitis, corneal erosions, and liver dysfunction. Therefore, a definite diagnosis of drug eruption due to peplomycin was made.

Extended survival time for esophageal cancer patients treated with aggressive surgery and concurrent chemoradiation.

In attempts to improve overall long-term survival of patients with esophageal cancer, including medically inoperable patients and operable ones with disseminated disease, we treated operable patients with aggressive surgery and postoperative chemoradiation, and inoperable patients with chemoradiation alone. Chemoradiation consisted of 5,000-6,000 cGy of radiation and two courses of chemotherapy (cisplatin, vindesine, and pepleomycin). Of 90 patients seen between 1986 and 1991, 63 operable patients underwent surgery and 35 received postoperative chemoradiation, while 19 of 27 inoperable patients received chemoradiation. Results were compared with those of 48 unselected historical control patients treated since 1981. Survival at 5 years was significantly improved for the multimodality group (17.7 +/- 5.0%), as compared with the historical control group (10.4 +/- 4.4%). Thus, the overall therapy for patients with esophageal cancer has been improved.

[CPE chemotherapy for tongue carcinoma--clinical effects and side effects].

UNLABELLED: Recent advances in chemotherapy have markedly improved the treatment results for oral cancer. Among many chemotherapeutic regimens, the usefulness of multiple combination chemotherapy with cisplatin as the primary drug has been frequently reported. During the past 6-year period, we have performed combination chemotherapy with cisplatin as the primary drug, peplomycin, and etoposide (CPE chemotherapy) as one of the chemotherapeutic regimens for oral cancer. The subjects were 11 patients (7 males and 4 females) with tongue cancer treated by CPE chemotherapy as neoadjuvant chemotherapy at our department between March, 1990 and April, 1995. RESULTS: PR in 8 (73%), and NC in 3 (27%). No patient showed CR and PD. The side effects observed were reversible findings such as transient myelosuppression, nausea-vomiting, and alopecia. No patient showed severe or persistent suppression of hematopoietic function.

[Evaluation of neo-adjuvant chemotherapy for oral squamous cell carcinoma].

In the present study, we investigated the clinical and histopathological effects of CP therapy consisting of cisplatin (CDDP 50 mg/m2) or carboplatin (CBDCA 300 mg/m2) and peplomycin (PEP 5 mg/day) for 25 patients with oral squamous cell carcinoma. The effects of treatment and associated complications were as follows: 1) Complete response (CR) was achieved in 8 and partial response (PR) in 14 of the 25 cases. The overall clinical response rate was 88%. The histological response rate was 64%. 2) The clinical effects were not always consistent with the histopathological effects. There were discrepancies between the clinical and histopathological effects, especially in PR determined by clinical findings. 3) The principal adverse reaction was gastro-intestinal disturbances, but symptoms were able to be controlled. Signs of hematologic toxicity and renal disturbance were mild and did not preclude the continuance of therapy. The results of this study indicated that neo-adjuvant chemotherapy with CDDP and PEP was highly effective for the local control of oral squamous cell carcinoma.

Hyperthermic intravesical peplomycin perfusion treatment for bladder cancer.

Thirty-three patients with malignant bladder tumours were treated by hyperthermic intravesical perfusion. The study group included 25 patients with superficial T1 bladder tumours, 4 with T2 tumours and 4 with T3 tumours. Physiological saline solution containing 40 micrograms/ml peplomycin with/without 2% ethanol was used as a perfusate. Perfusion was carried out for 2 h 3 times per week and this regimen was repeated every other week, totalling 6 sessions in 3 weeks. Three patients achieved a complete response (CR), 5 a partial response (PR) (more than 50% tumour reduction), 8 a minimal response (MR) (25-50% tumour reduction) and the remaining 17 patients showed no response (NC). Complete, partial and minimal responses were obtained only in patients with T1 tumours. The NC patients included 4 with T2 and 4 with T3 lesions. Profuse haematuria from invasive tumour was markedly reduced after treatment. A major side effect was irritation of the bladder and urethra. Our results indicate that hyperthermic perfusion with ethanol and peplomycin is clinically safe, is accompanied by very little pain and may be useful for the management of superficial bladder tumours in elderly patients.

Azelastine hydrochloride (Azeptin) inhibits peplomycin (PLM)-induced pulmonary fibrosis by contradicting the up-regulation of signal transduction.

Inhibition of peplomycin (PLM)-induced pulmonary fibrosis by azelastine hydrochloride (Azeptin) was examined using ICR mice, and the effects of both drugs on signal transduction were investigated. Microscopically, Azeptin (a total of 56 mg/kg for 28 days) suppressed pulmonary fibrosis in mice which received an i.p. injection of a total of 60 or 75 mg/kg PLM. In parallel with the microscopic findings, smaller amounts of collagen were synthesized in the lungs of Azeptin-injected mice. PLM enhanced the expression of interleukin-1 beta- and transforming growth factor-beta-mRNA in lungs. In contrast, Azeptin suppressed the expression. Compatible with these in vivo results, Azeptin and PLM contradictively regulated protein tyrosine phosphorylation and c-myc mRNA expression in human gingival and mouse pulmonary fibroblasts. In addition, NF-kappa B was activated by fibroblast treatment with 5 micrograms/ml PLM for 1 h, but intranuclear NF-kappa B was decreased by cell treatment with 10(-5) M Azeptin. From these results, it is concluded that Azeptin inhibits PLM-induced pulmonary fibrosis by antagonizing the up-regulation of signal transduction.

Cisplatin, vincristine, methotrexate, peplomycin, etoposide (COMPE) therapy for disseminated germ cell testicular tumors.

BACKGROUND: The advent of cisplatin rendered disseminated testicular germ cell tumor an often curable malignant disease. Patients with a heavy metastatic burden, however, remain poor risks; furthermore, many patients experience nausea or other adverse events. This paper reports a trial of a cisplatin-based (COMPE) combination chemotherapy regimen based on synchronization theory. METHODS: Twenty patients with disseminated germ cell testicular tumors were treated with COMPE; any residual tumor mass was surgically resected. RESULTS: Seventeen patients (85%) achieved complete remission by chemotherapy. The actuarial overall and cause-specific 3-year survival rates were 89% and 94%, respectively. In the subset of 16 "good-risk" patients, all remain alive after a median follow-up of 43 months. Complications were quite tolerable, with nephrotoxicity in particular being extremely mild. CONCLUSION: COMPE is an effective chemotherapy regimen in patients with disseminated germ cell testicular tumors. Complications arising from this therapy are mild.

Neoadjuvant chemotherapy for patients younger than 50 years with high-risk squamous cell carcinoma of the cervix.

OBJECTIVE: To evaluate the response rate and toxicity and to improve survival, neoadjuvant chemotherapy (NAC) was utilized in patients younger than 50 years with locally advanced cervical squamous cell carcinoma. METHODS: Twenty-one patients were treated with preoperative NAC. Eligibility included patients with previously untreated stage IB or IIA with deep stromal invasion assessed by magnetic resonance imaging or bulky tumor or IIB squamous cell carcinoma who were younger than 50 years. The NAC consisted of cisplatin (60 mg/m(2)) on day 1, vinblastine (4 mg/m(2)/day) on days 1 and 2, and peplomycin (10 mg/day) on days 1, 8, and 15 (PVP). Treatment was repeated every 3 weeks for a total of two cycles. All 21 patients underwent radical hysterectomy following NAC. Postoperative radiotherapy was given to 18 patients. We used 21 patients who underwent radical hysterectomy and postoperative radiation therapy as a nonrandomized control group. RESULTS: The response rate for NAC was 86% (18/21). Two patients required discontinuation of PVP treatment after one administration because of grade 4 neutropenia and thrombocytopenia, and decreased carbon monoxide diffusion capacity, respectively. In the NAC group, stromal invasion was significantly reduced (P = 0.0103), and the incidence of lymph node metastasis was decreased. No patients had positive parametrial and vaginal margins. The overall 5-year survival rate was 84.0% in the NAC group, which was significantly better than that in the control group (58.9%) (P = 0.0434). CONCLUSIONS: NAC for younger patients with locally advanced cervical carcinoma is thought to be safe, well tolerated, effective, and useful for increasing operability, decreasing pathological risk factors, and improving survival.