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.

Preoperative intra-arterial chemotherapy with docetaxel, cisplatin, and peplomycin combined with intravenous chemotherapy using 5-fluorouracil for oral squamous cell carcinoma.

The objectives of this study were to evaluate survival in 141 patients with stage II-IV oral squamous cell carcinoma (OSCC) treated with preoperative intra-arterial chemotherapy with docetaxel, cisplatin, and peplomycin combined with intravenous chemotherapy using 5-fluorouracil (IADCPIVF) via the superficial temporal artery, and to clarify the prognostic factors. The study population included 59 patients with stage II OSCC, 34 with stage III, and 48 with stage IV. After IADCPIVF, 139 patients underwent surgery; minimally invasive surgeries (MIS) including excisional biopsy were performed on 96 patients with a remarkably good response to IADCPIVF. The primary tumour response rate was 99.3% (complete response rate 56.7%, good partial response rate 17.0%, fair partial response rate 25.5%). Additionally, there were no serious adverse events associated with IADCPIVF. The 5-year overall survival rate was 74.6% (stage II 83.6%, stage III 72.7%, stage IV 64.8%). In the multivariate analysis of survival, T classification and clinical tumour response were significant prognostic factors. Eight (8.3%) of the patients who received MIS had primary recurrence and six were salvaged. In conclusion, IADCPIVF is safe and efficacious for treating OSCC, and MIS could reduce the extent of primary tumour resection in the case of a remarkably good response.

Inhibitory effect of neoadjuvant chemotherapy on metastasis of oral squamous cell carcinoma in a mouse model.

The presence or absence of metastasis bears an important influence on the prognosis of head and neck cancer patients. Neoadjuvant chemotherapy has become widely employed as an initial treatment. However, the actual effectiveness of neoadjuvant chemotherapy on metastasis is still unestablished. Therefore, using an orthotopic implantation model in which cervical lymph node metastasis of oral squamous cell carcinoma can be reproduced, we investigated the inhibitory effect of neoadjuvant chemotherapy on metastasis. A highly invasive and metastatic human oral squamous cell carcinoma cell line, OSC-19 cells, was implanted into the tongues of nude mice. After implantation, the mice were divided into four groups: S (surgery), C+S (preoperative chemotherapy+surgery), S+C (surgery+postoperative chemotherapy), and a control (nontreatment) groups. The treatment (tumor resection or chemotherapy) was started 7 days postimplantation. The effects of each treatment on cervical lymph node metastasis were investigated by examining the rate of lymph node metastasis formation at 28 days postimplantation. In the control group, five of the 11 mice died of cachexia before the end of the experiment. However, all mice in the S, C+S, and S+C groups survived until 28 days after implantation. The cervical lymph node metastasis rates were 81.8% in S, 18.1% in C+S, 63.6% in S+C, and 100% in control groups. Thus, metastasis to the cervical lymph node was markedly inhibited by the combination of neoadjuvant chemotherapy and tumor resection. The findings of this study indicate that neoadjuvant chemotherapy is effective for inhibiting metastasis, and that it is necessary to begin chemotherapy as early as possible to achieve an inhibitory effect on metastasis. Considering these effects, if anticancer drugs are used, better therapeutic results can be expected.

[Prognosis analysis of 83 cases of cervical adenosquamous carcinoma].

BACKGROUND & OBJECTIVE: Cervical adenosquamous carcinoma is a special histological type of cervical carcinoma. Its clinic-pathologic characteristics and prognostic factors have seldom been reported. This study was to explore the clinic-pathologic characteristics and prognostic factors of cervical adenosquamous carcinoma. METHODS: Clinical data of 83 pathologically confirmed adenosquamous cervical carcinoma patients in Sun Yat-sen University Cancer Center from Nov. 1982 to May 2006 were analyzed. RESULTS: The median overall survival (OS) of 83 patients was 47 months and the median disease-free survival was 43 months. The 5-year survival rate was 74.0%, and the recurrence rate (DFS) was 30.1% (25/83). The median OS and DFS were 58 months and 54 months versus 37 months and 21 months in patients with or without lymph node metastasis (P=0.005, P<0.001). The median DFS was 47 months and 16 months for patients with the tumor diameter >4 or < or =4 cm (P=0.015), respectively. Lymph node metastasis was correlated to FIGO stage, tumor diameter and invasion depth. The recurrence rate of patients with ovarian preservation was 33.3% (3/9). CONCLUSIONS: Lymph node metastasis is an independent risk factor for prognosis in cervical adenosquamous carcinoma. Adjunctive postoperative irradiation would improve the OS and DFS. Tumor diameter greater than 4cm is an independent prognostic risk of DFS. The impact of ovarian preservation on prognosis is unclear.

Chromosome arm 1q gain associated with good response to chemotherapy in a malignant glioma. Case report.

The authors describe the case of a patient with a glioblastoma multiforme who showed remarkably good response to chemotherapy. A genetic analysis using comparative genomic hybridization (CGH) revealed that the tumor had a gain on the q arm of chromosome 1 (1q). Using CGH for a series of genetic analyses of more than 180 patients with gliomas, six were found to have a demonstrated 1q gain. Although the tumors in all six of these cases were histopathologically diagnosed as high-grade gliomas, compared with other malignant gliomas they demonstrated a good prognosis because of their favorable chemotherapeutic sensitivity. In immunohistochemical tests, most of the tumor cells in these cases were negative for O6-methylguanine-DNA methyltransferase, which antagonizes the effect of DNA-alkylating chemotherapeutic agents. The authors believed that a gain of 1q could be produced through the genetic events that cause loss of 1p, because these chromosomal aberrations have an imbalance of DNA copy number in common (1p < 1q). A gain of 1q is an infrequent chromosomal aberration and its clinical importance should be investigated in a larger study; however, patients with malignant gliomas demonstrating a 1q gain possibly show longer survival and good response to chemotherapy similar to patients with tumors demonstrating 1p loss. The importance of using genetic analysis for gliomas is emphasized in this report because it may help in selecting cases responsive to chemotherapy and because appropriate treatment for these patients will lead to progress in the treatment of malignant gliomas.

A successful IVF-pregnancy in a patient who underwent conservative surgery followed by a regimen of cisplatin, vinblastine and peplomycin to treat an advanced ovarian mixed germ cell tumour: a case report.

Mixed germ cell tumours of the ovary, one type of malignant ovarian germ cell tumours (MOGCTs), are rare gynaecologic cancers usually affecting young women. We report the case of a patient with an advanced ovarian mixed germ cell tumour who underwent fertility-saving surgery followed by a chemotherapy regimen of cisplatin, vinblastine and peplomycin. The patient was disease-free 8 years after initial presentation. She conceived and gestated dichorionic twins after IVF-embryo transfer. To the best of our knowledge, the patient is the first to be treated successfully with the combination chemotherapy regimen and then conceive safely using assisted reproductive technology (ART).

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.

Mn-SOD antisense upregulates in vivo apoptosis of squamous cell carcinoma cells by anticancer drugs and gamma-rays regulating expression of the BCL-2 family proteins, COX-2 and p21.

ROIs and their scavengers are associated with apoptosis induction by anticancer drugs and gamma-rays, but the details have not been clarified. We examined the effect of transfection of Mn-SOD antisense on apoptosis by 5-FU, PLM, CDDP and gamma-rays using nu/nu mice. After inoculation of Mn-SOD antisense-transfected SCC cells into the subcutis of each mouse's back, they slowly multiplied to form tumors sized 1,460 +/- 70 mm(3) at day 60, while control vector-transfected SCC cells rapidly multiplied, with a mean tumor size of 2,330 +/- 220 mm(3). Inversely, mice in the Mn-SOD antisense group survived longer (mean survival duration 94.4 +/- 12.7 days) compared to those in the empty vector group (67.3 +/- 6.8 days). After treatment with 5-FU (5 microg/day), PLM (50 microg/day), CDDP (10 microg/day) and gamma-rays (2 Gy/day), mean survival times were largely prolonged, to 126.3 +/- 22.7, 123.0 +/- 22.1, 136.3 +/- 24.0 and 143.0 +/- 20.8 days, respectively, while mean survival times in the empty vector group were 91.7 +/- 14.8, 85.7 +/- 13.3, 97.5 +/- 16.0 and 100.7 +/- 17.1 days, respectively. Immunohistologically, tumors in the Mn-SOD antisense group revealed additional nick end-labeled cells compared to those in the empty vector group. In comparison, strong expression of Bax, Bak and p21(waf1/cip1) and suppressed expression of Bcl-2, Bcl-X(L) and COX-2 were observed in the Mn-SOD antisense group and the expression pattern of these proteins was the inverse in the empty vector group. The increased expression of these proapoptotic proteins appeared to be p53-independent because p53 protein expression was not increased in the antisense group. These immunohistologic results were supported by Western blotting of each protein. In conclusion, Mn-SOD antisense transfection is advantageous for apoptosis induction of SCC cells by anticancer drugs and gamma-rays through induction of proapoptotic Bcl-2 family proteins and suppression of antiapoptotic protein expression.

Effects of chemotherapy on invasion and metastasis of oral cavity cancer in mice.

BACKGROUND: Using an orthotopic implantation model in which oral cancer invasion and metastasis can be reproduced, we investigated the inhibitory effects of anticancer agents on invasion and metastasis. METHODS: A highly invasive and metastatic human oral squamous cell carcinoma cell line, OSC-19, was implanted into the oral floor of nude mice, and cisplatin or peplomycin was administered to the mice 7 or 14 days after implantation. The effects of each anticancer drug and different administration timings on cancer invasion and metastasis were investigated. RESULTS: Tumor size and the ratio of proliferating cell nuclear antigen-positive cells was significantly reduced. In the control group, the tumors showed grade 4C mode of invasion, whereas in the groups treated with anticancer drugs, grade 3 was observed in 77.3% of the mice, with an inhibitory effect on tumor invasion being observed. The rate of metastasis in the cervical lymph node was significantly decreased in the groups treated with the cisplatin or peplomycin on day 7 after implantation. The tumor stage progression in the metastatic lymph nodes was also inhibited. CONCLUSIONS: Chemotherapy is effective not only for tumor diminution but also for inhibiting invasion and metastasis. In light of these effects, administration of anticancer drugs may be clinically useful in this regard.

Peplomycin-induced apoptosis in oral squamous carcinoma cells depends on bleomycin sensitivity.

Oral squamous carcinoma cell line SSCKN cells were shown to be highly sensitive to bleomycin, whereas SCCTF cells were minimally sensitive to this reagent. To determine whether the anticancer drug resistance to oral squamous carcinoma cells could be related to the degree of the drug-induced apoptosis, we examined the effects of peplomycin on induction of apoptosis in these cells. After reaching subconfluence, SCCKN and SCCTF cells were exposed to various concentrations of peplomycin. Peplomycin caused cytotoxicity in both SCCKN and SCCTF cells in a dose-dependent fashion with the maximal effect at concentrations of 1 and 10 microM, respectively, as determined by phase-contrast microscopy and WST-1 cell viability assay. By using the Hoechst 33342 staining, we observed marked nuclear condensation and fragmentation of chromatin in SCCKN cells treated with 1 microM peplomycin. However, SCCTF cells treated with 1 microM peplomycin showed neither nuclear condensation nor fragmentation. DNA ladder formation was also detected in both cell lines by treatment with peplomycin. The induced DNA ladder formation in SCCKN and SCCTF cells was dose-dependent, with the maximal effect at concentrations of 5 and 50 microM, respectively. Bleomycin also induced DNA ladder formation in SCCKN and SCCTF cells with different sensitivities. Mitomycin C induced DNA laddering in both SCCKN and SCCTF cells; however, the intensity of DNA ladder formation was almost the same in both cell lines. The present results indicate that peplomycin-induced apoptosis in oral squamous carcinoma cell lines depends on the sensitivity of these cells to bleomycin.

Manganese superoxide dismutase negatively regulates the induction of apoptosis by 5-fluorouracil, peplomycin and gamma-rays in squamous cell carcinoma cells.

We investigated the relationship between manganese superoxide dismutase (Mn-SOD) activity and apoptosis induced by anticancer drugs and radiation. Although the activity of copper, zinc-SOD did not differ greatly among 9 squamous cell carcinoma (SCC) cell lines (OSC-1 to OSC-9), the Mn-SOD activity did differ among the cell lines. The Mn-SOD activity was increased by treatments with 5-fluorouracil (5-FU), peplomycin and 137Cs, reaching plateau levels at 12 h after treatment and then decreasing gradually. When OSC-1 and OSC-3, and OSC-2 and OSC-4 were examined as representative cell lines with low and high Mn-SOD activity, respectively, the decrease was more prominent in OSC-1 and OSC-3 than in OSC-2 and OSC-4. The intracellular levels of superoxide and hydrogen peroxide (H2O2) were increased after treatment with the anticancer agents, and the increases were larger in OSC-1 and OSC-3 than in OSC-2 and OSC-4. The decrease of mitochondrial membrane potential (deltapsi(m)) by the anticancer agents was marked in OSC-1 and OSC-3. Correspondingly, the release of cytochrome c, the activation of caspase-3 and the cleavage of poly(ADP-ribose)polymerase were stronger in OSC-3 than in OSC-4. In addition, apoptosis induced by the anticancer agents was prominent in OSC-3, exhibiting a close relationship with the deltapsi(m) and the H2O2 level. These results indicate that Mn-SOD in SCC cells modulates apoptosis induction and the inactivation of Mn-SOD might be a promising strategy for SCC treatment.

A new treatment for penile conservation in penile carcinoma: a preliminary study of combined laser hyperthermia, radiation and chemotherapy.

OBJECTIVE: To investigate the role of laser hyperthermia in penis-conserving therapy for penile carcinoma. PATIENTS, MATERIALS AND METHODS: Penile carcinoma KPK-1 cells were transplanted into nude mice to induce tumour; the effects of laser hyperthermia, the chemotherapeutic agent peplomycin, or their combination on the inhibition of KPK-1 tumour growth were assessed. In a clinical study, two patients with well-differentiated, stage T2 penile tumours with corporeal involvement were treated to conserve the penis using concurrent radiation, laser hyperthermia and peplomycin. They had no pathologically identified regional lymph node metastasis. Radiation was given for 5 days a week for 3 weeks at a total dose of 30 Gy. Nd:YAG laser hyperthermia was administered at 42-43 degrees C for 15 min twice a week for 3 weeks immediately after radiation. Peplomycin (10 mg per day) was administered intravenously over 24 h together with the laser hyperthermia. RESULTS: The combined treatment with laser hyperthermia and peplomycin completely inhibited KPK-1 tumour growth, but the treatment with either laser hyperthermia or peplomycin alone had little effect. The results were also corroborated by the histopathological findings; the necrotic area in mice treated with combined therapy was much larger than that in those treated with laser hyperthermia alone. Both patients given combined laser hyperthermia, radiation and peplomycin were treated successfully, with the penis and sexual function conserved, and both survived for > 7 years with no evidence of any local or regional recurrence. There were no major complications related to the combined treatment. CONCLUSIONS: This preliminary study showed that combined treatment with laser hyperthermia, radiation and peplomycin might be a promising therapy for conserving the penis in some patients with stage T2 penile tumours.

Induction chemotherapy is associated with an increase in the incidence of locoregional recurrence in patients with carcinoma of the oral cavity: results from a single institution.

BACKGROUND: This study was conducted to determine long term survival rates and the pattern of failure in patients with carcinoma of the oral cavity treated with induction chemotherapy or preoperative radiotherapy followed by surgery. METHODS: A retrospective analysis was performed of 141 eligible patients with Stage II-IV International Union Against Cancer (UICC) staging system squamous cell carcinoma of the oral cavity at the study department between 1985 and 1994. These patients received one of three treatments: surgery with or without peplomycin chemotherapy (Group A; n = 49); preoperative radiotherapy with or without concomitant peplomycin chemotherapy followed by surgery (Group B; n = 59); and induction chemotherapy followed by surgery (Group C; n = 33). Induction chemotherapy was comprised of two cycles of cisplatin, vincristine, peplomycin, with or without mitomycin C. RESULTS: When all 141 patients were analyzed, there was no significant difference in overall survival or disease free survival. However, a statistically significant increase in the incidence of neck recurrence in Group C was observed compared with Group A (P = 0.002). Within 79 patients with N0 disease, a statistically significant disadvantage was detected for Group C in terms of disease free survival compared with Group A (P = 0.038). In patients with Stage II disease (50 patients), there was a significant difference in disease free survival, with Group C inferior to both Group A (P = 0.04) and Group B (P = 0.066). CONCLUSIONS: Induction chemotherapy was associated with a significant increase in regional failure for patients with carcinoma of the oral cavity with N0 disease and those with Stage II disease.

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.

In vitro effects of hyperthermia combined with cisplatin or peplomycin on the human maxillary carcinoma cell line IMC-2.

We examined the interactive effects of hyperthermia combined with cisplatin (CDDP) (0.5 micrograms/ml) or peplomycin (PEP) (1.0 microgram/ml) on surviving fractions of human maxillary carcinoma IMC-2 cells. Either CDDP or PEP enhanced the 44 degree C thermosensitivity of thermotolerant cells after heating at 42 degrees C for 2 hours. The development of thermotolerance at 42 degrees C with either of the two drugs for 2 hours was not inhibited by CDDP, but it was partially inhibited by PEP. Moreover, for PEP throughout the entire period of 42-44 degrees C step-up heating, the 44 degree C thermosensitivity of thermotolerant cells after heating at 42 degrees C with PEP for 2 hours was enhanced similarly to that at 44 degrees C with PEP. Heating at 42 degrees C combined with either of the two drugs showed a marked interactive effect.

Epinephrine or peplomycin combined with hyperthermia in irradiated Lewis lung carcinoma: effects on tumor growth, skin reaction, and lung metastasis.

Although hyperthermia potentiates the effect of radiation, the combined effect decreases as the time between irradiation and hyperthermia increases. The purpose of this study was to prevent the rapid loss of efficacy by the local injection of epinephrine or peplomycin(PEP), two agents known as hyperthermic potentiators. In this study, Lewis lung carcinoma implanted in the foot of BDF1 mice was used for the assessment of tumor growth, skin reactions, and lung metastasis. The tumors were irradiated, then warmed in a water bath for 45 min. The retarding effects of hyperthermia on tumor growth and skin reactions were lost 2 days after irradiation. However, when PEP or epinephrine was injected before hyperthermia, tumor growth was distinctly delayed. The effect of epinephrine was greater than PEP and still showed enhancement 8 days after irradiation. For skin reactions, no significant enhancing effect was observed. Lung metastasis was significantly inhibited by the addition of epinephrine either 0 or 2 days after irradiation. In conclusion, the local administration of epinephrine combined with hyperthermia significantly retarded tumor growth without an increase in skin reactions or lung metastases. Possible mechanism underlying this phenomenon was discussed.

[A phase II clinical trial of pepleomycin].

From November 1993 to December 1994, a prospective multi-centre phase II clinical trial was done in 137 patients with advanced cancer on China-made pepleomycin (PEP). PEP was effective in patients with cancer of the head and neck, malignant lymphmo and lung cancer, with response rate of 66.7%, 50% and 30%, respectively. The major adverse reactions were fever and mild gastrointestinal reaction. In the controlled study of combination chemotherapy with China-made and Japan-made PEP, the response rates and side effects were similar. The results indicate that China made PEP can be used in lieu of that made in Japan.