Caffeic acid selectively eliminates teratogenic human-induced pluripotent stem cells via apoptotic cell death.

BACKGROUND: Induced pluripotent stem cells (iPSCs) generated from reprogrammed adult somatic cells are considered as a promising cell source in cell-based regenerative medicine. To avoid teratoma formation, which is a safety issue in iPSC-based cell therapy, it is important to selectively remove undifferentiated iPSCs that remain in the differentiated cell product before in vivo transplantation. Caffeic acid (CAA, 3,4-dihydroxy-cinnamic acid) is a phenolic compound synthesized from various vegetables, fruits, and herbs; it has shown various pharmacological activities against inflammation, cancer, infection, diabetes, and neurodegenerative diseases. However, the beneficial effects of CAA in iPSC-based cell therapy, such as the selective elimination of iPSCs and anti-teratoma effects, have not yet been explored. RESULTS: Here, we found that CAA induced apoptotic cell death in iPSCs; this process did not occur in iPSC-derived mesenchymal progenitor cells (MPCs) or human dermal fibroblast (hDFs). Under co-culture conditions with MPCs and hDFs, CAA treatment selectively removed iPSCs. In addition, CAA treatment in mixed cell culture with iPSCs and MPCs prior to grafting markedly suppressed iPSC-derived teratoma formation. Finally, CAA did not induce DNA damage in MPCs or hDFs. CONCLUSION: Taken together, these results suggest that CAA is effective in preparing safe iPSC-based therapeutic cells without the risk of teratoma formation and DNA damage in normal cells and iPSC-derived differentiated cells.

Drug screening with a novel tumor-derived cell line identified alternative therapeutic options for patients with atypical teratoid/rhabdoid tumor.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare intracranial tumor occurring predominantly in young children. The prognosis is poor, and no effective treatment is currently available. To develop novel effective therapies, there is a need for experimental models for AT/RT. In this research, we established a cell line from a patient's AT/RT tissue (designated ATRT_OCGH) and performed drug screening using 164 FDA-approved anti-cancer agents, to identify candidates for therapeutic options. We found that bortezomib, a proteasome inhibitor, was among the agents for which the cell line showed high sensitivity, along with tyrosine kinase inhibitors, topoisomerase inhibitors, and histone deacetylase inhibitors, which are known to exert anti-AT/RT effects. Concomitant use of panobinostat potentiated the inhibitory effect of bortezomib on AT/RT cell proliferation. Our findings may provide a rationale for considering combination therapy of panobinostat and bortezomib for treatment of AT/RT.

Efficacy of cabazitaxel in mouse models of pediatric brain tumors.

BACKGROUND: There is an unmet need in the treatment of pediatric brain tumors for chemotherapy that is efficacious, avoids damage to the developing brain, and crosses the blood-brain barrier. These experiments evaluated the efficacy of cabazitaxel in mouse models of pediatric brain tumors. METHODS: The antitumor activity of cabazitaxel and docetaxel were compared in flank and orthotopic xenograft models of patient-derived atypical teratoid rhabdoid tumor (ATRT), medulloblastoma, and central nervous system primitive neuroectodermal tumor (CNS-PNET). Efficacy of cabazitaxel and docetaxel were also assessed in the Smo/Smo spontaneous mouse medulloblastoma tumor model. RESULTS: This study observed significant tumor growth inhibition in pediatric patient-derived flank xenograft tumor models of ATRT, medulloblastoma, and CNS-PNET after treatment with either cabazitaxel or docetaxel. Cabazitaxel, but not docetaxel, treatment resulted in sustained tumor growth inhibition in the ATRT and medulloblastoma flank xenograft models. Patient-derived orthotopic xenograft models of ATRT, medulloblastoma, and CNS-PNET showed significantly improved survival with treatment of cabazitaxel. CONCLUSION: These data support further testing of cabazitaxel as a therapy for treating human pediatric brain tumors.

Atypical teratoid/rhabdoid tumor case report: treatment with surgical excision, radiation therapy, and alternative medicines.

Intracranial atypical teratoid/rhabdoid tumors (AT/RT) are rare with a poor prognosis. We report one case of a 7-year old girl living over 17 months after the diagnosis of AT/RT in the left frontal lobe. Treatment was partial surgical resection and post-operative radiation therapy. Radiation therapy resulted in complete response with no evidence of residual or recurrent disease more than 17 months after diagnosis. The patient has been maintained on an extensive regimen of alternative therapies since completion of radiation therapy.

Testicular germ cell tumor with rhabdomyosarcoma successfully treated by disease-adapted chemotherapy including high-dose chemotherapy: case report and review of the literature.

Treatment and prognosis have not been well characterized in germ cell tumors (GCT) with a malignant nongerm cell component. Patients with a mediastinal tumor, neural or rhabdomyosarcomatous differentiation and distant metastases have the poorest prognosis. We report a rare case of mixed GCT composed of seminoma, teratoma and rhabdomyosarcoma with the rhabdomyosarcomatous component metastasized into the liver and bone marrow (BM) causing hypercalcemia. The patient was treated with differentiation-tailored chemotherapy (CHT) including a disease-adapted high-dose (HD) CHT regimen with purified autologous PBSCT (APBSCT) and pamidronate. To date, remission has lasted for 4 years. Tumor-adapted CHT including HD-CHT with APBSCT can induce long term remissions in high-risk patients with transformed GCT. A review of the literature is given.

[Cases of refractory testicular cancer treated with all trans-retinoic acid].

We reported two cases of chemotherapy-refractory testicular cancer treated with all trans-retinoic acid (ATRA). Case 1. A 21-year-old male patient underwent salvage surgery for lung metastasis which had developed after treatment with three different cisplatin-based chemotherapy regimens for malignant teratoma. After recovery from surgery, he was treated with oral ATRA at daily dose 80 mg/m2 for four weeks. Case 2. A-45-year-old patient suffered from lung metastasis after orchiectomy for teratocarcinoma. The patient failed to achieve a complete response despite two different cisplatin-based chemotherapy and high dose chemotherapy regimens with bone marrow rescue. He was treated with oral ATRA for five weeks. Both patients showed disease progression with increase in tumor size and elevation of tumor marker during ATRA therapy. Side effects were acceptable except the headache in Case 2, who needed a dose reduction of ATRA. In conclusion, oral ATRA with this dose failed to show clinical antitumor activity in patients with refractory testicular cancer.

[Rare metabolic and cerebral complications after polychemotherapy of a testicular tumor]. / Seltene metabolische und zerebrale Komplikationen nach Polychemotherapie eines Hodentumors.

In a 21-year-old patient with a tumor of the right testis, CT indicated a pathologically altered lymph node in the interaortocaval region. After high inguinal orchiectomy we performed a modified retroperitoneal lymph node dissection and monitored its success by immediate section for microscopic examination. Pathohistological investigation yielded immature teratoma. The patient was given two courses of adjuvant polychemotherapy containing cisplatin. Two days after the conclusion of the second course he was readmitted with grand mal epilepsy and visual agnosia. Two months later another grand mal epileptic fit occurred. The patient also suffered from marked metabolic disorders, such as hypokalemia, hyperreninism, hyperaldosteronism, kaliuresis, and hypertension. We consider these to be toxic side effects of cisplatin resulting in nephropathy. Evidence of cisplatin-induced encephalopathy was obtained by NMR tomography and EEG which indicated barrier disorders. Symptoms were relieved and continuous normalization of blood pressure, potassium level, and water and electrolyte balance was achieved by the administration of potassium substitution, ACE inhibition, and an aldosterone antagonist. The patient has since remained in a stable condition.

Etoposide pharmacokinetics in children: the development and prospective validation of a dosing equation.

Pharmacokinetic studies of etoposide administered at 100-200 mg/m2 to 33 children are described. Twenty-seven studies were performed in children aged < 10 years. Repeat studies were performed in 11 patients. Median pharmacokinetic parameters were as follows: plasma clearance, 26 ml/min/m2; volume of distribution, 4.9 liters/m2; area under the etoposide plasma concentration-time curve (AUC), 3.9 mg/ml x min per 100 mg/m2. Interindividual variability in pharmacokinetic parameters was large (coefficient of variation (CV) = 30, 28, and 27%, respectively) in comparison with intraindividual variability (CV = 12, 14, and 12%, respectively). Variability in AUC was much greater in those patients treated with 150-200 mg/m2 etoposide than with 100 mg/m2 (CV, 35 versus 13%) and was related to variability in renal function and prior exposure to cisplatin. Data from the first 20 studies were used to develop pharmacokinetic monitoring equations which were validated in a further 13 patients. The most accurate equation relies upon the elimination constant of 51Cr-EDTA and a single blood specimen taken at the end of the etoposide infusion. [formula: see text] where K = 51Cr-EDTA elimination rate constant. This equation showed no significant bias, and the predictive error was small with respect to AUC calculated according to a two-compartment model. Predictive error did not increase with increasing AUC, whereas a marked increase in predictive error was seen for dosing according to body surface area. Dosing according to body surface area alone led to marked over- or underexposure to etoposide in 8 patients. Pharmacokinetic monitoring using the equation described would have identified these patients and permitted dose modification. This approach provides an accurate means of monitoring etoposide AUC for administration times of 1-4 h without the need for detailed pharmacokinetic sampling. It will allow a significant reduction in the variability of exposure seen with surface area-based dosing.

Cisplatin-induced changes of selenium levels and glutathione peroxidase activities in blood of testis tumor patients.

Haematocrit and glutathione peroxidase activity in blood, as well as selenium levels in blood, erythrocytes and plasma, were determined in 15 patients during four courses of cisplatin combination treatment for testicular teratoma. The haematocrit steadily declined, necessitating frequent blood transfusions during or after treatment. For patients without blood transfusions during treatment the reduction of the haematocrit averaged 40%. Glutathione peroxidase activity in blood declined also; for patients without blood transfusion the reduction was 30%, which is fully explained by the decrease of the haematocrit. The enzyme activity per volume of erythrocytes remained constant during the treatment. Erythrocyte selenium level did not change significantly, but plasma selenium levels of all patients dropped within each course of chemotherapy, and progressively with each subsequent course. Between cycles the levels were largely restored to almost normal values. These results may be explained by a decreasing availability of selenium in the body to maintain the normal plasma level, due to increased retention of cisplatin in tissues and subsequent alteration of selenium metabolism.

Total parenteral nutrition as an adjuvant to patients undergoing chemotherapy for testicular carcinoma: protection of body composition--a randomized, prospective study.

The efficacy of total parenteral nutrition (TPN) in the protection of body composition, when given as an adjuvant to CVB (cisplatin-vinblastine-bleomycin) treatment to patients with testicular teratocarcinoma, was investigated. Twenty-three patients without previous malnutrition were randomized to receive either TPN or spontaneous oral intake only during their hospital stay, in the course of a total treatment period of 10 weeks. The patients spent weeks 1, 4, 7, and 10 in the hospital to undergo chemotherapy. Energy and nitrogen intakes were profoundly decreased in the spontaneous oral-intake group, whereas the intakes decreased in the TPN group only at home when they relied on oral intake. In spite of the cytotoxic drugs, the TPN group remained in nitrogen balance when undergoing TPN at the hospital. However, they lost substantial body weight and body nitrogen over 10 weeks when compared with the oral-intake group. This loss in body mass was mainly a result of the prolonged anorexia that all the patients had after weekly termination of chemotherapy. This study demonstrates that well-nourished patients can use intravenous nutrition even while receiving cytocidal and cytostatic drug administration. However, intermittent periods of adequate nutrition in the hospital had only a marginal impact, since the positive effects of nutrition were offset by the pronounced anorexia that occurred in all patients outside the hospital for a considerable time after cytostatic treatment.

Intestinal lymphangiectasia secondary to radiotherapy and chemotherapy.

We report a case of intestinal lymphangiectasia secondary to radiotherapy and chemotherapy. The patient also had small bowel bacterial overgrowth and pancreatic insufficiency. Lymphatic ectasia as a histological feature has been described previously in association with postradiotherapy malabsorption, but radiation-induced lymphangiectasia producing clinical manifestations has hitherto not been reported. Replacement of dietary long-chain fats with medium-chain triglycerides, pancreatic enzyme supplements, and a short course of oxytetracycline, resulted in dramatic clinical improvement. The possibility of intestinal lymphangiectasia should be borne in mind in patients with postradiotherapy malabsorption. A low serum albumin and lymphocyte count should draw attention to this possibility.

Prophylaxis against hypomagnesaemia induced by cis-platinum combination chemotherapy.

Hypomagnesaemia is recognised as a feature of the renal tubular defect produced by cis-platinum therapy for cancer. It may be sufficiently severe to cause tetany and grand mal fits. Attempts to correct established hypomagnesaemia whilst continuing cis-platinum therapy have not proved satisfactory. We have therefore investigated the prophylactic addition of 3 g magnesium sulphate to the high-dose platinum regimen with which metastatic malignant teratoma is treated in this unit. Serum magnesium levels have been measured in eight patients treated in this way and compared with those recorded for eight matched patients previously treated without routine magnesium supplements. Magnesium levels fell into the range frequently associated with clinical manifestation in five of the eight unsupplemented patients and only one of those given magnesium prophylactically. Mean serum magnesium levels were significantly higher in the supplemented group when compared using the paired t-test (P less than 0.01). Routine supplementation with intravenous magnesium sulphate is a simple and effective way of preventing symptomatic hypomagnesaemia associated with cis-platinum therapy.