Vitamin D3 stimulates embryonic stem cells but inhibits migration and growth of ovarian cancer and teratocarcinoma cell lines.

BACKGROUND: Deficiency in Vitamin D3 (cholecalciferol) may predispose to some malignancies, including gonadal tumors and in experimental models vitamin D3 has been proven to inhibit the growth of cancer cells. To learn more about the potential role of vitamin D3 in cancerogenesis, we evaluated the expression and functionality of the vitamin D receptor (VDR) and its role in metastasis of ovarian cancer cells and of murine and human teratocarcinoma cell lines. METHODS: In our studies we employed murine embrynic stem cells (ESD3), murine (P19) and human (NTERA-2) teratocarcimona cells lines, human ovarian cancer cells (A2780) as well as purified murine and human purified very small embryonic like stem cells (VSELs). We evaluated expression of Vitamin D3 receptor (VDR) in these cells as well as effect of vitamin D3 exposure on cell proliferation and migration. RESULTS: We here provide also more evidence for the role of vitamin D3 in germline-derived malignancies, and this evidence supports the proposal that vitamin D3 treatment inhibits growth and metastatic potential of several germline-derived malignancies. We also found that the ESD3 murine immortalized embryonic stem cell line and normal, pluripotent, germline-marker-positive very small embryonic-like stem cells (VSELs) isolated from adult tissues are stimulated by vitamin D3, which suggests that vitamin D3 affects the earliest stages of embryogenesis. CONCLUSIONS: We found that however all normal and malignant germ-line derived cells express functional VDR, Vitamin D3 differently affects their proliferation and migration. We postulate that while Vitamin D3 as anticancer drug inhibits proliferation of malignant cells, it may protect normal stem cells that play an important role in development and tissue/organ regeneration.

Unusual autopsy finding in a case of metastatic teratocarcinoma.

An unusual autopsy finding was seen in a young case of metastatic teratocarcinoma of the right testis. The patient presented with features of myocardial ischemia and died of sudden cardiac arrest. At autopsy, the lungs were studded with variably sized metastatic nodules composed of glistening hyaline cartilage. Examination of the coronary arteries revealed complete occlusion of the left anterior descending and left circumflex artery lumina by tumor emboli composed of glistening white chondromyxoid material. Histopathology confirmed the presence of mature hyaline cartilage and chondromyxoid material in tumor emboli. The individual died due to severe coronary insufficiency and sudden cardiac arrest secondary to complete luminal occlusion of the left anterior descending and left circumflex artery lumina by tumor emboli composed of hyaline cartilage.

Late relapse in testicular germ cell tumors.

AIMS AND BACKGROUND: Analysis of patients with late relapse of testicular germ cell tumors (GCTs) with reports on clinicopathological features and outcomes. METHODS: We identified all patients diagnosed with testicular GCTs at our Institute between 1988 and 2004 who developed relapse > or = 24 months after completion of primary therapy. A retrospective case-note review was performed to extract clinical, pathological, treatment and outcome data. RESULTS: Six patients (1.25%) developed late relapse. All patients presented with stage I disease and were classified as "good risk" according to the International Germ Cell Consensus Classification. Mean time to late relapse was 48 months. Markers at late relapse were normal in all patients. Relapse was confined to retroperitoneal sites in five patients and located in the mediastinum in one patient. Five patients were managed by chemotherapy alone while one underwent combined treatment with surgery followed by chemotherapy. All patients obtained a complete response and all remained free from recurrence with a mean follow-up of 115 months. CONCLUSIONS: The incidence of late relapse in this small series is low. Chemonaive patients with late relapse were successfully salvaged with chemotherapy alone or surgical excision followed by cisplatin-based chemotherapy. The optimal duration of follow-up in patients with testicular GCTs is not known and practice varies widely. At our Institute we advise lifelong follow-up of all patients with malignant GCTs of the testis.

Paclitaxel, bleomycin, etoposide, and cisplatin (T-BEP) as initial treatment in patients with poor-prognosis germ cell tumors (GCT): a phase II study.

First line treatment of patients pts with poor-prognosis GCT, using BEP, is unsatisfactory. T-BEP (paclitaxel followed by BEP) demonstrated promising efficacy in the group of pts with intermediate and poor prognosis GCT. We present the results achieved with 1st line T-BEP in pts with poor-prognosis CGT. Twenty-four pts received T-BEP as initial therapy. Three pts (12.5%) had primary mediastinal GCT. Four cycles of T-BEP were given 21 days apart. Paclitaxel 175 mg/m2 was administered on day 1 before administration of BEP. The administration of G-CSF was not scheduled. Surgical resection of all radiographic residua was considered. All pts were assessable for response. Complete or partial response with negative tumor markers was achieved in 13 pts (54.2%; CI 95%: 34.3-74.1%). Median follow-up is 35.6 months. Median survival was not achieved and median time-to-progression is 9.5 months. Myelosuppression was the major toxicity with Gr3-4 granulocytopenia experienced in 52.1% of all courses. There were two treatment-related deaths due to sepsis. Patients treated with 1st line T-BEP didn't achieve higher response rate or time to progression. However, the overall survival observed in our study is surprisingly long. We do not recommend using this regimen without G-CSF support due to substantial toxicity.

Cervical mature teratoma 17 years after initial treatment of testicular teratocarcinoma: report of a late relapse.

BACKGROUND: Late relapses of testicular germ cell tumor are uncommon. We report a case of cervical mature teratoma appeared 17 years after treatment of testicular teratocarcinoma. CASE PRESENTATION: A 20-year-old patient underwent left sided orchiectomy followed by systemic therapy and retroperitoneal residual mass resection in 1989. He remained in complete remission for 200 months. In 2005 a huge left supraclavicular neck mass with extension to anterior mediastinum appeared. Radical surgical resection of the mass was performed and pathologic examination revealed mature teratoma. CONCLUSION: This is one of the longest long-term reported intervals of a mature teratoma after treatment of a testicular nonseminoma germ cell tumor. This case emphasizes the necessity for follow up of testicular cancer throughout the patient's life.

Pharyngeal teratocarcinosarcoma: review of the literature and report of two cases.

Teratocarcinosarcomas are rare malignant neoplasms histologically characterized by the presence of benign and malignant epithelial and mesenchymal elements. They are seen almost exclusively in the sinonasal tract of men. We report two cases of teratocarcinosarcomas involving the posterior pharyngeal wall in a 55-year-old male and 60-year-old men. The tumors consisted of epithelial components including squamous, neuroendocrine, and glandular structures; neuroepithelium, and mesenchymal components with prominent rhabdomyoblastic, osteoblastic and chondroid differentiation. Immunohistochemical studies demonstrated markers characteristic of each component. The tumors were resected, and the patients received postoperative radiation therapy. One patient is alive with recurrent tumor 33 months after treatment and the other died 26 months after radiation therapy with distant metastasis.

Placental teratocarcinoma in a mare with possible metastasis to the foal.

A teratocarcinoma was diagnosed in the amnion of a 5-year-old Arabian mare that delivered a healthy, full-term foal. The foal died at 2.5 months of age as a result of metastasis of an undifferentiated component of the mass. This case is unique because it is the first reported case of placental teratocarcinoma in animals and the malignant component apparently metastasized to the foal resulting in its death.

[Paraneoplastic hyperthyroidism in a patient with metastasizing teratocarcinoma and excessively high HCG]. / Paraneoplastische Hyperthyreose bei metastasiertem Teratokarzinom mit exzessiver HCG-Erhöhung.

Clinically manifest hyperthyroidism is a rare paraneoplastic syndrome in patients with excessive HCG production due to testicular cancer. A 40-year-old patient with right testicular cancer (teratoma, embryonal cell carcinoma), diffuse pulmonary metastases and high serum HCG levels presented with symptomatic hyperthyroidism. The patient received immediately thyrostatic therapy and 4 cycles of PEI chemotherapy (Cisplatin, Etoposide, Ifosfamide). Thyroid function had returned to normal by the beginning of the second course of chemotherapy. After right orchiectomy and resection of residual pulmonary masses which revealed vital tumor cells, two additional courses of chemotherapy were performed. The patient is well and without evidence of disease 11 months after therapy. All patients with testicular cancer and excessive HCG production should be evaluated for biochemical and clinical signs of hyperthyroidism and treated accordingly with antithyroidal medication and immediate cytoreductive chemotherapy.

[Metastasizing malignant germ cell tumor of the testis with infiltration of the thoracic aorta--a case for metastasis surgery]. / Metastasierender maligner Keimzelltumor des Hodens mit Infiltration der Aorta thoracica--Kasuistik zur Metastasenchirurgie.

HISTORY AND FINDINGS: A 33-year-old man was admitted 7 years after a testicular teratomatous carcinoma had first been diagnosed, treated by a right orchiectomy and two-stage radical retroperitoneal lymphadenectomy. Five years later the first mediastinal metastases were treated with high-dosage chemotherapy and autologous germ-cell transplantation, and remaining paraaortic--mediastinal tumour tissue was resected. Two years later another tumour at that site was only partially resected. A curing treatment seemed impossible, because the aortic wall had been invaded. TREATMENT AND COURSE: Five months after re-thoracotomy the metastasis and the invaded aortic segment were resected, the latter replaced by a vascular prosthesis. Histology indicated metastasis of a malignant teratoma of intermediate type. There has been no evident recurrence in the last 20 months. CONCLUSION: Combined orchidectomy, lymphadenectomy, high-dosage chemotherapy with cisplatin and autologous germ-cell transplantation at present constitute the standard treatment of malignant testicular germ-cell tumour. In case of metastatic infiltration of vital structures, such as the aortic wall, special operative procedures can prolong the period of remission when the success of a standard treatment seems limited.

Bilateral pulmonary resection for lung metastases: report of two cases.

Resection of bilateral pulmonary metastases is exceptional. However, in carefully selected patients extensive resections might be successfully performed. We report two patients who underwent a pneumonectomy and excision of pulmonary metastases in the other lung, via a left wedge resection for patient 1 and left segmentectomy for patient 2. Resections were carried out for metastases of a malignant fibrous histyocytoma and for a teratocarcinoma. Both patients are still alive 9 months and 4 years after their last metastasectomy, respectively.

Teratocarcinoma presenting with duodenal metastases diagnosed on endoscopic fine needle aspiration.

Upper gastrointestinal bleed as the first symptom of metastatic testicular tumors is rare. We describe a 17-year-old man who presented with upper gastrointestinal bleed; endoscopic fine needle aspiration cytology from a duodenal mass suggested germ cell tumor, which was later confirmed on histology of the testis.

The management of inferior vena cava obstruction complicating metastatic germ cell tumors.

BACKGROUND: Inferior vena cava obstruction (IVCO) is a poorly characterized complication of metastatic germ cell tumor (GCT). The authors identified 31 cases to describe the clinical features, radiologic findings, complications, and treatment of this clinical entity. METHODS: Patients with GCT and IVCO were identified from case records of a GCT database. The records of 333 male patients with metastatic GCT (27% with seminoma and 73% with nonseminomatous GCTs) were screened for either clinical or computed tomography (CT) scan evidence of inferior vena cava compression or involvement. RESULTS: Thirty-one patients were identified (9.3% of patients with metastatic GCT). Common presenting symptoms were leg swelling and dilated abdominal wall veins. Approximately 29% of patients had thromboembolic complications and there was a single case of fatal pulmonary embolism. Nine patients had no clinical features at presentation but either had CT scan evidence of IVCO or developed symptoms during treatment. Right-sided testicular primary tumors were associated more frequently with IVCO compared with left-sided primary tumors (14% vs. 4% of cases of metastatic GCT, respectively). All patients had an abdominal mass measuring > 5 cm in maximum transverse dimension. CONCLUSIONS: The authors recommend careful clinical and radiologic evaluation for the presence of IVCO in cases of bulky metastatic GCT. A high index of suspicion must accompany the evaluation of a patient with a right-sided primary testicular tumor and a paracaval abdominal mass measuring > 5 cm in maximum transverse dimension. When IVCO is identified, prophylactic anticoagulation is recommended.

Late pelvic recurrence of nonseminomatous testicular carcinoma after negative retroperitoneal lymph node dissection.

We report a case of pathologic Stage I teratoma recurring in the pelvis as embryonal carcinoma 12 years after radical orchiectomy and bilateral retroperitoneal lymph node dissection (RPLND). The patient received three cycles of chemotherapy (cisplatin, etoposide, bleomycin) followed by complete surgical excision of the pelvic mass. Successful treatment of these rare late recurrences usually requires chemotherapy and complete surgical excision. Pelvic relapse may potentially result from incomplete iliac node resection at the time of RPLND, altered lymphatic drainage from an incompletely resected spermatic cord, or a second primary extragonadal tumor focus. Our case emphasizes the importance of meticulous surgical technique during RPLND and the necessity for follow-up beyond 5 years in patients with testicular cancer.

Shunt-related abdominal metastasis of cerebral teratocarcinoma: report of an unusual case and review of the literature.

OBJECTIVE AND IMPORTANCE: Internal drainage of cerebrospinal fluid to the abdominal cavity via a ventriculoperitoneal shunt (VPS) is a common procedure for therapy of obstructive hydrocephalus; because this condition is often caused by brain tumors blocking the natural cerebrospinal fluid pathways, the VPS as an artificial anastomosis can provide the means for the spreading of tumor cells by the cerebrospinal fluid. We report the case of a VPS-related abdominal metastasis of a teratocarcinoma and review the pertaining literature. CLINICAL PRESENTATION AND INTERVENTION: A 24-year-old man with a history of three brain tumors that were operated on when the patient was 14, 21, and 23 years of age developed an acute ileus 7 months after VPS insertion for cerebral teratocarcinoma. Intraoperatively, a massive abdominal tumor was observed, which turned out to be a peritoneal metastasis of the aforesaid brain tumor. The patient died as a result of his illness 1 month later. RESULTS: To date, 58 VPS-related metastases of brain tumors have been described. The male-to-female ratio is 1.6:1, the mean age at shunt insertion is 12.2 years, and the interval between shunt operation and diagnosis of metastases is 16.8 months. During the observation time, 69.2% of the patients died as a result of their illness or abdominal metastases. The most common sources of the metastases were germinomas (27.7%), medulloblastomas (19.1%), and endodermal sinus tumors (10.3%). CONCLUSION: The presented case is only the second VPS-related abdominal spreading of a cerebral teratocarcinoma. Metastases via VPS are rare but should be considered as a possible complication and mode of systemic spread in patients with primary intracranial malignancy.

Reduction of connexin43 expression and dye-coupling during neuronal differentiation of human NTera2/clone D1 cells.

Gap junctions are plasma membrane specializations that allow direct communication among adjoining cells. We used a human pluripotential teratocarcinoma cell line, NTera-2/clone D1 (NT2/D1), as a model to study gap junctions in CNS neurons and their neuronal precursors. These cells were differentiated following retinoic acid (RA) treatment for 4 weeks and antiproliferative agents for 3 weeks, respectively, to yield post-mitotic CNS neuronal (NT2-N) cells. The cytoplasmic RNA was isolated from NT2/D1 cells both before and during RA treatment and from differentiated neurons (NT2-N cells). These RNA samples were examined using Northern blot analysis with cDNA probes specific for connexin26, -32, and -43. Connexin26 and -32 mRNAs were absent in NT2/D1 and NT2-N cells. Connexin43 mRNA was expressed at high levels in NT2/D1 cells before RA treatment, but it decreased significantly during RA induction. There was no detectable connexin43 mRNA in NT2-N cells. Western blot analysis confirmed the expression of connexin43 protein in NT2/D1 cells before and during RA treatment. The protein profile detected in Western blot analysis indicated two bands representing different phosphorylation states of connexin43. Our immunocytochemistry results did not show connexin26 and -32 immunoreactivity in NT2/D1 and NT2-N cells. However, we detected connexin43 immunoreactivity in NT2/D1 cells with a decreasing pattern upon RA induction. Both Western blotting and immunocytochemistry confirmed the absence of connexin43 protein in NT2-N cells. NT2/D1 cells passed calcein readily to an average of 18 cells, confirming the functionality of gap junctions in these cells. The extent of dye-coupling decreased about 78% when NT2/D1 cells were RA treated for 4 weeks. NT2-N differentiated neurons did not pass dye to the adjacent cells. We conclude that both connexin43 expression and dye coupling capacity decrease during neuronal differentiation of NT2/D1 cells.

[Giant testicular tumor associated with scrotal gangrene: a case report].

A case of giant testicular tumor associated with scrotal gangrene is reported. A 33-year-old man had a swollen scrotum (15 cm) accompanied with necrosis and a foulodor. The tumor had invaded the scrotum, perineum and the left spermatic cord. Serum alpha-fetoprotein level was 15,487 ng/ml. The chest radiograph revealed multiple metastases. Bilateral high orchiectomies and local resection with a wide margin were performed. The tumor weighed 2.5 kg and the histopathological diagnosis was teratocarcinoma. He was treated with 3 courses of chemotherapy with cisplatin, etoposide and peplomycin. A second-look surgery revealed no viable cancer cells in the residual masses. The patient has been free of recurrence 4 months postoperatively.

Late relapse of germ cell tumors after cisplatin-based chemotherapy.

BACKGROUND: Sparse data are available with regard to the incidence, clinical characteristics, therapeutic management and prognosis of male patients with germ cell tumors, who relapse more than two years after completion of cisplatin-based chemotherapy. PATIENTS AND METHODS: A review of 530 patients treated at two institutions from 1978 to April 1994 was conducted. Twenty-five cases of late relapse were identified. Cumulative risk of late relapse was calculated according to the Kaplan-Meier method. RESULTS: 418 of 523 patients (80%) who received their first-line treatment at our institutions were relapse-free at two years. Among these 418 patients 18 cases (4.3%) developed a late relapse. The cumulative risk of late relapse was 1.1% at five years and 4.0% at ten years excluding patients with prior early relapses who carried risks of 9.4% and 29%, respectively (P < 0.0001). No case of late relapse was observed among patients receiving adjuvant chemotherapy. The risk of late relapse was lower in patients with good-risk non-seminomatous germ cell tumors than in poor-risk patients according to Medical Research Council criteria (P < 0.01). Seven further patients were referred from other institutions for treatment of late relapse. At a median follow-up of 38 months (range, 3 to 121) after treatment of late relapse 9 of 25 patients (36%) are continuously disease-free. Six of these nine patients had surgical resection of carcinoma or teratoma as a component of their therapy. CONCLUSION: The incidence of late relapse after cisplatin-based chemotherapy of germ cell tumors is related to initial tumor burden and is somewhat higher than previously expected. Chemotherapy seems to have only minor curative potential, but localized resectable disease can be cured by surgery. Annual follow-up evaluations allow to detect the majority of late relapses at an asymptomatic stage and should be extended throughout the patient's life.