Phase II study of ifosfamide with mesna in adult patients with recurrent diffuse astrocytoma

Summary Sixteen patients who developed CT or MRI scan evidence of recurrent diffuse astrocytoma after radiation therapy and nitrosourea-containing chemotherapy received ifosfamide (2500 mg/m²/day for 3 consecutive days) and mesna (500 mg/m²/dose, 5 doses/day for 3 consecutive days). Toxicity consisted primarily of leukopenia in that 60 percent of patients developed leukocyte nadirs less than 1500/mcL. Excessive somnolence occurred in three patients and may have contributed to a case of fatal pneumonia in one patient but was reversible in the other two. No patient had CT or MRI scan evidence of tumor regression. One patient remains stable at 11.3+ months, but all other patients developed evidence of progressive disease less than 6 months from initiation of therapy. The median times to tumor progression and death were 2.0 and 4.8 months, respectively. In conclusion, while ifosfamide and mesna can be given safely at this dose and schedule, there is no evidence of antitumor effect. The degree of leukopenia observed likely would prevent further dose escalation of ifosfamide or addition of other myelosuppressive agents without additional means of bone marrow support in this population of patients.Additional participating institutions include: Geisinger Clinic and Medical Center CCOP, Danville, Pennsylvania 17822 (Richard M. Goldberg); University of Nebraska Medical Center, Omaha, Nebraska 68105 (John F. Foley); Illinois Oncology Research Association CCOP, Peoria, Illinois 61603 (James B. Gerstner); and The St. Cloud Clinic of Internal Medicine, Ltd., St. Cloud, Minnesota 56301 (John Weitz).     

Treatment of patients with advanced colorectal cancer with cisplatin, 5-fluorouracil, and leucovorin

Based on in vitro studies that have demonstrated synergy between 5-fluorouracil (5-FU), leucovorin (LV), and cisplatin (CDDP) against human colon cancer cell lines, a clinical trial was initiated to determine the effects of this combination in patients with advanced unresectable colorectal carcinoma. Fifty-nine patients were enrolled in the study and 12 of them had received prior conventional 5-FU chemotherapy. Treatment consisted of 4 weekly courses of high-dose LV (200 mg/m2) administered by intravenous (IV) bolus, followed by 5-FU (550 mg/m2) and CDDP (20 mg/m2) each administered as a 2-hour infusion on 4 consecutive days. After a median of 5.5 treatment cycles, objective tumor response was seen in 20 of 59 patients (34%) (this included 3 complete remissions). The response rate in the 47 previously untreated patients was 38% (95% confidence limits, 26% to 53%). Stable disease occurred in 16 (27%) patients, whereas the tumor progressed in 23 (39%) patients. The median survival time was 11.5 months, with 15% of the patients alive at 2 years. The regimen was well tolerated and the primary side effects were mild and reversible gastrointestinal symptoms and myelosuppression. There was no episode of life-threatening toxicity. Eastern Cooperative Oncology Group (ECOG) Grade III adverse reactions that required 25% dose reductions occurred in only 14% of the patients. The results of this trial suggest that 5-FU, LV, and CDDP is an active, safe, and well-tolerated combination regimen in patients with advanced colorectal cancer.     

Granulomatous angiitis of the spinal cord associated with Hodgkin's disease

A 28-year-old man had a 5-month history of focal and generalized neurologic symptoms culminating in a thoracic myelopathy. Evaluation revealed granulomatous angiitis of the spinal cord in association with occult nodular sclerosing Hodgkin's disease. In previous reports, manifestations indicative of intracranial involvement have dominated the clinical presentation of granulomatous angiitis associated with Hodgkin's disease. Successful therapy for Hodgkin's disease may result in marked improvement of associated granulomatous angiitis, whereas the lack or failure of therapy results in a uniformly fatal outcome. Definitive antemortem diagnosis of granulomatous angiitis requires a biopsy of involved tissue. The cause of granulomatous angiitis, as well as the nature of its association with Hodgkin's disease, remains unexplained.     

Effective treatment of advanced breast cancer with vinorelbine, mitomycin C plus human granulocyte colony-stimulating factor.

A phase II trial was performed to evaluate the efficacy and tolerance of vinorelbine (VNB), mitomycin C (MMC), and recombinant human granulocyte colony-stimulating factor (G-CSF) in advanced breast cancer. Between October 1992 and July 1994, 55 patients entered this trial. Nine patients had locally advanced disease and 46 had distant metastases, including 14 who had received previous palliative chemotherapy with (n = 9) or without anthracyclines (n = 5). Therapy consisted of VNB 40-50 mg m(-2) diluted in 250 ml saline infused over 30 min every 3 weeks, and MMC 15 mg m(-2) administered by intravenous bolus injection every 6 weeks. G-CSF was given at 5 microg kg(-1) day(-1) subcutaneously from days 2 to 7 following each cytotoxic drug administration. Treatment was continued in case of response or stable disease for a total of six courses. The overall response rate was 73% for all 55 patients (95% confidence interval, 59-84%), including 12 (22%) complete response (CR) and 28 (51%) partial response (PR); 13 patients (24%) had stable disease (SD), and only two (4%) progressed. All nine patients with locally advanced disease were rated responsive (two pCR, seven PR) and underwent surgery with curative intent. Eight out of nine remain disease free after a median observation period of 18 months (range, 13.5-28 months). Among the 32 previously untreated patients with metastatic disease, nine (28%) achieved CR, 15 PR (47%), seven SD (22%) and one PD (3%). Second-line chemotherapy with this regimen resulted in 7/14 (50%) objective remissions (one CR, six PR), six had SD and one PD. The median time to progression was 12 months (range, 2-24+ months) in previously untreated patients with disseminated disease, and 6.0 months (range, 2-22 months) in those who had failed prior chemotherapy. After a median follow-up time of 20 months, 24 patients with distant metastases are still alive with disease; median survival has not been reached yet. The dose-limiting toxicity was myelosuppression: six (11%) and ten patients (18%) had World Health Organization grade 3, and eight (14%) and nine patients (16%) had grade 4 leucopenia and granulocytopenia respectively. Severe (WHO grade 3) non-haematological toxicities included nausea/vomiting in 7%, constipation in 9%, peripheral neuropathy in 5%, infectious episodes in 7%, phlebitis due to drug extravasation in 5%, alopecia in 9%, and acute reversible pulmonary toxicity in 11%. Our data suggest that vinorelbine, mitomycin C plus G-CSF has an excellent anti-tumour activity in advanced breast cancer, probably superior to most other available combination chemotherapy regimens. This combination does not seem to present significant cross-resistance with previous CMF or anthracycline regimens. Apart from reversible, acute pulmonary toxicity, a rare adverse reaction that had previously been described for VNB, as well as the combination of natural vinca alkaloids with mitomycin C, and few episodes of grade 3 neurotoxicity (all of which occurred at the initial 50 mg m(-2) VNB dose level), the tolerance of this regimen seems acceptable and justifies further evaluation in front-line and salvage therapy of advanced breast cancer.     

Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases

A review was done of 120 cases of malignant peripheral nerve sheath tumor (MPNST) seen during a 71-year period. Of the 120 patients, 52 were males and 68 were females with a mean age at diagnosis of 35.3 years; 12 patients were younger than 20 years. The series included 62 (52%) patients with neurofibromatosis, 13 (11%) with postradiation sarcomas, and 19 (16%) with metaplastic foci. The incidence of MPNST arising in neurofibromatosis was 4.6% in the current series and 0.001% in the general clinic population. Tumors greater than 5 cm and the presence of neurofibromatosis adversely affected the prognosis (P less than 0.05). When both features were present, survival was greatly decreased. Patients with tumor in the extremities did better than those with head or neck lesions. Metaplastic foci or previous radiation at the tumor site did not alter the prognosis. Each tumor was graded 1 to 4 on the basis of cellularity, pleomorphism, mitotic index, and necrosis. No significant correlation was noted between survival and either grade or mitotic rate. Survival was improved when total rather than subtotal resection was done. This was most marked in patients with a small lesion, which may reflect the difficulty in adequately excising large tumors. Adjuvant radiation or chemotherapy did not appear to affect survival. The MPNST is an aggressive uncommon neoplasm, and large tumor size, the presence of neurofibromatosis, and total resection are the most important prognostic indicators.     

VERIDOS: A New Tool for Quality Assurance for Intensity Modulated Radiotherapy

Background: The use of intensity modulated radiation fields needs an extended quality assurance concept. This consists of a linac related part and a case related part. Case related means the verification of an individual treatment plan, optimized on a CT data set of an individual patient and prepared for the treatment of this patient. This part of the quality assurance work is usually time consuming, delivers only partially quantitative results and is uncomfortable without additional help. It will be shown in this paper how the software VERIDOS will improve the optimization of the case related part of the quality assurance work. Material and Methods: The main function of the software is the quantitative comparison of the calculated dose distribution from the treatment planning software with the measured dose distribution of an irradiated phantom. Several additional functions will be explained. Two self-developed phantoms made of RW3 (solid water) and GAFCHROMIC films or Kodak EDR2 films for the measurement of the dose distributions were used. VERIDOS was tested with the treatment planning systems Helay-TMS and Brainscan. Results: VERIDOS is a suitable tool for the import of calculated dose matrices from the treatment planning systems Helax-TMS and Brainscan and of measured dose matrices exported from the dosimetry software Mephysto (PTW). The import from other treatment planning systems and scanning software applications for film dosimetry is generally possible. In such case the import function has to be adapted to the special header of the import matrix. All other functions of this software tool like normalization (automatically, manually), working with corrections (ground substraction, factors), overlay/comparison of dose distributions, difference matrix, cutting function (profiles) and export functions work reliable. Conclusions: VERIDOS improves the optimization of the case related part of the quality assurance work for intensity modulated radiation therapy (IMRT). The diverse functions of the software offer the radiation physicist a wide base to verify the IMRT plan independent from the mode of its delivery (compensator technology or MLC technology). Hintergrund: Der Einsatz intensitätsmodulierter Felder setzt ein erweitertes Qualitätssicherungskonzept voraus. Dies gliedert sich in einen rein maschinenbezogenen und einen fallbezogenen Teil. Als fallbezogen wird hier die Überprüfung eines individuellen Bestrahlungsplans, der am CT-Datensatz eines speziellen Patienten optimiert wurde und der für dessen Bestrahlung vorgesehen ist, verstanden. Dieser Teil der Qualitätssicherung nimmt in aller Regel viel Zeit in Anspruch, erbringt nur teilweise quantitative Ergebnisse und ist ohne zusätzliche Hilfsmittel wenig komfortabel. In den vorliegenden Ausführungen soll gezeigt werden, wie dieses Programm zur Optimierung des fallbezogenen Teils der Qualitätssicherung beiträgt. Material und Methode: Die Hauptfunktion des Programms besteht darin, im Bestrahlungsplanungsprogramm berechnete Dosisverteilungen mit im Phantom gemessenen Dosisverteilungen quantitativ zu vergleichen. Weitere Funktionen werden erläutert. Zur Erfassung der Dosisverteilung wurden zwei selbst entwickelte RW3-Phantome und sowohl GAFCHROMIC- als auch Kodak EDR2-Filme eingesetzt. Getestet wurde VERIDOS mit den Bestrahlungsplanungssystemen Helax-TMS und Brainscan. Ergebnisse: VERIDOS eignet sich zum Import von berechneten Dosismatrizen aus den Bestrahlungsplanungssystemen Helax-TMS und Brainscan. Es eignet sich zum Import von gemessenen und ausgelesenen Dosismatrizen aus der PTW-Dosimetriesoftware Mephysto. Der Import aus weiteren Bestrahlungsplanungssystemen und PC-Scannerapplikationen zur Filmdosimetrie ist generell möglich. In solch einem Fall müsste die Importfunktion an den jeweiligen Header der zu importierenden Matrix angepasst werden. Alle Funktionen des Auswerteprogramms wie Normierung (automatisch, manuell), Einfügen von Korrekturen (Schleierabzug, Faktoren), Überlagerung/Vergleich von Dosisverteilungen, Differenzbildung, Herausschneiden von überlagerten Profilen und Export funktionieren zuverlässig. Schlussfolgerungen: VERIDOS leistet einen Beitrag zur Optimierung der fallbezogenen Qualitätssicherung bei der intensitätsmodulierten Strahlentherapie (IMRT). Die verschiedenen Funktionen innerhalb des Programms bieten dem Klinikphysiker eine breite Basis zur Beurteilung der Güte der Realisierbarkeit des IMRT-Planes unabhängig davon, ob die Dosismodulation mit Kompensatoren oder MLC gewährleistet wird.     

Medulloblastoma: II. A pathobiologic overview.

The pathobiology of medulloblastoma is reviewed in light of emerging data regarding its immunocytochemical and cytobiologic, as well as molecular biologic, characteristics. The nature of the lesion, particularly its nosologic relation to primitive neuroectodermal tumor, is discussed, as is its place in the World Health Organization classification of tumors of the central nervous system.     

Endodermal sinus tumor (yolk sac tumor) of the ear

Endodermal sinus tumors (yolk sac tumors) are malignant germ cell tumors that usually arise in the gonads. We report what is, to our knowledge, the first known case of an endodermal sinus tumor of the ear. The tumor was present in a developmentally delayed child with an abnormal temporal bone and exhibited histopathologic and immunocytochemical features identical to those of endodermal sinus tumors of gonadal origin. The tumor resolved after chemotherapy, and the patient remained alive without evidence of disease at the time of this writing. The purpose of this report is to add a rare tumor to the differential diagnosis of neoplasms of the ear in children and to familiarize otorhinolaryngologists and head and neck surgeons with its pathologic features and clinical management.     

Liver function in acute viral hepatitis as determined by a hepatocyte-specific ligand: 99mTc-galactosyl-neoglycoalbumin.

Twelve patients with recently diagnosed acute viral hepatitis underwent serial 99mTc-galactosyl neoglycoalbumin scanning of the liver (for up to 8 mo). Injection of 99mTc-galactosyl neoglycoalbumin (150 mBq) at a rate of 3.5 mg (50 nmol; 1 ml) revealed that the liver is the exclusive site of tracer uptake. Simulation of 99mTc-galactosyl neoglycoalbumin kinetics allowed quantification of galactosyl neoglycoalbumin binding to human hepatic binding protein. Return of liver function test scores to normal values was associated in two patients with hepatitis A, in four patients with hepatitis B and in two patients with non-A, non-B hepatitis virus infection, with increases in hepatic binding protein concentration (up to three times the initial concentration), binding rate constant and hepatic blood flow. In the other four patients (three patients with hepatitis B and one patient with cytomegalovirus infection) a prolonged course of disease was monitored. In the mean, hepatic binding protein increased from 0.41 +/- 0.11 mumol/L after onset of acute hepatitis (n = 12) to 0.78 +/- 0.21 mumol/L after 6 mo of follow-up (n = 10) (p less than 0.001). During this period, binding rate constant (72.4 +/- 12.6 vs. 82 +/- 11.5 mumol/L/sec; p less than 0.05) and hepatic blood flow (0.027 +/- 0.0051 vs. 0.031 +/- 0.0083 L/sec; p less than 0.05) increased. Hepatic binding protein concentration correlated highly with actual laboratory test results for liver function (r = 0.98; p = 0.0001). We conclude that scintigraphic evaluation of functional liver cell mass using the new receptor-tracer 99mTc-galactosyl neoglycoalbumin could provide an in vivo diagnostic means of quantifying liver function and assessing liver morphology. In addition, our findings suggest that changes in hepatic binding protein-receptor concentration are likely to occur in vivo.     

Pituitary Adenoma with Tumoral Granulomatous Reaction

Herein, we report a unique case of an adult male with a corticotrophic pituitary adenoma of silent subtype 1 exhibiting conspicuous idiopathic tumoral noncaseating granulomatous inflammation. The lesion was unassociated with clinical or laboratory evidence of either systemic sarcoidosis or infection. Histochemical and polymerase chain reaction (PCR) studies revealed neither fungi nor tubercle bacilli. We suggest that tumoral production of an as yet uncharacterized antigen may have induced the granulomatous inflammatory reaction.