Advances in allogeneic stem cell transplantation: directing graft-versus-leukemia at solid tumors

Allogeneic stem cell transplantation was originally developed as a method to rescue hematopoietic function following high dose "myeloablative" therapy in the treatment of hematological malignancies. In the first two decades of its use, dose-intensive chemotherapy alone was credited with curing those patients who achieved sustained remission following this procedure. However, more recently investigators have come to recognize that antineoplastic effects mediated by immunocompetent donor T-cells transplanted with the stem cell allograft can be induced against hematological malignancies. Indeed, this graft-vs-leukemia (GVL) or graft-vs-tumor (GVT) effect is now felt to represent the principal modality required to sustain durable remissions of hematological malignancies following this approach. The powerful and potentially curative nature of the GVT effect in hematological cancers has recently lured oncologists into exploring the therapeutic potential of allogeneic stem cell transplantation as an investigational approach for treatment-refractory solid tumors. We review here the development and early clinical results of allogeneic stem cell transplantation as potential immunotherapy for solid tumors.     

Predicting the spatial dynamics of rabies epidemics on heterogeneous landscapes

Often as an epidemic spreads, the leading front is irregular, reflecting spatial variation in local transmission rates. We developed a methodology for quantifying spatial variation in rates of disease spread across heterogeneous landscapes. Based on data for epidemic raccoon rabies in Connecticut, we developed a stochastic spatial model of rabies spread through the state's 169 townships. We quantified spatial variation in transmission rates associated with human demography and key habitat features. We found that large rivers act as semipermeable barriers, leading to a 7-fold reduction in the local rates of propagation. By combining the spatial distribution of major rivers with long-distance dispersal we were able to account for the observed irregular pattern of disease spread across the state without recourse to direct assessment of host-pathogen populations.     

Isolated Langerhans cell histiocytosis of the vulva: a case report and review of the literature

Isolated Langerhans cell histiocytosis (LCH) of the female genital tract is very rare. A review of the literature revealed that only 15 cases of primary vulvar LCH have previously been published in the English literature. We describe an additional case of confined vulvar LCH. A 49-year-old woman presented with an ulcerous lesion that turned out to be LCH confined to the vulva only. After surgical excision, four recurrences followed, which were treated again by surgery. After the fourth recurrence, adjuvant radiotherapy was applied. When the fifth recurrence occurred, only surgical excision was performed, and the patient has now been disease-free for 51 months. There are no standard treatment options for this rare disease. The most effective treatment options still remain elusive. In our case in the end surgery proved to be effective.     

Primary malignant mediastinal germ cell tumours: improved prognosis with platinum-based chemotherapy and surgery.

A retrospective analysis was performed of 18 patients with primary malignant germ cell tumours of the mediastinum treated with platinum-based chemotherapy between 1977 and 1990. All seven patients with pure seminoma were treated initially with chemotherapy and four of these patients received additional mediastinal radiotherapy. Only one patient relapsed; his initial therapy had included radiotherapy and single-agent carboplatin and he was successfully salvaged with combination chemotherapy. With a follow-up of 11 to 117 months (median 41 months) all seven patients with seminoma remain alive and disease free giving an overall survival of 100%. Eleven patients had malignant non seminoma; following chemotherapy eight of these had elective surgical resection of residual mediastinal masses. Complete remission was achieved in nine (82%) patients, however, one of these patients died from bleomycin pneumonitis. With a follow-up of 12 to 113 months (median 55 months) eight of 11 (73%) patients with malignant mediastinal teratoma remain alive and disease free.     

A phase I study of combined UFT plus leucovorin and radiotherapy for pancreatic cancer

PURPOSE: This Phase I study combines tegafur and uracil (UFT) with leucovorin and conventional radiation for the treatment of pancreatic cancer. The design seeks to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of this regimen as well as to define a future Phase II dose level. METHODS: Patients with locally advanced and unresectable pancreatic cancer were treated with 45 Gy of radiation therapy. The initial UFT dose was 150 mg/m(2)/day given with leucovorin 90 mg/day, both divided into 3 daily doses for 35 days concurrent with radiation. UFT doses were escalated at increments of 50 mg/m(2)/day. Dose-limiting toxicity (DLT) was defined as Grade 3 or greater nausea, vomiting or diarrhea despite medical intervention; or Grade 3 or greater neutropenia/thrombocytopenia; or Grade 3 or greater hepatic toxicity; or inability of the patient to take 75% or more of the planned UFT/leucovorin; or radiotherapy interruption of greater than 1 week. The MTD for UFT/leucovorin was exceeded by one dose level when a certain dose caused DLT in 2 or more patients of 6. RESULTS: Five evaluable patients had Stage I resectable disease but had pathologic adenopathy. Seven had Stage II unresectable disease. Compliance with therapy was excellent. At a daily dose of 300 mg/m(2) of UFT, we noticed minimal diarrhea and hematologic toxicity with mild-moderate nausea, anorexia, and fatigue. Three patients had Grade 4 toxicity: 1 had neutropenia on Day 38, 1 had diarrhea on Day 55, and 1 had vomiting on Day 15. CONCLUSION: Oral UFT/leucovorin and radiation therapy offers patients a viable treatment option for pancreatic cancer. The major known toxicity of diarrhea was tolerable. The MTD was not reached in this study. Our current plan is to expand this into a Phase I/II trial beginning at a UFT dose of 300 mg/m(2) and correlate this with clinical pharmacologic parameters. The potential benefit of long bioavailability and oral delivery of UFT compares favorably with continuous infusion regimens without the added morbidity of a catheter and pump.     

Differential effect of prior event information on reaction time with respect to paranoid vs nonparanoid symptomatology.

The effect on reaction time, of prior information concerning the imperative stimulus, was investigated with respect to the dimension of paranoid vs nonparanoid symptomatology of schizophrenia. In the first experiment, the auditory warning signal was followed by the imperative stimulus, which was a straight line, a triangle or a rectangle. Prior information was provided by means of correlation between pitch of the warning signal and shape of the imperative stimulus. The task was to depress the telegraph key promptly at the onset of the imperative stimulus. Twenty chronic undifferentiated schizophrenics, 20 paranoid schizophrenics and 20 alcoholics participated in the experiment. Reaction time of the chronic undifferentiated schizophrenics increased, and reaction time of the paranoid schizophrenics decreased, when the prior event information was provided. In the second experiment, the imperative stimulus consisted of not only different shapes but also different colors. Reaction times of 20 chronic undifferentiated and 20 paranoid schizophrenics were again affected in opposite directions by prior information. In the third experiment, the imperative stimulus was either 1, 3 or 5 dark dots. Twenty each of the chronic undifferentiated and paranoid schizophrenics participated in the experiment. The opposite effects of prior information on reaction time with respect to the dimension of paranoid vs nonparanoid symptomatology, were again demonstrated. It was concluded that paranoid vs nonparanoid symptomatology is based on two elementary processes which are dichotomous and characteristically different from each other.