Samuel H. Pepkowitz

Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients.

Cancer vaccine trials have failed to yield robust immune-correlated clinical improvements as observed in animal models, fueling controversy over the utility of human cancer vaccines. Therapeutic vaccination represents an intriguing additional therapy for glioblastoma multiforme (GBM; grade 4 glioma), which has a dismal prognosis and treatment response, but only early phase I vaccine trial results have been reported. Immune and clinical responses from a phase II GBM vaccine trial are reported here. IFN-gamma responsiveness was quantified in peripheral blood of 32 GBM patients given therapeutic dendritic cell vaccines. Posttreatment times to tumor progression (TTP) and survival (TTS) were compared in vaccine responders and nonresponders and were correlated with immune response magnitudes. GBM patients (53%) exhibited >or=1.5-fold vaccine-enhanced cytokine responses. Endogenous antitumor responses of similar magnitude occurred in 22% of GBM patients before vaccination. Vaccine responders exhibited significantly longer TTS and TTP relative to nonresponders. Immune enhancement in vaccine responders correlated logarithmically with TTS and TTP spanning postvaccine chemotherapy, but not with initial TTP spanning vaccination alone. This is the first report of a progressive correlation between cancer clinical outcome and T-cell responsiveness after therapeutic vaccination in humans and the first tracing of such correlation to therapeutically exploitable tumor alteration. As such, our findings offer unique opportunities to identify cellular and molecular components of clinically meaningful antitumor immunity in humans.

Tuberous sclerosis in a 20-week gestation fetus: immunohistochemical study.

Abstract We report an autopsy case of tuberous sclerosis complex (TSC) in a 20-week gestational age female fetus. The brain showed lesions suggestive of early cortical tubers and subependymal hamartomatous nodules. The large cells within these nodular clusters were variably immunoreactive for glial fibrillary acidic protein (GFAP) and vimentin and negative for synaptophysin and neurofilament. Subependymal radial glia expressed both vimentin and GFAP, but subpial radial glia either did not express these markers (in contrast to an age-matched control) or were absent. Tuberin expression was noted in heterotopic neurons in the white matter and brain cells consistent with Cajal Retzius cells in the neocortical molecular layer, very weakly in superficial cortical neurons, neurons in the basal ganglia, Purkinje cells and external granular cells of cerebellum, cranial nerve nuclei neurons, occasional germinal matrix cells, ependymal cells, choroid plexus epithelium, and pituitary gland neuroendocrine cells; it was not seen within the cells of subependymal nodules. The pattern of tuberin immunoreactivity was similar to that which we have observed in older TSC patients. Proliferating cell labeling indexes were comparable in the germinal matrix of the TSC patient and an age-matched control. Abnormal subpial radial glia may be responsible for some of the neuronal migration abnormalities that appear to result in neocortical tubers.

Combination vincristine and plasma exchange as initial therapy in patients with thrombotic thrombocytopenic purpura: one institution's experience and review of the literature

BACKGROUND:  Thrombotic thrombocytopenic purpura (TTP) was once a highly fatal disease with mortality reaching nearly 95 percent; however, application of therapeutic plasma exchange (TPE) has dramatically increased survival. Nevertheless, mortality remains substantial (10%‐30% in many published reports), requiring the search for more efficacious treatments. Vincristine (VCR) has been generally reserved for refractory TTP. Despite its effectiveness in a salvage mode, VCR has not been widely advocated as first‐line therapy in conjunction with TPE. We previously reported improved survival when VCR and TPE were administered at presentation in patients treated from 1979 to 1994. Utilizing this standardized approach, outcomes of an additional group of patients and the results of a literature review of VCR therapy for TTP are reported.

Intrauterine growth restriction caused by underlying congenital cytomegalovirus infection

BACKGROUND Human cytomegalovirus (HCMV) is the major viral etiology of congenital infection and birth defects. Fetal transmission is high (30%-40%) in primary maternal infection, and symptomatic babies have permanent neurological, hearing, and vision defects. Recurrent infection is infrequently transmitted (2%) and largely asymptomatic. Congenital infection is also associated with intrauterine growth restriction (IUGR). METHODS To investigate possible underlying HCMV infection in cases of idiopathic IUGR, we studied maternal and cord sera and placentas from 19 pregnancies. Anti-HCMV antibodies, hypoxia-related factors, and cmvIL-10 were measured in sera. Placental biopsy specimens were examined for viral DNA, expression of infected cell proteins, and pathology. RESULTS Among 7 IUGR cases, we identified 2 primary and 3 recurrent HCMV infections. Virus replicated in glandular epithelium and lymphatic endothelium in the decidua, cytotrophoblasts, and smooth muscle cells in blood vessels of floating villi and the chorion. Large fibrinoids with avascular villi, edema, and inflammation were significantly increased. Detection of viral proteins in the amniotic epithelium indicated transmission in 2 cases of IUGR with primary infection and 3 asymptomatic recurrent infections. CONCLUSIONS Congenital HCMV infection impairs placental development and functions and should be considered as an underlying cause of IUGR, regardless of virus transmission to the fetus.

A case-control study of the impact of WBC reduction on the cost of hospital care for patients undergoing coronary artery bypass graft surgery.

BACKGROUND : WBC reduction of blood components may reduce the incidence of transfusion reactions. The cost of this intervention might be offset by a reduction in the incidence of postoperative infection, thereby reducing the length of hospital stay and thus the cost of care for patients receiving transfusion. Cedars‐Sinai Medical Center provided WBC‐reduced blood components to all patients for a period of 2 years, creating an opportunity to compare the incidence of postoperative infection, length of hospital stay, and total hospital costs for patients undergoing coronary artery bypass graft surgery, before, during, and after WBC reduction.

Transfusion-associated Graft-versus-Host Disease in an Immunocompetent Patient

Transfusion-associated graft-versus-host disease (TAGVHD) is a rare complication of transfusion (1) that occurs when immunocompetent donor lymphocytes attack host tissues expressing foreign histoco...

Treatment of thrombotic thrombocytopenic purpura: A role for early vincristine administration

Plasma exchange (PE) is considered first‐line treatment for thrombotic thrombocytopenic purpura (TTP) to the point that many clinicians regard it as definitive therapy. Studies have reported response rates to PE ranging from 39% to 78%. In our experience, a minority of patients have been cured solely by PE. While adjuvant therapies (e.g., vincristine, splenectomy) have proved effective in anecdotal reports, protocols using these therapies in the treatment of TTP have not been established.

Platelet-Rich Plasma for the Replenishment of Bone

This review examines the use of platelet-rich plasma (PRP) in the treatment of bone injuries and to stimulate bone formation. Studies examining both in vivo bone healing and in vitro actions of PRP on osteoblasts are reviewed. Overall, the available literature suggests that PRP does not appreciably impact bone healing or induce bone formation. However, there is some evidence to suggest that PRP might augment recruitment of osteoblast progenitors to injection sites or in sites expected to experience delayed healing. In this capacity PRP might be utilized to initiate repair of an otherwise poorly healing skeletal lesion. The demonstration that PRP is a viable therapy is hindered by a lack of standardized criteria for what constitutes PRP, and more studies are needed to compare the efficacy of PRP to that of transforming growth factor-β or platelet-derived growth factor used as sole agents.

Disseminated Coccidioidomycosis in Pregnancy

Coccidioidomycosis is a fungal infection contracted through the inhalation of airborne spores, which are most frequently present in desert areas of the southwestern United States and Mexico. Primary immune response to infection is by T(H)1, a subset of helper T cells. Although pulmonary symptoms are most common, hematogenous systemic spread can also occur. Pregnancy is a well-noted risk factor for disseminated Coccidioides infection. The objective of this review is to provide an overview of coccidioidomycosis and to review immunologic and hormonal factors that increase risk of dissemination in pregnancy. Dissemination may occur more frequently in pregnant patients than in nonpregnant women because of shifts in T-cell immunity, changes in cytokine production, and increased hormone levels. There is disagreement regarding the precise incidence of systemic spread in pregnancy, but most sources agree that risk is substantially increased and vigilance must be high in patients with exposures in endemic areas.

Therapeutic Plasma Exchange: An Underutilized Therapeutic Modality?

Abstract:  Since its clinical availability approximately 25 years ago, therapeutic plasma exchange (TPE) has become recognized as appropriate primary therapy for many diverse medical conditions. In some aspects TPE has been constrained in its use according to schedules of efficacy. Expansion of TPE to other indications is likely once attention is focused on its ability to enable patients to avoid potentially toxic pharmacologic interventions if employed as a chronic therapy, and especially when it is accepted that adjunctive use, not only a curative role, is a valuable use of this therapeutic modality.