Treatment results among adults with childhood tumors: a 20-year experience

Controversy exists regarding the most appropriate treatment for the rare adult patient who develops a so-called pediatric cancer. We have reviewed our 20-year experience with these patients and analyzed their outcome. A total of 299 patients with rhabdomyosarcoma (106), Wilms' tumor (97), and neuroblastoma (96) were evaluated and treated at Stanford University Medical Center between January 1967 and December 1987. Only 26 of these patients (8.7%) were diagnosed during "adulthood"; their age range was 18-67 years, median 23 years. Wilms' tumor; Five patients presented with Wilms' tumor at age greater than or equal to 18 years; four had unfavorable histology. All underwent multimodality therapy; however, only two have survived, one currently disease-free and one with disease. Neuroblastoma: Five patients presented with neuroblastoma at age greater than or equal to 18 years. Four underwent attempted surgical resection, post-operative irradiation (RT), and chemotherapy (CT); the other received no adjuvant CT. Only two of the five patients survive, both with disease. Rhabdomyosarcoma: Of the 16 adults (greater than or equal to 21 years) with rhabdomyosarcoma, 14 (87%) had advanced Intergroup Rhabdomyosarcoma Study-group disease (eight Group III, six Group IV). All 16 underwent aggressive multimodality therapy. At 10 months-16 years follow-up, only five patients survive, four of whom are apparently cured of their tumor. Neither histologic subtype nor site of presentation were of prognostic value. This series demonstrates that adults with Wilms' tumor, neuroblastoma, or rhabdomyosarcoma have a worse prognosis than do children with the same diagnosis. Possible explanations for this disparity in outcome include different tumor biology, less tolerance for treatment, and different natural history among adults relative to children.     

Gamma interferon responses induced by a panel of recombinant and purified mycobacterial antigens in healthy,non-mycobacterium bovis BCG-vaccinated Malawian young adults

We have previously shown that young adults living in a rural area of northern Malawi showed greater gamma interferon (IFN-gamma) responses to purified protein derivatives (PPD) prepared from environmental mycobacteria than to PPD from Mycobacterium tuberculosis. In order to define the mycobacterial species to which individuals living in a rural African population have been exposed and sensitized, we tested T-cell recognition of recombinant and purified antigens from M. tuberculosis (38 kDa, MPT64, and ESAT-6), M. bovis (MPB70), M. bovis BCG (Ag85), and M. leprae (65 kDa, 35 kDa, and 18 kDa) in >600 non-M. bovis BCG-vaccinated young adults in the Karonga District of northern Malawi. IFN-gamma was measured by enzyme-linked immunosorbent assay (ELISA) in day 6 supernatants of diluted whole-blood cultures. The recombinant M. leprae 35-kDa and 18-kDa and purified native M. bovis BCG Ag85 antigens induced the highest percentages of responders, though both leprosy and bovine tuberculosis are now rare in this population. The M. tuberculosis antigens ESAT-6 and MPT64 and the M. bovis antigen MPB70 induced the lowest percentages of responders. One of the subjects subsequently developed extrapulmonary tuberculosis; this individual had a 15-mm-diameter reaction to the Mantoux test and responded to M. tuberculosis PPD, Ag85, MPT64, and ESAT-6 but not to any of the leprosy antigens. We conclude that in this rural African population, exposure to M. tuberculosis or M. bovis is much less frequent than exposure to environmental mycobacteria such as M. avium, which have antigens homologous to the M. leprae 35-kDa and 18-kDa antigens. M. tuberculosis ESAT-6 showed the strongest association with the size of the Mantoux skin test induration, suggesting that among the three M. tuberculosis antigens tested it provided the best indication of exposure to, or infection with, M. tuberculosis.     

The ability of heat-killed Mycobacterium vaccae to stimulate a cytotoxic T-cell response to an unrelated protein is associated with a 65 kilodalton heat-shock protein

Exogenous antigens are generally presented by Class II major histocompatibility (MHC) molecules. When administered with an adjuvant, however, they are capable of inducing a CD8+ T-cell response where antigen recognition is associated with Class I MHC. Accordingly, immunization with soluble ovalbumin (OVA) alone does not activate CD8+ cytotoxic T cells (CTL) but when given in complete Freund's adjuvant (CFA), or in formulations of a number of novel adjuvants, an OVA-specific CD8+ CTL response can be detected. We show in this report that immunization with soluble OVA mixed with heat-killed Mycobacterium vaccae, but not with other common pathogenic and saprophytic mycobacteria, can activate OVA-specific CD8+ CTL. An OVA-specific CTL response is detected when mice are immunized by either the intraperitoneal or intranasal route and their spleen cells are re-stimulated in vitro. Adjuvant activity of heat-killed M. vaccae is present in M. vaccae culture filtrate, in soluble protein components of whole M. vaccae and in the 65 kDa heat-shock protein (hsp) of M. vaccae. Mycobacterium vaccae has previously been shown to have no adverse side-effects in humans. The current results suggest that M. vaccae may be useful as an adjuvant for vaccines and other immunotherapies where CD8+ CTL responses to exogenous proteins are crucial.     

In vitro effects of desflurane, sevoflurane, isoflurane, and halothane in isolated human right atria

BACKGROUND: Direct myocardial effects of volatile anesthetics have been studied in various animal species in vitro. This study evaluated the effects of equianesthetic concentrations of desflurane, sevoflurane, isoflurane, and halothane on contractile parameters of isolated human atria in vitro. METHODS: Human right atrial trabeculae, obtained from patients undergoing coronary bypass surgery, were studied in an oxygenated (95% O2-5% CO2) Tyrode's modified solution ([Ca2+]o = 2.0 mM, 30 degrees C, stimulation frequency 0.5 Hz). The effects of equianesthetic concentrations (0.5, 1, 1.5, 2, and 2.5 minimum alveolar concentration [MAC]) of desflurane, sevoflurane, isoflurane, and halothane on inotropic and lusitropic parameters of isometric twitches were measured. RESULTS: Isoflurane, sevoflurane, and desflurane induced a moderate concentration-dependent decrease in active isometric force, which was significantly lower than that induced by halothane. In the presence of adrenoceptor blockade, the desflurane-induced decrease in peak of the positive force derivative and time to peak force became comparable to those induced by isoflurane. Halothane induced a concentration-dependent decrease in time to half-relaxation and a contraction-relaxation coupling parameter significantly greater than those induced by isoflurane, sevoflurane and desflurane. CONCLUSIONS: In isolated human atrial myocardium, desflurane, sevoflurane, and isoflurane induced a moderate concentration-dependent negative inotropic effect. The effect of desflurane on time to peak force and peak of the positive force derivative could be related to intramyocardial catecholamine release. At clinically relevant concentrations, desflurane, sevoflurane, and isoflurane did not modify isometric relaxation.     

Disease severity impacts the relationship of apelin with arterial function in patients with rheumatoid arthritis

Apelin can improve arterial function by enhancing the expression of endothelial nitric oxide synthase but this effect depends markedly on endothelial integrity. We hypothesized that inflammation influences the potential impact of apelin on arterial function in rheumatoid arthritis (RA). We assessed the associations of apelin concentrations with arterial stiffness (pulse wave velocity), wave reflection (augmentation index, reflected wave pressure, and reflection magnitude), and pressure pulsatility (central systolic pressure (CSP), central pulse pressure (CPP), peripheral pulse pressure (PPP), pulse pressure amplification (PPamp), and forward wave pressure (Pf)) among 170 RA patients without cardiovascular disease. In multivariable regression models, apelin concentrations were not independently associated with arterial function measures (p?≥?0.15) in all patients. Inflammation markers were not consistently associated with apelin levels but joint deformity counts, Disease Activity Score in 28 joints (DAS28), and erythrocyte sedimentation rate (ESR) impacted apelin-pressure pulsatility relations (interaction p?≤?0.05). In stratified analysis, apelin was associated with CSP (partial r?=???0.33, p?=?0.01), CPP (partial r?=???0.26, p?=?0.04), PPamp (partial r?=?0.27, p?=?0.03), and Pf (partial r?=???0.33, p?=?0.01) in patients without but not with joint deformities; apelin was related to CSP (partial r?=???0.24, p?=?0.05) in those with a DAS28 joint <?2.8 (median value) (partial r?=???0.24, p?=?0.05) but not ≥?2.8, and to CSP (partial r?=???0.36, p?=?0.003) in those with an erythrocyte sedimentation rate <?13 mm/h (median value) but not ≥?13 mm/h. Apelin is associated with reduced pressure pulsatility in RA patients without but not with a high inflammatory burden. A loss of apelin protective effects on arterial function may contribute to the link between RA severity and cardiovascular risk.     

Comparison of total body irradiation versus non-total body irradiation containing regimens for de novo acute myeloid leukemia in children

With limited data comparing hematopoietic cell transplant outcomes between myeloablative total body irradiation (TBI) containing and non-TBI regimens in children with de novo acute myeloid leukemia, the aim of this study was to compare transplant-outcomes between these regimens. Cox regression models were used to compare transplant-outcomes after TBI and non-TBI regimens in 624 children transplanted between 2008 and 2016. Thirty two percent (n=199) received TBI regimens whereas 68% (n=425) received non-TBI regimens. Five-year non-relapse mortality was higher with TBI regimens (22% vs. 11%, P<0.0001) but relapse was lower (23% vs. 37%, P<0.0001) compared to non-TBI regimens. Consequently, overall (62% vs. 60%, P=1.00) and leukemia-free survival (55% vs. 52%, P=0.42) did not differ between treatment groups. Grade 2-3 acute graft versus host disease was higher with TBI regimens (56% vs. 27%, P<0.0001) but not chronic graft versus host disease. The 3-year incidence of gonadal or growth hormone deficiency was higher with TBI regimens (24% vs. 8%, P<0.001) but there were no differences in late pulmonary, cardiac or renal impairment. In the absence of a survival advantage, the choice of TBI or non-TBI regimen merits careful consideration with the data favoring non-TBI regimens to limit the burden of morbidity associated with endocrine dysfunction.