ICAM-1 deficiency suppresses host allosensitization and rejection of MHC-disparate corneal transplants

BACKGROUND: We used a murine model of orthotopic corneal transplantation to determine whether host deficiency in ICAM-1 promotes survival of corneal grafts with different degrees of allodisparity. METHODS: ICAM-1-/- and wild-type C57BL/6 (ICAM-1+/+) received corneal grafts from the following strains of mice: BALB/c (fully mismatched), BALB.b (mismatched at multiple minor H only), or B10.D2 [including major histocompatibility complex (MHC) mismatch]. Graft rejection, induction of allospecific delayed-type hypersensitivity (DTH) responses, and leukocytic infiltration of grafts were measured. RESULTS: There were no differences in long-term survival of allografts that were either fully mismatched or had only minor H disparity in ICAM-1+/+ vs. ICAM-1-/-hosts. However, whereas B10.D2 grafts were accepted in only 58% of the ICAM-1+/+ hosts, graft survival in ICAM-1-/- recipients was 100% (P=0.006). Moreover, none of the ICAM-1-/- mice receiving B10.D2 grafts developed allospecific DTH. CONCLUSIONS: Prolonged survival seen in MHC-mismatched grafts in ICAM-1-/- mice, along with a suppressed DTH response to donor alloantigens after transplantation, suggest that ICAM-1 is associated with recipient sensitization to MHC alloantigens.     

Serum antibodies to JC virus, BK virus, simian virus 40, and the risk of incident adult astrocytic brain tumors.

Genomic sequences of the human polyomaviruses, JC virus (JCV) and BK virus (BKV), and simian virus 40 (SV40) have been reported from several types of human brain tumors, but there have been no population-based seroepidemiologic studies to evaluate the association between polyomavirus infection and brain tumors. We conducted a case-control study, nested within a prospective cohort, to investigate the association between antibodies to JCV, BKV, and SV40, as measured in serum collected 1-22 years before diagnosis and incident primary malignant brain tumors. Brain tumor cases (n = 44) and age-, gender-, and race-matched controls (n = 88) were identified from participants of two specimen banks in Washington County, Maryland. IgG antibodies to the capsid proteins of JCV and BKV were assessed using ELISAs. SV40-neutralizing antibodies were measured using plaque neutralization assays. Similar to the general population, the prevalence of JCV and BKV infection was high in our study population (77 and 85%, respectively). Antibodies to SV40 were less prevalent (11%). The odds ratio for subsequent brain tumor development was 1.46 [95% confidence interval (CI), 0.61-3.5] for JCV, 0.66 for BKV (95% CI, 0.22-1.95), and 1.00 for SV40 (95% CI, 0.30-3.32). Given the high prevalence of JCV and BKV infections and the millions who were potentially exposed to SV40 through contaminated polio vaccines, future studies should attempt to replicate these findings.     

Participation of patients 65 years of age or older in cancer clinical trials.

PURPOSE: Although 61% of new cases of cancer occur among the elderly, recent studies indicate that the elderly comprise only 25% of participants in cancer clinical trials. Further investigation into the reasons for low elderly participation is warranted. Our objective was to evaluate the participation of the elderly in clinical trials sponsored by the National Cancer Institute (NCI) and assess the impact of protocol exclusion criteria on elderly participation. PATIENTS AND METHODS: We conducted a retrospective analysis using NCI data, analyzing patient and trial characteristics for 59,300 patients enrolled onto 495 NCI-sponsored, cooperative group trials, active from 1997 through 2000. Our main outcome measure was the proportion of elderly patients enrolled onto cancer clinical trials compared with the proportion of incident cancer patients who are elderly. RESULTS: Overall, 32% of participants in phase II and III clinical trials were elderly, compared with 61% of patients with incident cancers in the United States who are elderly. The degree of underrepresentation was more pronounced in trials for early-stage cancers than in trials for late-stage cancers (P <.001). Furthermore, protocol exclusion criteria on the basis of organ-system abnormalities and functional status limitations were associated with lower elderly participation. We estimate that if protocol exclusions were relaxed, elderly participation in cancer trials would be 60%. CONCLUSION: The elderly are underrepresented in cancer clinical trials relative to their disease burden. Older patients are more likely to have medical histories that make them ineligible for clinical trials because of protocol exclusions. Insurance coverage for clinical trials is one step toward improvement of elderly access to clinical trials. Without a change in study design or requirements, this step may not be sufficient.     

Insulin resistance is associated with decreased clinical status in cystic fibrosis

Patients with cystic fibrosis (CF) frequently have impaired glucose tolerance and progression to diabetes (DM) with clinical features of both insulin-dependent and non-insulin-dependent diabetes. One feature of non-insulin-dependent DM is decreased insulin sensitivity, also known as insulin resistance. The goal of this study was to determine whether patients with CF exhibit insulin resistance and to determine the potential effect of insulin resistance on clinical status. We also sought to determine whether insulin resistance is associated with a specific CF genotype. We studied 18 patients with CF (8 with normal glucose tolerance, 5 with impaired glucose tolerance, 5 with DM), and 20 lean control subjects matched for age, weight, and sex. All control subjects had normal glucose tolerance. The clinical status for each CF patient was determined according to a modified National Institutes of Health scoring system. Each subject underwent a three-step hyperinsulinemic euglycemic clamp (insulin doses of 10, 40, 120 mU/m ² per minute). Results from the 120 mU/m ² per minute infusion defined maximal glucose disposal rate (defined in milligrams per kilogram body weight per minute) at steady state with peripheral insulin levels 195 ± 20 mU/ml. Subjects with CF demonstrated insulin resistance (control subjects = 13.6 ± 1.1, patients with CF = 10.2 ± 1.6 mg/kg per minute; p = 0.003). When each subgroup was compared separately with control subjects, all subgroups were statistically insulin resistant (glucose disposal rate, patients with CF and normal glucose tolerance = 10.8; those with impaired glucose tolerance = 8.4; those with DM = 10.1 mg/kg per minute), and the patients with CF with impaired glucose tolerance were the most insulin resistant. When plotted versus glucose disposal rate, a striking positive correlation between worsened clinical status and insulin resistance ( r = 0.85) is demonstrated. Furthermore, there is no correlation between insulin resistance and fasting blood glucose, subject age, or percent ideal body weight (all r values not significant). In conclusion, patients with CF exhibit insulin resistance that is associated with worsened clinical status. We believe it is the combination of insulin resistance and decreased insulin secretion that is responsible for the high incidence of CF-related diabetes. (J Pediatr 1997;130:948-56)     

Atypical teratoid/rhabdoid tumors (ATRT): improved survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy.

PURPOSE: To describe clinical features, therapeutic approaches, and prognostic factors in pediatric patients with atypical teratoid/rhabdoid tumors (ATRT) treated at St Jude Children's Research Hospital (SJCRH). PATIENTS AND METHODS: Primary tumor samples from patients diagnosed with ATRT at SJCRH between July 1984 and June 2003 were identified. Pathology review included histologic, immunohistochemical analysis, and fluorescence in situ hybridization for SMARCB1 (also known as hSNF5/INI1) deletion. Clinical records of patients with pathologic confirmation of ATRT were reviewed. RESULTS: Thirty-seven patients were diagnosed with ATRT at SJCRH during the 19-year study interval. Six patients were excluded from this clinical review based on pathologic or clinical criteria. Of the remaining 31 patients, 22 were younger than 3 years. Posterior fossa primary lesions and metastatic disease at diagnosis were more common in younger patients with ATRT. All patients underwent surgical resection; 30 received subsequent chemotherapy. The majority of patients aged 3 years or older received postoperative craniospinal radiation. Two-year event-free (EFS) and overall survival (OS) of children aged 3 years or older (EFS, 78% + 14%; OS, 89% +/- 11%) were significantly better than those for younger patients (EFS, 11% +/- 6%; OS, 17% +/- 8%); EFS, P = .009 and OS, P = .0001. No other clinical characteristics were predictive of survival. Three of four patients 3 years or older with progressive disease were successfully rescued with ifosfamide, carboplatin, and etoposide therapy. CONCLUSION: Children presenting with ATRT before the age of 3 years have a dismal prognosis. ATRT presenting in older patients can be cured using a combination of radiation and high-dose alkylating therapy. Older patients with relapsed ATRT can have salvage treatment using ICE chemotherapy.     

Markers of past infection with simian virus 40 (SV40) and risk of incident non-Hodgkin lymphoma in a Maryland cohort.

Simian virus 40 (SV40) genome sequences have been detected in human non-Hodgkin lymphoma (NHL) tissues, and past infection with SV40 may be a risk factor for NHL. We conducted a population-based nested case-control study to investigate the association between serum antibodies to SV40 and incident NHL. Two research serum banks were established in Washington County, MD, with >45,000 volunteers contributing blood samples collected in 1974 and 1989. Incident cases of NHL diagnosed through 2002 (n = 170) were identified among participants by linkage to population-based cancer registries. Two controls were matched to each case (n = 340) on age, sex, and date of blood draw. Circulating immunoglobulin G antibodies to SV40 were measured using virus-like particle (VLP) ELISA. Positive samples were tested for cross-reactivity with JC virus (JCV) and BK virus (BKV) through competitive inhibition assays. Associations between SV40 antibody seropositivity and NHL were estimated using conditional logistic regression. Whereas SV40 antibodies were detected by VLP ELISA in 15% of cases and 10% of controls [matched odds ratio (OR), 1.97; 95% confidence interval (95% CI), 1.03-3.76], the SV40 reactivity of 85% of the SV40 antibody-positive sera was decreased by adsorption with BKV and/or JCV VLPs. Antibodies specific for SV40 (not cross-reactive) were identified in only 1.8% of cases and 1.6% of controls (OR, 1.51; 95% CI, 0.41-5.52). Our findings suggest that past infection with SV40 is not associated with an increased risk of developing NHL.     

Positive correlation of insulin-like growth factor-II with proliferating cell index in patients with colorectal neoplasia.

BACKGROUND: Insulin-like growth factor-II (IGF-II) stimulates cell proliferation and is considered a potential risk factor for colorectal cancer. Tumor levels of IGF-II seem to positively correlate with colorectal cancer cell proliferation. This investigation examined the association of circulating IGF-II to the proliferating cell index (PCI) of tumor and matched normal mucosa in patients with colorectal neoplasia. METHODS: Circulating IGF-II level (ng/mL) was determined in the peripheral blood plasma by ELISA. The proliferating cells in tumor or matched normal mucosa were immunohistochemically stained using the primary antibody against Ki-67. Computer image analysis was used and PCI was expressed as the percentage of Ki-67-positive cells/total counted cells. RESULTS: Sixty-four patients were evaluated; 45 had colorectal neoplasia (27 males/18 females; mean age, 66.8 +/- 11.8 years) and 19 had hyperplastic polyps (6 males and 13 females; mean age, 58.4 +/- 14.4 years). Among patients with colorectal neoplasia, blood IGF-II levels were positively correlated with PCI in the matched normal mucosa (r = 0.46, P < 0.05) but not in the tumor. In patients with hyperplastic polyps, blood IGF-II levels were not correlated with the PCI in the polyps. Blood IGF-II levels were higher in colorectal cancer patients with Dukes' C/D stage (P < 0.01) or with positive lymph nodes (P < 0.01). CONCLUSION: Circulating IGF-II positively correlated with PCI in normal colonic mucosa of patients with colorectal neoplasia, suggesting that IGF-II may have a role in initiating the carcinogenic pathway by stimulating cell proliferation. Blood IGF-II was increased in advanced colorectal cancer, indicating that it might enhance colorectal cancer progression and be a useful marker of poor prognosis.