Pretransplantation CMV-specific T cells protect recipients of T-cell-depleted grafts against CMV-related complications

We have studied cytomegalovirus (CMV) immunity in 17 CMV-positive recipients of T-cell-depleted or T-cell-replete grafts. In recipients of T-cell-replete grafts, the patient's CMV-specific T-cell response was completely ablated. Because primary anti-CMV responses were rare during the first year, immunity depended essentially on the transfer of donor CMV-specific T cells and, therefore, on the CMV positivity of the donor. In the recipients of T-cell-depleted grafts, CMV-specific cytotoxic T cells were of recipient origin in 2 patients who underwent transplantation with CMV-negative donors and in 3 of 8 patients who underwent transplantation with CMV-positive donors, and they were of mixed or donor origin in the other 5 patients studied. Recipient CMV-specific T cells responded vigorously to antigen ex vivo and persisted for several years without replenishment by donor cells. Furthermore, they appeared to have a protective effect because CMV-related complications were absent in the patients with CMV-specific T cells of recipient origin. Clinical outcomes of a cohort of 91 patients corroborated the experimental results. Patients with recipient T cells in their blood were protected regardless of the donor immune status. Hence, when a T-cell depletion protocol is used that favors the survival of recipient T cells, the patient's pretransplantation CMV-specific immunity protects against posttransplantation CMV-related complications.     

Effect of ovarian endometriosis on ovulation in rabbits

To study the relationship between endometriosis and ovulatory dysfunction, we induced ovarian endometriosis in the rabbit model Adipose tissue was placed in the contralateral ovary as a control. Ovulation was induced with human chorionic gonadotropin, and ovulation points were counted before and after induction of endometriosis. Periovarian adhesions were graded, and ovaries were histologically examined. A significant decrease in the number of ovulation points was observed in ovaries with endometrial tissue (p = 0.001) but not in ovaries that contained adipose tissue (p = 0.095). Periovarian adhesions decreased the number of ovulation points (p less than 0.01) in ovaries that contained adipose or endometrial tissues. Multivariate analysis demonstrated that an increase in adhesion severity was correlated with a decrease in the number of ovulation points (p less than 0.05), but endometrial tissue was not (p = 0.45). We conclude that, in the rabbit model, minimal ovarian endometriosis impairs ovulation primarily through a mechanism related to periovarian adhesions.     

Impairment of neutrophil chemotactic and bactericidal function in children infected with human immunodeficiency virus type 1 and partial reversal after in vitro exposure to granulocyte-macrophage colony-stimulating factor

Because polymorphonuclear neutrophils are the most important component of host defense against bacteria, we assessed their function in 13 children with asymptomatic and 12 with symptomatic infection with human immunodeficiency virus type 1 (HIV-1), and compared their values with healthy adult control values. The functions assessed were (1) chemotaxis, (2) bacterial phagocytosis, (3) superoxide generation, and (4) bactericidal activity. Chemotaxis of polymorphonuclear neutrophils toward the chemoattractant N-formylmethionyl leucyl phenylalanine (FMLP) was significantly decreased in symptom-free infected children compared with control subjects (p less than 0.0001), but was increased in children with symptomatic infection (p less than 0.025). Bactericidal activity of the neutrophils against Staphylococcus aureus was defective in 8 of 12 children with asymptomatic infection (p = 0.016), and in 8 of 9 children with symptomatic infection (p less than 0.00001). Superoxide generation by polymorphonuclear neutrophils on stimulation with FMLP and phagocytosis of S. aureus were normal. Serum from patients with symptomatic HIV-1 infection was not as efficient in low concentrations as normal serum in the ability to opsonize S. aureus. The in vitro bactericidal defect was partially corrected by granulocyte-macrophage colony-stimulating factor (GM-CSF). The results suggest that both cellular (neutrophils) and humoral defects contribute to the increased incidence of bacterial infections in HIV-1-infected children, and that GM-CSF may improve the defective bactericidal activity of polymorphonuclear neutrophils in these patients.     

Superficially invasive carcinoma of the vagina following treatment for cervical cancer: A report of six cases

Six patients with superficially invasive squamous carcinoma of the vagina are described. All patients meet recently proposed criteria for the diagnosis of microinvasive vaginal carcinoma. The depth of invasion measured from the surface was less than 2.5 mm. There was no lymph-vascular space involvement. The invasive foci arose within a field of carcinoma in situ. Five of these six patients had previously been treated for invasive cervical cancer with pelvic radiation from 82 to 246 months before the diagnosis of vaginal carcinoma. All but one patient had the carcinoma confined to the upper one-third of the vagina. All patients were treated with a single vaginal radium application following vaginectomy. One of these six patients expired from recurrent vaginal cancer 35 months following diagnosis. During the same 17-year period, 17 other cases of Stage I epidermoid cancer of the vagina were treated which did not meet the above criteria for microinvasion. There were no statistically significant differences between these two groups with regard to age at diagnosis, history of cervical cancer, hysterectomy, or pelvic radiation or in survival. Additional experience with early vaginal carcinoma is needed before microinvasive carcinoma of the vagina should be accepted as a distinct clinical entity.     

Pseudohermaphroditism, glomerulopathy, and Wilms tumor (Drash syndrome): frequency in end-stage renal failure

The sporadic concurrence of male pseudohermaphroditism and chronic glomerulopathy is associated with an extremely high risk of Wilms tumor. We report our experience with an infant who developed this triad (Drash syndrome) and review the 21 patients described in the literature, to emphasize the importance of early diagnosis and to suggest guidelines for management. The dysgenetic gonads are always intra-abdominal and carry a 20% to 30% risk for malignancy. The external genitalia are frequently ambiguous (77%); some children are phenotypically normal females. The glomerulopathy typically leads to end-stage renal failure in infancy; the subsequent death rate has, to date, been 68%. The clinical presentation of renal disease is variable and includes congenital nephrotic syndrome (14%) and infantile nephrotic syndrome (41%); 27% of patients develop proteinuria and renal insufficiency between the ages of 1 and 3 years. The high risk of Wilms tumor (55% in this review) mandates regular tumor surveillance, and prophylactic bilateral nephrectomy and gonadectomy once irreversible renal failure develops.     

Medical care program compliance--a year 2000 recipient perspective of Medicare claims

This article provides a brief assessment of patient and provider views and concerns regarding reimbursements under the Medicare program. Specifically targeted is the payment of pharmaceutical claims. Also addressed are the ongoing and respective responsibilities of individual clinical providers, associated hospitals, and recipients of care. A summation of significant results of direct interviews and follow-up discussions with 10 Medicare recipients also is provided.     

Selection of unrelated bone marrow donors by serology,molecular typing and cellular assays

As compared to hematopoietic stem cell transplantation (HSCT) with HLA genotypically identical donors, phenotypically matched unrelated HSCT is associated with lower survival. Serologically undisclosed HLA disparities account for the increased rate of post-transplant complications. With more than 1300 alleles currently identified, high-resolution molecular typing techniques have to be applied to distinguish the extensive degree of allelic polymorphism of the HLA system. Whereas a HLA-ABDR-serologically identical donor can be identified in the International Registry for >90% of the patients, only half of them can benefit of a highly compatible donor if donor selection is based on allele level matching for HLA-A/B/Cw/DRB1/B3/B5/DQB1 loci. During the last 10 years, we identified only approximately 20% of all known HLA alleles in the searches for our mainly Caucasoid patients. Rare alleles (i.e. alleles that represent <1% of a given serotype) do not have a major impact in patient/donor matching. Most of the incompatibilities are clustered in a limited number of serotypes that can be targeted first during the searches. However, due to linkage disequilibrium (e.g. B-Cw or DRB1-DQB1), incompatibilities at a given locus are often associated with disparities at adjacent loci. In vitro cellular assays such as the cytotoxic T-lymphocyte precursor frequency (CTLpf) analysis may contribute in discriminating functionally relevant HLA class I disparities, as well as minor antigen mismatches in case of sensitized donors. When a rare variant or an uncommon association in the patient's HLA haplotype has been found, the tissue typing laboratory may recommend considering a mismatched donor early in the search procedure instead of continuing a search with a low probability of success.     

Economic evaluation of vaccination programmes: a consensus statement focusing on viral hepatitis

The methods that have been used to estimate the clinical and economic impact of vaccination programmes are not always uniform, which makes it difficult to compare results between economic analyses. Furthermore, the relative efficiency of vaccination programmes can be sensitive to some of the more controversial aspects covered by general guidelines for the economic evaluation of healthcare programmes, such as discounting of health gains and the treatment of future unrelated costs. In view of this, we interpret some aspects of these guidelines with respect to vaccination and offer recommendations for future analyses. These recommendations include more transparency and validation, more careful choice of models (tailored to the infection and the target groups), more extensive sensitivity analyses, and for all economic evaluations (also nonvaccine related) to be in better accordance with general guidelines. We use these recommendations to interpret the evidence provided by economic evaluation applied to viral hepatitis vaccination. We conclude that universal hepatitis B vaccination (of neonates, infants or adolescents) seems to be the most optimal strategy worldwide, except in the few areas of very low endemicity, where the evidence to enable a choice between selective and universal vaccination remains inconclusive. While targeted hepatitis A vaccination seems economically unattractive, universal hepatitis A vaccination strategies have not yet been sufficiently investigated to draw general conclusions.     

Prolonged survival of patients receiving active immunotherapy with Canvaxin therapeutic polyvalent vaccine after complete resection of melanoma metastatic to regional lymph nodes

OBJECTIVE: To determine whether adjuvant postoperative active specific immunotherapy with a therapeutic polyvalent vaccine (PV) called Canvaxin can prolong survival following complete resection of melanoma metastatic to regional nodes (American Joint Committee on Cancer [AJCC] stage III melanoma). SUMMARY BACKGROUND DATA: Despite complete lymphadenectomy, 5-year overall survival (OS) for patients with melanoma metastatic to regional lymph nodes is only 20% to 50%, depending on the number of tumor-involved nodes. In 1984, the authors began phase II trials of Canvaxin PV as postsurgical adjuvant therapy for AJCC stage III melanoma. METHODS: Patients who received PV between 1984 and 1998 were compared with patients who did not receive PV postsurgical therapy between 1971 and 1998. The seven covariates recently defined by the AJCC Melanoma Staging Committee (number of metastatic nodes, palpable status, ulceration, age, primary site, pT stage, and gender) were included by Cox regression in a multivariate model of OS. A computerized program matched PV and non-PV patients by these covariates. RESULTS: Of 2,602 patients who underwent complete lymphadenectomy for AJCC stage III melanoma with regional nodal metastases and were followed up by the same team of oncologists between 1971 and 1998, 935 received PV and 1,667 did not. Median OS and 5-year OS were significantly higher in PV than non-PV patients (56.4 vs. 31.9 months and 49% vs. 37%, respectively; P =.0001). When the non-PV patients were matched by the four most significant covariates, 447 matched pairs were formed between patients seen before or after January 1, 1985, and the OS was not different between the two time periods ( P=.789). However, when the PV patients were matched with non-PV patients by six covariates forming 739 pairs, the PV patients survived longer ( P=.0001). Detailed analysis of the 1,505 patients who were seen or who began vaccine therapy within 4 months after lymphadenectomy, and who had more complete data on the seven prognostic covariates showed that median OS and 5-year OS were higher in 445 PV patients than in 1,060 non-PV patients: 70.4 versus 31 months and 52% versus 37%, respectively (P =.0001). Multivariate Cox regression analysis identified six significant prognostic factors: number of metastatic nodes, size of metastatic nodes, pT stage, ulceration, age, and PV therapy. PV therapy reduced the relative risk of death to 0.64 (95% confidence interval, 0.55-0.76) ( P=.0001); sex and site of primary were of borderline significance. CONCLUSIONS: This large single-institution study independently confirmed the significance of prognostic covariates in the new AJCC staging system. By using modern statistical methods that controlled for all known prognostic factors, it also demonstrated PV's ability to significantly enhance OS. A multicenter phase III randomized trial is underway to validate the efficacy of PV as a postsurgical adjuvant.     

Abdominal seat belt marks in the era of focused abdominal sonography for trauma

HYPOTHESIS: Focused abdominal sonography for trauma (FAST) is an unreliable method for assessing intra-abdominal injury in patients with seat belt marks. DESIGN: Retrospective review of trauma patients with intestinal injury and seat belt marks during a 3-year period. Records were reviewed for patient demographics, FAST results, computed tomographic (CT) scan results, and operative findings. The CT scan results were considered positive if bowel wall thickening, extraluminal air, or free fluid without solid organ injury were present. SETTING: University hospital designated as a level I trauma center. PATIENTS: Twenty-three patients who required operation for intestinal or mesenteric injury and who had an abdominal seat belt mark. MAIN OUTCOME MEASURE: Sensitivity of FAST in these patients. RESULTS: All patients were evaluated using both FAST and CT scan of the abdomen and pelvis. Eighteen patients (78%) had either negative or equivocal FAST results when significant intestinal injury was present. All 23 patients had CT scan findings suggestive of bowel or mesenteric injury. Moderate-to-large free intraperitoneal fluid without solid organ injury was the most common finding (n = 21, 91%). Operative findings included small-bowel perforation (n = 18, 78%), colonic perforation (n = 7, 30%), bowel deserosalization (n = 8, 35%), and isolated mesenteric injury (n = 5, 22%). Sixteen patients (70%) had multiple intra-abdominal injuries. All patients were taken directly from the emergency department to the operating room. Seventeen percent of operative explorations (4/23) were nontherapeutic (no repairs required). CONCLUSION: This study confirms that FAST cannot reliably exclude intestinal injury in patients with seat belt marks.