Separation of the complement-fixing and early antigens from Epstein-Barr soluble antigen.

The Epstein-Barr virus-associated complement-fixing (soluble) antigen (CFSA) and the early antigen (EA) were isolated by ion-exchange chromatography from the P3HR-1 lymphoblastoid cell line activated with 5-iodo-2'-deoxyuridine for 72 hours. As expected, these two antigens were not immunologically identical. The CFSA, but not the EA, was isolated from the RAJl lymphoblastoid cell line by the same method.

Immunologic identification of Epstein-Barr virus early antigen in a P3HR-1 cell extract.

We extracted the Epstein-Barr soluble antigen (EBSA) from the P3HR-1 human lymphoid cell line, which carries the Epstein-Barr virus (EBV), after P3HR-1 cells were activated with 5-iodo-2'-deoxyuridine. EBSA was identified as the early antigen (EA) complex by immunodiffusion and blocking immunofluorescence tests with high-titered human antiserum to EA. The identity of the EA complex was confirmed with antiserum to EA prepared in rabbits and adsorbed to assure its immunologic specificity. The EA was partially purified on Sephadex G-200. Further characterization by immunoelectrophoresis showed that the EBSA moved rapidly toward the anode. This indicated a highly negative charge. EBSA appeared to be distinct from the previously described complement-fixing S-antigen. It was demonstrable only in EA-producer lymphoid cell lines and reacted specifically with human antiserum to EA, whereas the S-antigen was found in all EBV-carrying lymphoid cell lines and reacted with all EBV antibody-positive human antisera.

Cloning and characterization of UROC28, a novel gene overexpressed in prostate, breast, and bladder cancers.

A novel gene, designated UROC28, was identified by an agarose gel-based differential display technique, and it was found to be up-regulated in prostate, breast, and bladder cancer. Expression of UROC28 was also up-regulated in prostate cancer cells in the presence of androgens as demonstrated by relative quantitative reverse transcription-PCR. The elevated expression of this gene was observed to increase in surgically removed tissues concomitantly with rising Gleason grade and was most elevated in metastatic tissue. UROC28 protein was detected in serum by Western slot blot analyses, and a significant higher UROC28 protein level was found in sera of prostate cancer individuals compared with normal individuals and individuals with nonmalignant prostatic hyperplasia. Northern analyses in normal tissues showed that the UROC28 cDNA hybridizes to two mRNAs at about 2.1 and 2.5 kb. Nucleic acid sequence analyses indicated that these two alternatively spliced mRNA variants differ only at the 3' untranslated region. These two mRNAs encode the same protein with 135 amino acids. Bioinformation analyses suggest that there is a possible transmembrane domain from amino acid aa34 to aa50, three protein kinase-C phosphorylation sites at aa62 (SQK), aa89 (TMK), and aa94 (SMK), and one myristylation site at aa118 (GLECCL). Genomic Southern hybridization and chromosomal mapping demonstrated that UROC28 is encoded by a single copy of gene at chromosome 6q23-24. In situ hybridization and immunohistochemistry experiments further confirmed up-regulation of this gene in prostate and breast cancers with the expression localizing to the glandular epithelium. This gene did not demonstrate increased expression in lung and colon cancer tissues.

Isolation and identification of human lung tumor-associated antigens.

Three human lung tumor-associated antigens (TAA's) have been identified in soluble and membrane-solubilized extracts of human squamous cell lung carcinoma with the use of antisera raised in rabbits. The antigens were identified and partially characterized by means of an agarose adsorption technique. These antigens, termed lung TAA's 1,2, and 3, are all soluble in 50% ammonium sulfate, are antigenically distinct, and do not cross-react with carcinoembryonic antigen or alpha-fetoprotein. Lung TAA's 1 and 2 are oncofetal antigens demonstrable in soluble extracts from 24-week-old but not from 26-week-old fetal lungs. Rabbit antibodies to these lung TAA's were not adsorbed by types A, B, and O human red blood cells, serum proteins as well as soluble or insoluble lung preparations. Of several commercial antisera to human proteins, none cross-reacted with lung TTA 1, but anti-human liver ferritin cross-reacted with lung TAA 2, and anti-human lactoferrin cross-reacted with lung TAA 3. Lung TAA 1 was partially adsorbed and cross-reacted with certain normal serum or plasma preparations used and appears to be a normal serum protein in Cohn Fraction IV-4. Lung TAA 2 and 3 appear only in lung tumor-soluble extracts, whereas the lung TAA 1 was demonstrable in soluble extracts of breast, colon, cervical and head and neck carcinoma. All may be tumor markers of value in immunodiagnosis.

Implication of cell kinetic changes during the progression of human prostatic cancer.

The daily percentage of cells proliferating and dying were determined for normal, premalignant, and cancerous prostatic cells within the prostate as well as for prostatic cancer cells in lymph node, soft tissue, and bone metastases from untreated and hormonally failing patients. These data demonstrate that normal prostatic glandular cells have an extremely low but balanced rate of cell proliferation and death (i.e., both <0.20%/day). This results in a steady-state, self-renewing condition in which there is no net growth, although the glandular cells are continuously being replaced (i.e., turnover) every 500 +/- 79 days. Transformation of these cells into high-grade prostatic intraepithelial neoplastic cells initially involves an unbalanced increase in the daily percentage of cells proliferating versus dying, such that net continuous growth occurs (i.e., mean doubling time, 154 +/- 22 days). As these early proliferation lesions continue to grow into late stage high-grade prostatic intraepithelial neoplastic cells, the daily percentage of cells dying increases further to a point equaling the daily percentage of proliferation. This results in cessation of net growth while inducing a 6-fold increase in the turnover time of these cells (i.e., 56 +/- 12 days), increasing their risk of further genetic changes. The transition of late stage high-grade prostatic intraepithelial neoplastic cells into localized prostatic cancer cells involves no further increase in proliferation but a decrease in death resulting in net continuous growth of localized prostatic cancers with a mean doubling time of >/=475 days. As compared to localized prostatic cancer cells, metastatic prostatic cancer cells within lymph nodes or bones of untreated patients have an increase in daily rate of proliferation coupled with a reduction in their daily percentage of cell death, producing net growth rates with a mean doubling time of 33 +/- 4 days and 54 +/- 5 days, respectively. Remarkably, there is no further increase in proliferation in hormonally failing patients, but instead an increase in the daily percentage of androgen-independent prostatic cancer cells dying within soft tissue or bone metastases. These changes result in doubling times which are two to three times longer (i.e., 126 +/- 21 and 94 +/- 15 days) in these lymph node and bone metastatic sites, respectively, compared to similar sites in hormonally untreated patients. These data demonstrate that the daily percentage of proliferation for either androgen-dependent or -independent metastatic prostatic cancer cells is remarkably low (i.e., <3. 0%/day), consistent with why antiproliferative chemotherapy has been of such limited value against such metastatic cells. These results also suggest that prostatic carcinogenesis starts in the second to third decade of life and may require over 50 years for progression to pathologically detectable metastatic disease.

Neuroendocrine differentiation in prostate cancer: enhanced prediction of progression after radical prostatectomy.

It is controversial whether neuroendocrine (NE) differentiation in adenocarcinoma of the prostate is associated with more aggressive behavior. Most studies included patients with tumors of a wide range of grades and stages and an end point of disease-specific survival, a relatively insensitive marker of progression. The authors studied completely embedded radical prostatectomy specimens from 104 patients with clinically organ-confined carcinoma and no history of adjuvant or neoadjuvant therapy. Progression was marked by a serum prostate-specific antigen (PSA) concentration greater than or equal to 0.2 ng/mL. Seventy-six men did not progress, with a mean follow-up period of 8.0 years (range = 7 to 10 years). Forty-eight men progressed at a mean time after surgery of 3.6 years (range = 1 to 8 years). Twenty-one percent of the tumors were organ confined: 79% had capsular penetration. Seminal vesicles and lymph nodes were negative in all cases. A representative section through the main tumor mass was stained for chromogranin A. Reactive neoplastic cells were counted subjectively as well as individually enumerated. Gleason grade, pathological stage, and degree of NE differentiation all correlated with progression. Only grade and extent of NE differentiation predicted progression in a multivariate analysis. NE differentiation did not correlate with stage or grade. Extent of NE differentiation separated patients (59 cases) with tumors of Gleason sum less than or equal to 6 into groups with high and low risks for progression (P < .008) independent of Gleason sum. Extent of NE differentiation provides prognostic information in addition to that provided by grade in cases of early prostate cancer treated by radical prostatectomy.

Free/total PSA ratio improves differentiation of benign and malignant disease of the prostate: critical analysis of two different test populations.

OBJECTIVES: To evaluate the ability of free PSA (fPSA), total PSA (tPSA), and the free/total PSA (f/t PSA) ratio to differentiate between benign prostate disease (benign prostatic hyperplasia [BPH] and no evidence of malignancy [NEM]) and prostate cancer (CaP) using two different testing populations, and to compare predictive probabilities for the two test populations. METHODS: One test population consisted of sera from 531 men with clinically well-defined and biopsy-confirmed BPH (n = 255) or CaP (n = 276), with tPSA values ranging from 2 to 20 ng/mL. All of these serum samples were retrospective and obtained from patients evaluated in academic settings before any treatment. A second test population consisted of a prospective analysis of sera obtained from 4870 men, collected by urologists throughout the United States and processed at a single pathology laboratory. All these patients had a systematic biopsy evaluated and diagnosed at the same pathology laboratory, with the diagnosis categorized as either NEM (n = 2961) or CaP (n = 1909). No additional information on concurrent disease or pre- or current treatment status was known for this test population. For both populations, two tPSA reflex range groups, 2 to 10 and 2 to 20 ng/mL, were evaluated. RESULTS: Both test populations benefited from the application of either fPSA alone or the f/t PSA ratio to differentiate benign from malignant disease (t test P value less than 0.001). The receiver operating characteristic (ROC) curve for the f/t PSA ratio had an area under the curve (AUC) of 72% for n = 531 versus 63% for n = 4870, irrespective of the tPSA reflex range. Average fPSA values demonstrated a linear correlation to a range of tPSA concentrations for both test populations. Predictive probabilities (adjusted for established cancer prevalence rates in the academic population [n = 531]) calculated using f/t PSA ratios also demonstrated their value in contrasting the performance characteristics in the two test populations. CONCLUSIONS: The fPSA and f/t PSA ratio improved the differentiation of benign disease and CaP in two different patient samples. The f/t PSA ratio demonstrated an increased sensitivity and specificity when applied to differentiate clinically well-defined BPH and CaP (n = 531). The differences in the results between the two test samples are probably attributable to the variability of the patient's disease and treatment status in the larger, less refined, community-based population. The use of predictive probabilities provides the opportunity to provide patient-specific cancer probabilities instead of using population-based specific single cutoffs.

Ability to predict biochemical progression using Gleason score and a computer-generated quantitative nuclear grade derived from cancer cell nuclei.

OBJECTIVES: To determine the ability to predict prostate cancer progression using shape, size, and chromatin texture nuclear grading features preselected by logistic regression analyses based on expert-selected prostate cancer cell nuclei captured using a computer-assisted image analysis system. METHODS: One hundred fifteen patients with clinically localized prostate cancer were identified at the Johns Hopkins medical institutions. The mean follow-up period was 10.4 +/- 1.7 years in 70 patients without disease progression, whereas the mean time to progression for the entire group was 3.8 +/- 2.5 years. Using 5-microns Feulgen-stained tissue sections, approximately 150 cancer cell nuclei were selected and captured for each case using a CAS-200 Image Analysis System. Thirty-eight different nuclear morphometric descriptors (NMDs) were calculated for each cell nucleus. The variance of the NMDs for each tumor was examined by univariate and multivariate logistic regression analyses and by Cox survival analyses to assess their ability to predict prostate cancer progression. RESULTS: Postoperative Gleason scoring was significantly correlated with disease progression (P < 0.00001; sensitivity, 73%; specificity, 84%; receiver operating characteristic curve area under the curve (ROC-AUC), 83%). Using backward stepwise logistic regression at a stringency of P < 0.05, the variances of 11 of the NMDs were found to be multivariately significant for progression prediction (P < 0.00001; sensitivity, 78%; specificity, 83%; ROC-AUC, 86%). A single value, termed the quantitative nuclear grade (QNG), was created from the variances of these, 11 multivariately significant NMDs using the logistic regression function. The QNG and the postoperative Gleason score were combined to create a model for the prediction of progression having a sensitivity of 89%, specificity of 84%, and ROC-AUC of 92%. These two parameters (QNG and Gleason score) clearly separated the patient sample into three statistically distinct risk groups and predicted the time to progression on the basis of Kaplan-Meier survival probability analysis. CONCLUSIONS: The QNG, combined with the postoperative Gleason score, may assist in the more accurate stratification of patients undergoing radical prostatectomy into low-, moderate-, and high-risk groups for cancer recurrence and may permit the early initiation of adjuvant therapy.

Observations on pathology trends in 62,537 prostate biopsies obtained from urology private practices in the United States.

OBJECTIVES: To evaluate pathology trends of 62,537 first-time prostate needle-core biopsies submitted by office-based urologists, processed at a single pathology laboratory. METHODS: Prostate biopsy cases obtained over a 2-year period were assessed. Patient information included age, digital rectal examination (DRE) status, and prostate-specific antigen (PSA) serum levels. Biopsy pathology results included the number of tissue samples per case, Gleason score, presence of Gleason grades 4 or 5, percent of biopsy length with evidence of cancer, number of samples with cancer per biopsy, and determination of DNA ploidy status using microspectrophotometry. RESULTS: Adenocarcinoma, suspicious lesions, and isolated high-grade prostatic intraepithelial neoplasia (PIN) were diagnosed in 38.3%, 2.9%, and 4.1% of the biopsies, respectively. For each serum PSA and age range assessed, the positive biopsy rate and incidence of critical pathologic features increased consistently. The average percentage of biopsy length with evidence of tumor, the percentage of cases with Gleason grades 4 or 5, and the percentage of cases with an abnormal DNA ploidy all decreased significantly over the 2-year period (P <0.01). CONCLUSIONS: The number of tissue cores and anatomic sites (locations) being sampled per biopsy are increasing. The tumor size detected and percentage of cases with Gleason grades 4 and 5 are decreasing. There has been a slight increase in the number of biopsies performed on men younger than 60 years of age and a slight decrease in biopsies performed on men older than 70 years of age. The decline in meaningful pathologic features observed in biopsies over time may be clinically relevant to improved disease management.

A deficit of chondroitin sulfate proteoglycans on the bladder uroepithelium in interstitial cystitis.

OBJECTIVES: To investigate the abundance of chondroitin sulfate proteoglycans at the bladder lumenal and subepithelial surfaces in bladder biopsies derived from patients with interstitial cystitis (IC) and controls. METHODS: Tissue sections derived from biopsies from 31 IC patients and 24 pathologically normal control sections were labeled for proteoglycans using the 2B6 anti-"stub" antibody and detected by immunohistochemistry. RESULTS: On the lumenal surface, 5 of 31 (19%) IC sections were positive for proteoglycans versus 14 of 24 (58%) control sections (P = 0.00011). At the basal surface, 5 of 19 IC patients were positive versus 7 of 12 controls (P = 0.032). CONCLUSIONS: A deficit of bladder lumenal and basal proteoglycans is associated with IC. The deficit in basal layer proteoglycans suggests an altered urothelial differentiation program. The lumenal deficit suggests that the charge-dependent exclusion of ions from the bladder surface is compromised in IC.

Transrectal ultrasound-guided biopsy causes hematogenous dissemination of prostate cells as determined by RT-PCR.

OBJECTIVES: To determine if transrectal ultrasound-guided (TRUS) prostate biopsy causes dissemination of prostate cells into the circulation as assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) targeted against prostate-specific antigen (PSA) mRNA. METHODS: RT-PCR PSA analysis was performed before and after prostatic invasive manipulations in 50 men. The cases consisted of 47 patients with TRUS and 3 with transurethral resection of the prostate (TURP). Peripheral venous blood (8 mL) was drawn before and within 60 minutes after the procedure. Total RNA was extracted from fractionated blood, and RNA/cDNA quality was assured and normalized with beta-actin RT-PCR analysis. The PSA primers hybridize exons 3 and 5, yielding a 254-basepair PCR product. The assay detects one LNCaP cell in a background of 100 million lymphoid cells and a single copy of PSA cDNA on an ethidium bromide gel. RESULTS: Among the 47 TRUS cases, 43 specimens were evaluable. Forty-two cases were negative before biopsy; among these patients, 4 cases (9.5%) converted to a positive RT-PCR PSA result. Both benign and malignant TRUS biopsies were capable of producing a positive RT-PCR PSA signal implicating iatrogenic dissemination of cells. All three TURP cases converted from a negative to a highly intense positive signal. CONCLUSIONS: We conclude that a positive RT-PCR PSA signal may result from release of prostate cells into the peripheral circulation after a TRUS biopsy and TURP. TURP causes greater dissemination than TRUS. Based on these preliminary data, we recommend that future molecular staging studies should be based on blood specimens drawn before performance of TRUS biopsy. This may be an important mechanism of prostate cancer dissemination meriting further investigations.

Interleukin-8 serum levels in patients with benign prostatic hyperplasia and prostate cancer.

OBJECTIVES: Using arbitrarily primed polymerase chain reaction (AP-PCR) ribonucleic acid (RNA) fingerprinting, we discovered a messenger RNA (mRNA) that encoded the cytokine interleukin-8 (IL-8) that was up-regulated in the peripheral blood leukocytes (PBLs) of patients with metastatic prostate cancer (CaP) compared with similar cells from healthy individuals. We compared the total prostate-specific antigen (PSA) levels, the free/total (f/t) PSA ratios, and the immunoreactive IL-8 serum concentrations in patients with either biopsy-confirmed benign prostatic hyperplasia (BPH) or CaP. METHODS: The sera from 35 apparently healthy normal volunteers and 146 patients with biopsy-confirmed BPH and CaP obtained from two academic centers were retrospectively examined to determine the serum levels of IL-8, total PSA (tPSA), and the f/t PSA ratio. Logistic regression and trend analysis statistical methods were used to assess the results. RESULTS: Normals (n = 35), BPH patients (n = 53), patients with clinical Stages A to C CaP (n = 81), and patients with metastatic CaP (n = 1 2) had mean levels of IL-8 of 6.8, 6.5, 15.6, and 27.8 pg/mL, respectively. The IL-8 serum concentrations correlated with increasing CaP stage and also differentiated BPH from clinical Stages A, B, C, or D CaP better than tPSA and performed similarly to the f/t PSA ratio. The combination of the IL-8 levels and f/t PSA ratios using multivariate logistic regression analysis distinguished BPH from Stages A, B, C, or D CaP or only Stages A and B with a receiver operating characteristic area under the curve of 89.8% and 87.5%, respectively (P <0.0001). CONCLUSIONS: The IL-8 serum concentration in our clinically well-defined patient sample was independent of the f/t PSA ratio as a predictor of CaP. When test samples are controlled for extraneous clinical origin of inflammation or infection, the combination of the IL-8 and f/t PSA assay results may offer an improved approach for distinguishing BPH from CaP.

Free and complexed prostate-specific antigen serum ratios to predict probability of primary prostate cancer and benign prostatic hyperplasia.

OBJECTIVES: Ratios of free to total prostate-specific antigen (f/t PSA ratio) improved differentiation of benign prostatic hyperplasia (BPH) from prostate cancer (CaP). Using sera obtained at least 1 month prior to biopsy-confirmed diagnosis and logistic regression adjusted for disease prevalence, probability curves are constructed to predict the presence of CaP. METHODS: The patient population included 122 (44%) BPH sera and 155 (56%) prostate carcinoma sera collected prior to any therapy. The total PSA range = 2.0-20.0 ng/mL; median age = 69 years. External reference standards for both free and total PSA assays were used to standardize the assays and correct the ratio. Probability curves and tables for cancer incidence were formulated for a subset of the total test population (total PSA range = 2.0-10.0 ng/mL; 98 BPH, 118 CaP patients) by using logistic regression and prior cancer prevalence statistics derived from a published patient screening study. RESULTS: Median f/t PSA ratios were 0.18 and 0.12 in the overall sample and 0.19 and 0.12 in the subset for BPH and CaP, respectively (P = 0.0001). The median total PSA concentrations for BPH and CaP were 5.8 and 6.7 ng/mL when total PSA range = 2.0-20.0 ng/mL and were 4.9 and 5.9 ng/mL when total PSA range = 2.0-10.0, respectively. CONCLUSIONS: Cancer probability curves were constructed to help guide decisions concerning biopsy and other aspects of prostate cancer disease management. Further validation of this approach in another series of patients is necessary and is planned.

Stromal-epithelial measurements of prostate cancer in native Japanese and Japanese-American men.

We measured the histologic stromal and epithelial tissue components of the benign (normal) and malignant tissue compartments of Japanese-Americans (J-A) and native Japanese (NJ) men living in Japan. The patient cohort included 25 NJ men undergoing radical prostatectomy (RP) in Nagoya, Japan and 25 J-A (second or third generation US born). We conducted tissue image quantitation (in-house image software) of the stromal and epithelial compartments in malignant and adjacent normal tissue areas from a tissue microarray (TMA) selected from radical prostatectomy (RP) blocks. Stromal-epithelial (S-E) areas were determined using immunohistochemical stains for CAM-5.2 epithelial cytokeratin marker and the Masson trichrome stain to measure the stroma component. We observed differences in the volumes of normal and cancer epithelium and stroma within both the J-A and NJ study populations (P<0.01). Only the individual average cancer epithelium (CE) volume (JA=24.1 vs NJ=29.9) differed significantly between the NJ and J-A study populations (P=0.03). Consequently, the S-E ratio in NJ group was significantly different from that of J-A population (P=0.05). The decrease in S-E ratio noted in the malignant tissues of NJ prostate tissue may provide a biological marker for differentiation of the two groups and suggests a need for further investigations into the molecular basis for these histologic differences.

Recurrent adenotonsillitis: a new concept.

An update of original data is presented. These data continue to confirm the physiological effect of adenotonsillectomy on the abnormal oropharyngeal and nasopharyngeal microflora of children with recurrent adenotonsillitis. A new concept suggesting a bacterial-viral etiology of recurrent adenotonsillitis is presented. The advantages of such a concept are reviewed.

Clinical significance of viral latency.

Evidence is accumulating to show that a number of viruses have the ability to adapt to man's defense mechanisms and survive in a latent state for what appears to be the life of the human host. Unfortunately, latent viral presence, which may appear clinically benign initally, may manifest itself later as severe and often fatal disease. Some members of the herpes virus family have latent potential and are discussed in detail. Clinical competence would suggest a thorough understanding of these late manifestations of occult viral presence.

Long-term primary culture of epithelial cells from rainbow trout Oncorhynchus mykiss) liver.

Long-term primary cultures of epithelial cells from rainbow trout (Oncorhynchus mykiss) liver have been established. Nearly homogenous (> 97%) populations of hepatocytes were placed into primary culture and remained viable and proliferative for at least 70 d. In addition to hepatocytes, proliferative biliary cells persisted in the cultures for at least 30 d. Finally, a third type of epithelial cell, which we have termed a "spindle cell," consistently appeared and proliferated to confluence in these cultures. The confluent cultures of spindle cells were successfully subcultured and passaged. The initial behavior, growth, and optimization of serum and media requirements for these cells is described. All three cell types proliferated as measured by thymidine incorporation, autoradiography, proliferating cellular nuclear antigen analysis, and propidium iodine staining. Further efforts to characterize the cells included western blotting and immunohistochemical staining with antibodies to cytokeratins previously reported in fish liver. From these data, it appears that all three cell populations are epithelial in nature. Furthermore, significant changes in actin organization, often indicative of transformation or pluripotent cells, were observed with increased time in primary culture.

Epstein-Barr virus infection and neoplasia.

Once acquired, Epstein-Barr virus (EBV), a latent virus, remains in the body for what appears to be the lifetime of the human host. Circumstantial data suggest EBV is involved in clinical disease including malignancies far more often than previously recognized. A serologic test for early antigen (EA) is more specific for diagnosing active EBV disease than the monospot or heterophile test. A case study of active Epstein-Barr infection is reported showing persistently elevated early antigen titers prior to and following malignant transformation.

Viral and epidemiologic studies of idiopathic sudden hearing loss.

The relationship between viral seroconversions and idiopathic sudden hearing loss (ISHL) is studied. Compared with our control group, the incidence of viral seroconversions is greater among ISHL patients, both for single and multiple viral infections. There was a significantly greater number of patients with seroconversions to mumps, rubeola, varicella-zoster, cytomegalovirus, and influenza B. We were unable to find a relationship between viral seroconversion and type or degree of hearing loss, vertigo, or chance for recovery. The incidences of viral conversion and sudden hearing loss track one another closely, suggesting that viral infection is a major cause of ISHL. During this 3-year study in Boston, ISHL was most prevalent in the spring.

Association of Epstein-Barr virus with acute exudative tonsillitis.

This report is concerned with acute exudative tonsillitis as a pathologic response to the Epstein-Barr virus (EBV). The concept of a bacterial-viral etiology etiology for tonsillitis has been suggested, and previous studies implicate EBV as a major pathogen in exudative tonsillitis. A prospective study of 16 patients with this diagnosis was conducted. EBV serologic data plus viral and bacterial throat cultures were compiled and evaluated. EBV as a casual agent alone or concurrent with other organisms was seen in 56% (9) of the patients under study. EBV activation was associated with infection by other organisms in 19% (3) of the cases. The overall total incidence of EBV in association with severe acute exudative tonsillitis was 75% (12). The data further documents EBV as a significant causal or associative agent in acute exudative tonsillitis.