ERK Inhibitor LY3214996-Based Treatment Strategies for RAS-Driven Lung Cancer.

RAS gene mutations are the most frequent oncogenic event in lung cancer. They activate multiple RAS-centric signaling networks among them the MAPK, PI3K, and RB pathways. Within the MAPK pathway, ERK1/2 proteins exert a bottleneck function for transmitting mitogenic signals and activating cytoplasmic and nuclear targets. In view of disappointing antitumor activity and toxicity of continuously applied MEK inhibitors in patients with KRAS-mutant lung cancer, research has recently focused on ERK1/2 proteins as therapeutic targets and on ERK inhibitors for their ability to prevent bypass and feedback pathway activation. Here, we show that intermittent application of the novel and selective ATP-competitive ERK1/2 inhibitor LY3214996 exerts single-agent activity in patient-derived xenograft (PDX) models of RAS-mutant lung cancer. Combination treatments were well tolerated and resulted in synergistic (ERKi plus PI3K/mTORi LY3023414) and additive (ERKi plus CDK4/6i abemaciclib) tumor growth inhibition in PDX models. Future clinical trials are required to investigate if intermittent ERK inhibitor-based treatment schedules can overcome toxicities observed with continuous MEK inhibition and-equally important-to identify biomarkers for patient stratification.

Suspicious urine cytology (class III) in patients with bladder cancer: should it be considered as negative or positive?

OBJECTIVES: Urine cytology is the gold standard in the diagnosis and follow-up of bladder cancer. Cytology, however, exhibits variable sensitivity depending on tumour grade and interpretation of urine specimens is highly dependent on the skill of the examiner. Positive cytology, classes IV and V by Papanicolaou classification, is a strong predictor for coexisting or subsequent malignancy, while the role of suspicious cytology, class III, is controversial. The objective of the study was to evaluate the role of the suspicious finding in cytological analysis, and whether it should be considered as a negative or positive sign for coexisting malignancy. MATERIAL AND METHODS: Six hundred and fifty-two consecutive patients with bladder cancer were studied in a prospective multicenter trial. One hundred and fifty-one of the patients were newly diagnosed, and the remaining 501 patients were under follow-up. A voided urine sample was obtained prior to TURB or prior to routine follow-up cystoscopy in those under the surveillance and split for culture and cytology. The cytopathological results were analyzed by a central review and only patients with samples available for review analysis were included. Sensitivity and specificity, as well as positive (PPV) and negative (NPV) predictive values of urine cytology were calculated by classifying the class III samples as negative or positive. RESULTS: A total of 570 patients were evaluable. One hundred and twenty nine (22.6%) were newly diagnosed and 441 were under follow-up, of whom 117 (26.5%) had recurrence. Cytology was classified as suspicious in 33/129 (25.6%) patients with primary tumour, and in 41/441 (9.3%) of those under the follow-up, of whom 20 (48.8%) had recurrence. Sensitivity increased from to 31.0% to 56.6% in primary tumours (p < 0.001) and from 17.8% to 34.7% in recurrent tumours (p < 0.001) if class III was determined as positive, whereas the specificity decreased from 96.6% to 90.1% (p < 0.001). Accordingly, the NPV increased from 76.3% to 79.1% and the PPV decreased from 65.6% to 56.2%. CONCLUSIONS: The poor sensitivity of voided urine cytology improved significantly when suspicious samples were determined as positive while the specificity remained high, a clear advantage compared with most of the new tumour marker tests. In addition, nearly half of the follow-up patients with suspicious class III cytology had recurrence implying that this patient category is at substantial risk for co-existing malignancy. Therefore, it is recommended that suspicious class III cytology together with class IV and V specimens should be considered positive.

Prognostic utility of human complement factor H related protein test (the BTA stat Test).

The purpose of the study was to determine, in addition to well-known prognostic factors, histological grade, stage, tumour size and multiplicity, the correlation of BTA stat Test on disease free interval (DFI) on primary superficial bladder cancer. A total of 116 patients with newly diagnosed bladder cancer were evaluated in a prospective multicentre study. A voided urine sample was obtained prior to TURB and split for culture, cytology and BTA stat testing. Follow-up data for the patients were collected until the first recurrence or the last visit and the DFI was analysed by Kaplan-Meier method and Cox analysis. Ninety-seven of the 116 (83.6%) patients were eligible for analysis. The BTA stat Test was positive in 73 (75.3%) patients, whereas cytology detected 20 (20.6%) cases. The DFI was found to be shorter among patients with a positive BTA stat Test, and also among those with intermediate or high-grade tumours. The BTA stat Test result divided patients with grade 2 tumours into two prognostic groups, in that those testing positive had 68.6% risk of recurrence during the first year compared to 42.9% risk of those with a negative test result (P = 0.041). Although the effect of tumour size on DFI was notable, the difference did not reach statistical significance (P = 0.064). Number of tumours was not related to DFI, nor was the difference between different stage of tumour of significance. BTA stat Test is not only sensitive in detection of primary bladder cancer, but also might have some independent prognostic significance.

Human complement factor H related protein test for monitoring bladder cancer.

PURPOSE: The BTA stat test is a rapid, noninvasive, qualitative urine test that detects bladder tumor associated antigen (human complement factor H related protein) in urine. We compared BTA stat test to voided urine cytology in patients monitored for bladder cancer in a prospective trial, and determined whether this test is effective in detection of recurrence not seen by regular cystoscopy. MATERIALS AND METHODS: A total of 445 consecutive patients with bladder cancer were studied. A voided urine sample was obtained before cystoscopy and divided for culture, cytology and BTA stat testing. In cases of a positive BTA stat test but negative cystoscopy, excretory urography or renal ultrasound, random biopsies and collected ureteral urine samples for ureteral cytology were obtained. The overall sensitivity and specificity as well as positive and negative predictive values for BTA stat test, cytology and their combination were calculated. RESULTS: Of the 445 patients 118 (26.5%) had bladder cancer recurrence on cystoscopy, which was detected by BTA stat test and cytology in 63 (53.4%) and 21 (17.8%), respectively. Of the remaining 327 patients not having recurrent tumor on cystoscopy 81 (24.8%) had a positive BTA stat test. Excretory urography or renal ultrasound and random biopsies in 48 (59.3%) of these patients revealed 7 recurrences, making the total number of recurrent tumors 125 of 412 (30.3%). The overall sensitivities and specificities for the BTA stat test, cytology and their combination were 56.0%, 19.2%, 60.0% and 85.7%, 98.3% and 85.0%, respectively. CONCLUSIONS: The sensitivity for detection of recurrent tumor on BTA stat test is superior to that of voided urine cytology in all bladder cancer categories, whereas the specificity of voided urine cytology is higher than that for BTA stat test. However, a sixth of the patients with apparent false-positive BTA stat test results chosen for further investigation had recurrent tumors that were not found on routine cystoscopy. Although the sensitivity and specificity were highest when both tests were used, the differences were not significant overall. Therefore, the BTA stat test could potentially replace urine cytology for followup of superficial bladder cancer.

The dilemma of suspicious urine cytology in patients being followed for bladder cancer.

BACKGROUND AND AIMS: Urine cytology is gold standard for clinical tests used in the diagnosis and follow-up of bladder cancer. Cytology, however, exhibits variable sensitivity depending on tumour grade and interpretation of urine specimens is highly dependent on the skill of the examiner. Furthermore, a "suspicious" cytology report (class III) makes clinicians uncomfortable. In these cases, a more objective test, such as the BTA stat Test, may be useful in providing clarification. The aim of this study was to evaluate the dilemma of suspicious routine urine cytology and to determine whether the BTA stat Test provides diagnostic aid in this rare but controversial category. MATERIAL AND METHODS: 506 consecutive patients who were being followed for bladder cancer were included in the study. A voided urine sample was obtained prior to routine follow-up cystoscopy and split for culture and testing with the BTA stat Test. Clinical status of the disease was evaluated in patients with suspicious urine cytology, and the diagnostic aid of the BTA stat Test in these patients was determined. RESULTS: A total of 57 patients (11.3%) had urine cytology classified as suspicious. The BTA stat Test was positive in 29 (50.9%) and negative in 28 (49.1%) patients. Nineteen (33.3%) patients had recurrence at routine cystoscopy. Of the remaining 38 patients, 10 were further investigated due to a positive BTA stat Test. Two additional recurrences were detected bringing the total number of recurrences to 21 (36.8%), 48.3% (14/29) of the patients with positive and 25.0% (7/28) of the patients with negative BTA stat Test had recurrence (p = 0.069). Overall, 65.5% (19/29) of the patients with a positive BTA stat Test were found to have recurrence either at routine cystoscopy, at further investigations, or at the next cystoscopy compared to that of 35.7% (19/28) in those with negative testing (p = 0.024). The overall sensitivity of the BTA stat Test was 66.7%, and the specificity was 58.3%. CONCLUSIONS: At least a third of the patients under follow-up for bladder cancer with suspicious cytology had a recurrence, indicating that these patients are a risk group for recurrence. More importantly, a BTA stat Test result seems to provide some help in distinguishing those patients with very high risk for recurrence, for whom invasive further investigations should be conducted and a close follow-up policy maintained.

Cyclosporin A-induced cell kill in vitro in various clinical-hematological types of B-cell chronic lymphocytic leukemia.

We investigated whether a known T cell modulator, Cyclosporin A (CyA) is also toxic to chronic lymphocytic leukemia (B-CLL), in vitro. In contrast to seven other drugs and two types of irradiation the dose-response curves for CyA were very steep among the 36 CLL patients investigated, and the intraindividual variation of ID(80) values was remarkably lower. The mode of CyA-induced cell death was 'apoptotic-like' as indicated by flow cytometric analysis, revealing cell condensation and annexin positivity. The partially smeary DNA fragmentation pattern together with the relatively slow process of cell death revealed a distinctive pattern of cell death in CLL. Leukemia cells from patients at an advanced clinical stage, of a diffuse histologic type and showing fast progression were the most sensitive to CyA. These new observations may have therapeutic implications in CLL.

Is potential to produce inhibins related to prognosis in ovarian granulosa cell tumors?

OBJECTIVE: The prognosis of ovarian granulosa cell tumors is difficult to predict by conventional histological methods. STUDY DESIGN: The tumors of 30 patients operated on for a granulosa cell tumor were retrospectively studied for the expression of the inhibin alpha-subunit. The immunohistochemical staining results were correlated to the FIGO stage of the tumor and the prognosis of the patients. RESULTS: Twenty-six (87%) of the ovarian granulosa cell tumors stained positively for the inhibin alpha-subunit. All FIGO stage I and II tumors expressed inhibin alpha-subunit. All FIGO stage I and II tumors expressed inhibin, whereas the majority of stages III and IV did not (p=0.001, chi2-test). The survival of the patients with inhibin immunopositive tumors was significantly longer (median 183 months, SE 41, p=0.000, log rank test) than that of patients without inhibin expression (median 2.5 months, SE 5.25). CONCLUSIONS: Patients with ovarian granulosa cell tumors with a potential to produce the inhibin alpha-subunit may have a more favorable prognosis than those with inhibin immunonegative tumors.

Sensitivity of human complement factor H related protein (BTA stat) test and voided urine cytology in the diagnosis of bladder cancer.

PURPOSE: We compared the sensitivity of the BTA statdagger test, a rapid, noninvasive, qualitative urine test that detects bladder tumor associated antigen (human complement factor H related protein) in urine, to that of voided urine cytology in patients with primary bladder cancer. We also assessed the effect of tumor size, number, histological grade and stage on test sensitivity. MATERIALS AND METHODS: We evaluated 151 patients with newly diagnosed bladder cancer in a prospective multicenter study. A voided urine sample obtained before transurethral bladder tumor resection was divided for culture, cytology and BTA stat testing. RESULTS: Overall sensitivity of the BTA stat test and urine cytology for detecting primary bladder cancer was 81.5% and 30.3%, respectively (p <0.0001). The sensitivity of each test increased as tumor size, number, histological grade and stage increased. CONCLUSIONS: Sensitivity of the BTA stat test was superior to that of voided urine cytology in all tumor categories. This noninvasive, easy to perform, point of care test may have the potential to replace cytology for diagnosing bladder cancer.

Androgen receptor and vitamin D receptor in human ovarian cancer: growth stimulation and inhibition by ligands.

The data suggest that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and androgens are essential for regulation of growth and differentiation in, e.g., human reproductive tissues. We investigated the possible cross-talk between 1,25(OH)2D3 and androgens in the human ovarian cancer cell line OVCAR-3. Our data demonstrate that 1,25(OH)2D3 and androgen (dihydrotestosterone, DHT) regulate the growth of OVCAR-3 cells. Nine days' treatment of OVCAR-3 cells with 100 nM DHT resulted in 48% stimulation of growth, whereas growth inhibition (73%) was observed after treatment with 100 nM 1,25(OH)2D3. The combination of 1,25(OH)2D3 and DHT showed that 1,25(OH)2D3 clearly reduces the growth-stimulatory effect of DHT on OVCAR-3 cells. Moreover, Western blot analysis revealed that these cells contain receptors for 1,25(OH)2D3 (VDR) and androgen (AR). Expression of VDR and AR was up-regulated by their cognate ligands. Up-regulation of AR by 1,25(OH)2D3 and of VDR by DHT provides evidence of cross-talk between 2 signaling pathways in OVCAR-3 cells. We also studied the immuno-histochemical distribution of VDRs and ARs in rat ovaries and human ovarian cancer cases. In rat ovaries, VDRs were observed mainly in granulosa and theca cells and ARs in granulosa cells and surface epithelium. In the human ovarian cancer cases studied, 43% were VDR-positive and 64% AR-positive. Combining the results suggests that the growth of ovarian tissue might be regulated by 1,25(OH)2D3 and androgen.

Surgery for ovarian masses during childhood and adolescence: a report of 79 cases.

STUDY OBJECTIVE: Abdominal pain is a common symptom in female children and adolescents that may be caused by appendicitis, other gastrointestinal or urological conditions, or gynecological problems. This study evaluates retrospectively the preoperative work-up and the operative treatment of ovarian masses in young girls at our institution. SETTINGS: The medical records of all female patients aged 17 years or less operated on for an ovarian mass in 1971-1995 at the Tampere University Hospital were reviewed. RESULTS: Seventy-nine patients were identified. In the 1970's preoperative sonography was done on only 15% of the patients. In the 1990's the figure was 65%. Thirty-seven (47%) of all operations were emergency procedures; of these, 41% were performed by a gynecologist. Seven of the tumors were malignant. Thirty-four patients had a benign neoplasm and 26 had functional ovarian cysts. Eight patients were operated on for an adnexal torsion and four patients had other adnexal conditions. Unilateral salpingo-oophorectomy was performed on 20 patients, unilateral oophorectomy on 12 patients, and ovarian resection on 27 patients. An occasional appendectomy was performed on 37 patients. CONCLUSIONS: Surgery for benign neoplasms and functional lesions seems to be too extensive. This is likely to be due to inadequate preoperative work-up and to the fact that many of the operations were performed on an emergency basis and by non-gynecologists. A gynecological examination with sonography should be included in the diagnostic work-up of a young girl's abdominal complaints. With a proper preoperative work-up adequate treatment, which often consists of expectation, can be chosen for the patient and subsequent problems related to fertility and abdominal complaints can be avoided.

Ovarian testosterone secretion during perimenopause.

OBJECTIVE: The aim of the study was to investigate ovarian testosterone secretion during the last few years of reproductive life and after menopause. MATERIALS AND METHODS: Ovarian and peripheral venous levels of total testosterone were analyzed in 52 women aged 42-69 years (mean 51) undergoing hysterectomy with adnexal removal for benign indications at the Department of Obstetrics and Gynecology at Tampere University Hospital, Finland. The study population was divided into pre- (n = 19), peri- (n = 18) and postmenopausal (n = 15) women in addition to the classical division according to menstrual cycle. Corresponding serum estradiol, progesterone and gonadotropin levels were measured, and the degree of ovarian stromal hyperplasia was analyzed. RESULTS: The levels of all steroid hormones were higher in the ovarian vein than in the periphery. A significant positive correlation was found between age and ovarian vein testosterone levels (r = 0.3, P = 0.01). In premenopausal women, it was 1.5 nmol/l (median; range 0.78-6.0), in perimenopausal women 2.2 nmol/l (range 0.9-13.6), and 2.5 nmol/l (range 0.6-26.6) in postmenopause, respectively. Peripheral testosterone level did not increase with age. Ovarian stromal hyperplasia was significantly associated with increased testosterone secretion (P = 0.009). CONCLUSION: The ovary seems to increase the secretion of testosterone into circulation during the menopausal transition period, as the highest levels were measured in postmenopausal women. High testosterone levels in the ovarian vein, however, were not reflected in the peripheral venous blood.

Inhibin A and B in peri- and postmenopause.

OBJECTIVE: The aim of the study was to investigate the origin of inhibin A and B during the last years of the reproductive age and after menopause by measuring their levels in the ovarian and peripheral venous blood. METHODS: The study population consisted of 43 women, aged 42-69 years (mean 50), who underwent hysterectomy with ovarian removal for a benign disease. A total of 24 of them were in follicular phase, 11 in luteal phase, and eight were postmenopausal. Peripheral and ovarian venous blood was collected for measurement of inhibin A and B. In addition, sex steroid hormone and gonadotropin levels were measured. RESULTS: Ovarian venous inhibin B correlated significantly with ovarian estradiol secretion (r = 0.5, P = 0.001). The levels of inhibin B were significantly higher in the ovarian vein than in the peripheral vein (P = 0.006). The highest inhibin B concentrations were detected in the mid-proliferative (mid-follicular) phase (median 31.6 pg/ml range 25.9-47.9). In postmenopausal women, inhibin B was not detectable. No correlation between FSH and ovarian inhibin B was found. Inhibin A rose rapidly in late proliferative (late follicular) phase (median 28.5, range < 2-51.8) and dominated in the circulation throughout the luteal phase (median 20.9, range 8.8-60). For inhibin A, no concentration gradient existed between the ovarian and peripheral vein. Unlike inhibin B, inhibin A was detectable in ovarian and peripheral blood in postmenopausal women. A significant negative correlation between ovarian and peripheral inhibin A and FSH was found (r = -0.386, P = 0.015; r = -0.345, P = 0.034, respectively). CONCLUSION: Inhibin B correlates with ovarian estradiol secretion and seems to reflect follicular function. Inhibin A dominates in circulation during the luteal phase but is detectable at low concentrations both in follicular phase and even in postmenopause. Our findings suggest that inhibin A may play a role in FSH suppression in the female reproduction. In addition to the ovary, there may be extragondal source(s) of inhibin A.

Prognostic significance of p53 expression in ovarian granulosa cell tumors.

OBJECTIVE: The purpose of the study was to investigate the significance of p53 expression for the prognosis in patients with ovarian granulosa cell tumors (GCT). METHODS: The records of 30 patients operated on for GCT at Tampere University Hospital, Finland, were reviewed. The mean age at the time of the diagnosis was 55 years. Twenty-one of the tumors were of FIGO stage I, three were of stage II, three were of stage III, and three were of stage IV. Paraffin-embedded tumor specimens were analyzed by immunohistochemistry for expression of mutated p53 protein and by flow cytometry. RESULTS: Eleven tumors were positive for p53 and 19 were negative. The median crude survival of p53-negative patients was 10 times that of p53-positive ones (210 months vs 21 months, P = 0.037, log-rank test). The association between p53 immunoreactivity and stage was statistically significant (P = 0.026 Pearson chi2 test), while there was no association between p53 expression and DNA ploidy or S-phase fraction. CONCLUSION: Although the results should be considered as preliminary, expression of mutated p53 in ovarian granulosa cell tumors seems to be associated with unfavorable prognosis.

Frequent loss of the 11q14-24 region in chronic lymphocytic leukemia: a study by comparative genomic hybridization. Tampere CLL Group.

The genetic basis and molecular pathogenesis of chronic lymphocytic leukemia (CLL) and the molecular mechanisms responsible for its progression remain poorly understood. Here, karyotyping techniques specifically optimized for CLL, comparative genomic hybridization (CGH), and fluorescence in situ hybridization were used to search for CLL-specific genetic aberrations. CGH and karyotyping both revealed copy number changes in 12 of the 25 CLL cases (48%) analyzed. Loss at 11q emerged as the most common aberration (6 cases), followed by a gain of chromosome 12 (4) and loss at 13q (3). Concordance between CGH and G-banding was found in 23 of the 25 cases (92%), which is more than reported in a recent similar CGH study of CLL. Owing to the basic differences in G-banding and CGH, however, their simultaneous clinical application is recommended. The frequent loss of 11q14-24 suggests that this chromosomal region deserves further attention as a candidate locus involved in the pathogenesis of CLL.

Impaired ovarian function and risk factors for atherosclerosis in premenopausal women.

OBJECTIVES: The aim of the study was to obtain information on the possible relationship between impaired ovarian function and risk factors for cardiovascular disease. MATERIAL AND METHODS: Serum lipid levels, plasma fibrinolytic potential and histological and biochemical changes in the intima of the uterine artery were investigated in premenopausal women with irregular menstrual cycles, and the results were compared with those from regularly menstruating women. In addition, the same parameters were studied in postmenopausal women on hormone replacement therapy (HRT) and in postmenopausal women who had never used HRT. In total 64 patients undergoing hysterectomy for benign reasons were included the study. RESULTS: Plasma fibrinogen concentration was significantly higher in irregularly menstruating women as compared with women with regular cycles. In women with irregular cycles thickened or sclerotic arterial intima was a significantly more common finding as compared with regularly menstruating women. A significant positive correlation was observed between plasma fibrinogen concentration and intimal esterified cholesterol content in women with thickened or sclerotic uterine artery. CONCLUSIONS: These data suggest an important role for normal ovarian function in the prevention of atherosclerosis.

Hormone replacement therapy and atherosclerosis.

Atherosclerotic changes associated with long-term hormone replacement therapy (HRT) were evaluated in 20 postmenopausal women (mean age, 62.8 +/- 6.1 years). The duration of hormone therapy was 10.1 +/- 3.4 (SD) years. For 9 women the HRT was sequential estradiol valerate plus levonorgestrel, for 6 women estradiol valerate plus medroxyprogesterone acetate and for 5 women estradiol valerate alone. Examinations consisted of histologic and biochemical studies of the uterine artery and ultrasonographic examinations of carotid arteries, aorta and iliac arteries. The findings were compared with those in 20 postmenopausal women of similar age and with similar body mass indexes who had never received HRT. Additionally, the same examinations were performed on 10 premenopausal women (48.3 +/- 4.6 years). The uterine artery was histologically normal in all the premenopausal women studied. Among the postmenopausal women without HRT, a histologically normal uterine artery was found in 5% and in women on HRT in 55% of cases (P < .01). In medicolegal autopsies, atherosclerosis in the uterine artery correlated significantly with atherosclerosis in the coronary artery and aorta. The free cholesterol content of the intima media in premenopausal women was lower than in postmenopausal women without HRT. The percentage of linoleic acid in the intima was significantly lower and that of docosapentaenoic acid significantly higher in premenopausal women and in postmenopausal women on HRT than in postmenopausal women without HRT. In the ultrasonographic examination atherosclerosis in the carotid artery was less common in premenopausal women and in women on HRT than in postmenopausal women without HRT. In this material, histologic, biochemical and radiologic studies showed that HRT may be protective against atherosclerosis.

Atherosclerosis of the inferior epigastric and internal mammary arteries.

Atherosclerosis of the inferior epigastric artery (IEA) and the internal mammary artery (IMA) was evaluated in 21 patients with coronary heart disease. Both arteries were used simultaneously in coronary artery bypass grafting. Histologic samples were obtained from the proximal and distal segments of IEA and from the distal segment of IMA. Morphologic findings in regard to atherosclerosis were classified semiquantitatively as normal (0), or luminal narrowing <25% (1), 25-50% (2) or >50% (3), or as overt atherosclerosis and calcification (4). Atherosclerosis was absent or minimal (1) in distal samples from both arteries. Only one IMA showed moderate (2) luminal atherosclerotic obstruction. Two samples from proximal IEA showed moderate (2) or severe (4) atherosclerotic changes which limited their use as free grafts. These finding suggest that atherosclerosis is minimal and comparable in distal IEA and IMA in their natural environments even in patients with coronary heart disease. The long-term effect of aortic pressure on free IEA graft is still unclear.

Antibody response to adenovirus E1b-derived synthetic peptides and serum levels of p53 in patients with gastrointestinal and other malignant lymphomas.

Serum levels of p53 and antipeptide antibody levels to adenovirus type 12 (Ad12) E1b protein were measured in a case-control study of 62 newly diagnosed patients with malignant lymphoma. While patients with gastrointestinal lymphoma did not differ from their matched controls, p53 positive lymphoma patients had significantly (P < 0.04) increased antipeptide IgG antibody levels to the Ad12 E1b. Concomitant detection of serum p53 and antipeptide antibodies to Ad12 E1b was associated with an increased risk (OR = 17.0, 95% confidence limits 1.5, 58.5) of malignant lymphoma suggesting synergism between expression of Ad12 E1b and accumulation of p53 in patients with malignant lymphoma.

Follicular dendritic cells have prognostic relevance in Hodgkin's disease.

The authors' previous study showed the presence of follicular dendritic cell (FDC) networks--though altered--in neoplastic areas, not only in the nodular lymphocyte predominance type, but also in other types of Hodgkin's disease. The present retrospective study was performed on 102 patients to determine whether the presence or absence of FDC networks, or parts of them, in neoplastic areas has prognostic relevance in Hodgkin's disease. Follicular dendritic cells were visualized with the monoclonal antibody Ki-FDC1P, which selectively stains FDCs in paraffin-embedded tissues. Univariate statistical analysis, in which nodular sclerosis (NS) and mixed cellularity (MC) types were combined, showed three prognostically different groups: the best prognosis was associated with nodular lymphocyte predominance cases; the worst with FDC-negative NS or MC cases; and an intermediate prognosis with FDC-positive NS or MC cases. In the NS group, the prognosis of FDC-positive cases was better than that of FDC-negative cases. After multivariate analysis, stepwise modeling identified three prognostic factors at diagnosis: stage (P = .001), FDC status (P = .001), and age (P = .06). The authors conclude that in the most common types of Hodgkin's disease (nodular lymphocyte predominance, NS, and MC), FDC status in the neoplastic area(s) bears prognostic relevance, a positive FDC status predicting a favorable prognosis and a negative FDC status an unfavorable one.