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In patients with laryngeal carcinoma, nodal metastasis, recurrence after radiotherapy, and prognosis are important factors in clinical decision-making. Parameters such as tumor stage are considered insufficient for predicting these important items. The DNA ploidy status of the tumor may be a useful additional marker. The DNA ploidy status of 38 laryngeal cancers was determined by flow cytometry. Correlations were studied with TNM stage, differentiation, survival rate, relapse risk, recurrence after radiotherapy, and nodal metastasis. A positive correlation of DNA ploidy status with the development of lymph node metastases was found for diploid and peridiploid versus aneuploid tumors (DNA index, <1.4 versus ≥1.4; p = .007). No correlation was found between ploidy status and recurrence after radiotherapy. The overall survival rate (p = .01), but not the disease-specific survival rate or the relapse risk, showed a correlation with the ploidy status. The DNA ploidy status may be a useful marker for metastatic behavior in head and neck squamous cell carcinoma and may therefore be helpful in decision-making concerning elective treatment of the neck.

Short‐term preoperative radiotherapy in combination with surgery has been shown to decrease the rate of local recurrence in rectal cancer patients. The effects of this type of radiotherapy on the histopathology of rectal carcinoma has been hitherto unknown. Since various histopathological factors are associated with prognosis, the study of alterations induced by irradiation is an important issue. This paper examines the histopathology of resection specimens from 1306 patients who were treated in a randomized trial that evaluated the benefits of preoperative radiotherapy. In this trial, patients were treated with short‐term radiotherapy (5×5 Gy) and operated on within 5 days after radiation. Histopathological parameters were determined by the Pathology Review Committee of the trial and we compared tumours of patients with and without preoperative radiotherapy. Tumours of patients who were treated with preoperative radiotherapy were smaller, more often mucinous carcinomas (13% versus 7%, p<0.001) and more often poorly differentiated (35% versus 24%, p<0.001). After radiotherapy, there was less inflammatory reaction around the tumour (extensive in 7% versus 18%, p<0.001), which was mainly caused by a decrease in T lymphocytes and neutrophil granulocytes. The fibroblastic reaction was more pronounced in the radiotherapy group (extensive in 22% versus 10%, p<0.001). Remarkable histological alterations occurred within a week after 5 days of irradiation of rectal carcinomas. The prognostic value of these factors therefore needs to be re‐evaluated for irradiated patients. Copyright © 2002 John Wiley & Sons, Ltd.

Regional metastasis is an important factor in the prognosis and treatment of head and neck squamous cell carcinoma (HNSCC). The results of earlier studies suggested the possibility of predicting nodal metastasis in HNSCC using biological markers. To identify which factors may be relevant in the metastatic behaviour of these tumours, the expression of several markers involved in tumour progression was studied in both nodal metastases and their corresponding primary tumours. Expression of p53, Rb, cyclin D1, myc, bcl‐2, EGFR, neu, E‐cadherin, epithelial cell adhesion molecule (Ep‐CAM), and nm23 was studied in 54 primary tumours and their corresponding metastases in patients with HNSCC. The expression of most genes involved in tumourigenesis (p53, Rb, cyclin D1, myc, bcl‐2, EGFR, neu, and E‐cadherin) was similar in primary tumours and metastases. The expression of nm23 and Ep‐CAM was found to be more frequently lower than higher in metastases, compared with their primary tumours. Whereas most genetic alterations of primary tumours remain unchanged in metastases, expression of the cell adhesion molecule Ep‐CAM and of nm23 is more frequently reduced than increased in metastases, compared with their primary tumours, suggesting relevance to the process of metastasis. This also implies differences in the regulation of markers involved in tumourigenesis and the process of metastasis. Copyright © 2001 John Wiley & Sons, Ltd.

Neural network technology has been used for the daily screening of cervical smears in The Netherlands since 1992. The authors believe this method might have the potential to demarcate diagnoses of Grade 1‐2 cervical intraepithelial neoplasia (CIN 1‐2).Of 133,196 women who were screened between 1992–1995, there were 2236 CIN 1‐2 smears; 1128 of which were detected by means of neural network screening (NNS) (n = 83,404 women) and 1108 of which were diagnosed by conventional screening (n = 49,792 women). Cytologic and clinical outcomes (first cytologic or histologic follow‐up diagnosis) were retrieved for all the women in the study population (n = 1920). Stratification based on clinical outcome resulted in the cases being grouped as overdiagnosed, concordant, or underdiagnosed. The smears were performed by general practitioners, whereas the biopsies were obtained by gynecologists. The prevalence rate for CIN 1‐2 was 1.15% (95% confidence interval [95% CI], 1.08–1.23%) for NNS and 1.92% (95% CI, 1.80–2.04%) for conventional diagnosis (P < 0.001). Concordance with histology was significantly higher for NNS (53.9%; 95% CI, 50.7–57.0%) compared with conventional screening (29.2%; 95% CI, 26.4–32.2%). In addition, overdiagnosis was significantly lower for cases diagnosed by NNS (39.4%; 95% CI, 36.3–42.4%) compared with cases diagnosed by conventional screening (62.4%; 95% CI, 59.3–65.5%). Neural network‐based screening can lead to fewer women being burdened unnecessarily with a cytologic diagnosis of CIN 1‐2 by resulting in a sharp demarcation in these diagnoses and a corresponding reduction in unnecessary medical interventions. [See editorial on pages 171–172, this issue.] Cancer (Cancer Cytopathol) 2001;93:173–178. © 2001 American Cancer Society.

Purpose: Local recurrence (LR) after breast-conserving therapy (BCT) is associated with an increased risk for the development of distant metastasis. We studied risk factors for distant metastasis risk (DMR) and poor prognosis within a group of patients with LR as first event. Patients and Methods: From a cohort of 1481 breast carcinomas treated with BCT in the period 1980-1994, a total of 68 pT1-3 N0-1 patients developed LR as first event. We have studied risk factors for the development of distant metastasis within this group of patients with LR. In addition to clinical factors (age at BCT and LR, mode of detection, location of LR, and treatment of LR), the histology slides of the primary and the recurrent tumor were reviewed. Immunohistochemical staining was performed for the following proteins: bcl-2, cyclin D1, E-cadherin, EGF receptor, ER, PR, Ki-67, c- erb B-2/ neu , and p53. Statistical analyses were performed using conditional logistic regression. Results: At a median follow-up after LR of 5.6 years, the 5-year DMR was 53%. In univariate analysis, none of the factors of the primary tumor was found to be associated with DMR after LR. Of the recurrent tumor the following factors were found to be risk factors for high DMR after LR: interval between treatment of the primary tumor and LR at 2 years or less (relative risk, 2.38; 95% confidence interval, 1.22-4.76; p = 0.008) and high mitotic count (relative risk, 2.51; 95% confidence interval, 1.03-6.15; p = 0.04). All patients with noninvasive recurrent tumor were alive at the time of analysis. Patients with an interval of greater than 2 years and a recurrent tumor with high mitotic count were found to have an equally poor prognosis compared to patients with LRs detected after a short interval. Conclusion: LR after BCT is associated with higher DMR and poor prognosis. Patients with LR within 2 years after BCT are especially at high risk. Late recurrences with high mitotic count have the same poor prognosis as early recurrences. For these patients, systemic treatment at time of the detection of LR should be considered.

In a national survey, fine‐needle aspiration cytology of the thyroid gland was applied in only 67% of patients with thyroid carcinoma. The overall sensitivity rate was low (57%). See also pages 325–329 and 357–363.

Fine-needle aspiration cytology is recommended as the first and most decisive diagnostic step in the workup of patients with nodular thyroid disease. A retrospective analysis of all thyroid carcinomas diagnosed was conducted using the Netherlands Pathology Database PALGA, which covers all cytologic and histologic examinations in the Netherlands, with the aim of investigating nationwide whether fine-needle aspiration cytology of the thyroid (FNAC-t) actually had been used prior to surgery for thyroid carcinoma and if so, with what result. FNAC-t was used in 591 of the 890 patients (66%) analyzed, with a total of 769 aspirations (a single FNAC-t in 459 patients, multiple FNAC-ts in 132 patients). The overall sensitivity rate was 57%; when restricting the FNAC-ts to the most recent one for each patient, the sensitivity rate rose to 70%. Sensitivity was lowest for follicular carcinoma (67%) and was highest for anaplastic and medullary carcinomas (89%). Limiting these calculations to aspirations from patients with tumors > 10 mm was found to have very little influence on these rates (FNAC rate: 71%; overall sensitivity rate: 58%). If the application rate (66%) and sensitivity for the most recent aspiration (70%) were considered regardless of the tumor size, only 47% of the malignancies were detected by FNAC-t. When patients with tumors > 10 mm and all FNAC-ts in this group are considered, only 41% of thyroid carcinoma cases were detected cytologically. Contrary to common belief based on current guidelines for the workup of patients with nodular thyroid disease, the majority of thyroid carcinoma cases are not detected by FNAC-t. [See editorial on pages 325–329 and original article on pages 357–363, this issue]. Cancer (Cancer Cytopathol) 2000;90:330–334. © 2000 American Cancer Society.

Extracapillary proliferation and fibrinoid necrosis are the main diagnostic glomerular lesions in renal biopsy specimens of patients with idiopathic systemic vasculitis. Neither the incidence nor the correlation between extracapillary proliferation and fibrinoid necrosis in renal biopsy specimens from patients with systemic vasculitis has been systematically evaluated. By means of a three-dimensional analysis, we made a topographic reconstruction of the distribution of extracapillary proliferation and fibrinoid necrosis in affected glomeruli and tested different biopsy-processing protocols to optimize histopathologic analysis in clinical practice. Paraffin blocks of renal biopsy specimens from six patients diagnosed with systemic vasculitis were completely and serially sectioned in 2-μm thick sections and stained with the Gomori trichrome method. Glomeruli were scored per section for the presence of fibrinoid necrosis and extracapillary proliferation. Subsequently, a three-dimensional reconstruction was obtained for 87 glomeruli. In only one glomerulus did fibrinoid necrosis occur without extracapillary proliferation; in 51%, a combination of the two lesions was found; in 22%, extracapillary proliferation occurred in the absence of fibrinoid necrosis; and 26% did not show either lesion. Using the standard protocol from our department (ie, evaluation of 20 consecutive sections in various stainings), the chance of finding extracapillary proliferation was 100% and that of finding fibrinoid necrosis was 73%. If 5 sections stained with the Gomori trichrome were added, the latter percentage increased to 86%. Using skip-serial sections, even better results (87% to 92%) were obtained, with four skips as the best option (92%). In conclusion, our finding that fibrinoid necrosis rarely occurs in the absence of extracapillary proliferation may imply that both lesions are etiologically related. In addition, our observations indicate that the incidence of fibrinoid necrosis may be underestimated in clinical practice, depending on the number of sections evaluated.

To estimate the incidence of complications of diagnostic and operative hysteroscopic procedures in the Netherlands and describe their nature.

Patients with Ph+ chronic myelogenous leukemia who relapse after a first allogeneic stem cell transplant still have a possibility of long-term survival. To assess the value of the individual therapeutic options, the factors predicting outcome should be identified. We investigated data from 500 patients who relapsed before July 1996; follow-up was updated during 1998. The actuarial survival from relapse was 34.2% (95% confidence interval [CI]: 29.9%-38.5%) at 5 years and 23.4% (95% CI: 18.9%-27.9%) at 10 years. Survival after relapse was significantly related to 5 factors: time from diagnosis to transplant (< 2 years vs = 2 years), disease phase at transplant (first chronic phase vs other), disease stage at relapse (cytogenetic or chronic phase vs advanced phase), time from transplant to relapse (< 1 year vs = 1 year), and donor type (HLA-identical sibling vs volunteer unrelated donor). The effects of individual adverse risk factors were cumulative: The probability of survival at 10 years decreased stepwise from 42% (0 factors), 32% (1 factor), 14% (2 factors), 3% (3 factors), to 0% (4 or 5 factors). Novel strategies for high-risk patients are warranted. We conclude that these 5 factors should be taken into account when comparing results of salvage therapies in patients with Ph+ chronic myeloid leukemia relapsing after allogeneic stem cell transplant.

Patients with Ph+ chronic myelogenous leukemia who relapse after a first allogeneic stem cell transplant still have a possibility of long-term survival. To assess the value of the individual therapeutic options, the factors predicting outcome should be identified. We investigated data from 500 patients who relapsed before July 1996; follow-up was updated during 1998. The actuarial survival from relapse was 34.2% (95% confidence interval [CI]: 29.9%-38.5%) at 5 years and 23.4% (95% CI: 18.9%-27.9%) at 10 years. Survival after relapse was significantly related to 5 factors: time from diagnosis to transplant (< 2 years vs ≥ 2 years), disease phase at transplant (first chronic phase vs other), disease stage at relapse (cytogenetic or chronic phase vs advanced phase), time from transplant to relapse (< 1 year vs ≥ 1 year), and donor type (HLA-identical sibling vs volunteer unrelated donor). The effects of individual adverse risk factors were cumulative: The probability of survival at 10 years decreased stepwise from 42% (0 factors), 32% (1 factor), 14% (2 factors), 3% (3 factors), to 0% (4 or 5 factors). Novel strategies for high-risk patients are warranted. We conclude that these 5 factors should be taken into account when comparing results of salvage therapies in patients with Ph+ chronic myeloid leukemia relapsing after allogeneic stem cell transplant.

The objective of this study was to present the long-term results of total adrenalectomy for Cushing's disease. Forty-four patients undergoing total adrenalectomy for Cushing's disease between 1953 and 1989 at Leiden University Medical Center, The Netherlands, were studied retrospectively. Remission was achieved in 42 patients (95%), with a mean duration of 19 years. Adrenal remnants were observed in 12 patients (27%), and were without clinical consequence in the majority of patients, but caused early recurrent disease in 2 patients. Nine patients (20%) experienced Addisonian crises up to 30 years following treatment. Nelson's syndrome developed in 10 patients (23%) 7–24 years following total adrenalectomy. Prior pituitary irradiation was a protective factor against Nelson's syndrome as it delayed its onset (p= 0.025). On the other hand, subnormal dose or noncontinuous glucocorticoid replacement therapy was associated with increased risk of development of Nelson's syndrome (p= 0.047). The incidence of Nelson's syndrome increased with prolonged follow-up, and female patients seemed to be at increased risk. Quality-of-life assessment showed less favorable scores on mental health and health perception scales, for which no explanation can be found except the long-lasting metabolic effects of Cushing's disease, even when successfully treated. In conclusion, total adrenalectomy remains the final treatment for Cushing's disease. The presence of adrenal remnants which can cause recurrent disease and the development of Nelson's syndrome during prolonged follow-up enhance the need for continued regular follow-up. Pituitary irradiation prior to total adrenalectomy delays the onset of Nelson's syndrome.

The objective of this study was to present the long-term results of total adrenalectomy for Cushing's disease. Forty-four patients undergoing total adrenalectomy for Cushing's disease between 1953 and 1989 at Leiden University Medical Center, The Netherlands, were studied retrospectively. Remission was achieved in 42 patients (95%), with a mean duration of 19 years. Adrenal remnants were observed in 12 patients (27%), and were without clinical consequence in the majority of patients, but caused early recurrent disease in 2 patients. Nine patients (20%) experienced Addisonian crises up to 30 years following treatment. Nelson's syndrome developed in 10 patients (23%) 7–24 years following total adrenalectomy. Prior pituitary irradiation was a protective factor against Nelson's syndrome as it delayed its onset (p= 0.025). On the other hand, subnormal dose or noncontinuous glucocorticoid replacement therapy was associated with increased risk of development of Nelson's syndrome (p= 0.047). The incidence of Nelson's syndrome increased with prolonged follow-up, and female patients seemed to be at increased risk. Quality-of-life assessment showed less favorable scores on mental health and health perception scales, for which no explanation can be found except the long-lasting metabolic effects of Cushing's disease, even when successfully treated. In conclusion, total adrenalectomy remains the final treatment for Cushing's disease. The presence of adrenal remnants which can cause recurrent disease and the development of Nelson's syndrome during prolonged follow-up enhance the need for continued regular follow-up. Pituitary irradiation prior to total adrenalectomy delays the onset of Nelson's syndrome.

Objective: To estimate the incidence of complications of diagnostic and operative hysteroscopic procedures in the Netherlands and describe their nature.

The spleen-liver model, as a predictor for contrast-to-noise ratio (C/N) in liver metastases, was verified for seven sequences in 22 patients with 70 colorectal metastases. Optimization of conventional spin-echo, T1-magnetization-prepared gradient-echo and fat frequency-selective presaturation inversion-recovery fast spin echo can be done using the spleen-liver model. C/N of liver-spleen and liver-metastases, however, differed significantly on our T1 gradient-echo and T2-weighted fast spin-echo images, with and without fat-selective saturation. J. Magn. Reson. Imaging 1999;9:369–372. © 1999 Wiley-Liss, Inc.

The correlation between human papillomavirus (HPV) infection and tumor prognosis in 159 Russian women with cervical carcinoma was investigated. The presence of various HPV types was correlated with the histologic parameters of the carcinomas and with their immunoreactivity with antibodies to p53, Ki-67-Ag, and bcl-2. Formalin fixed, paraffin embedded tissue specimens representing 159 cases of International Federation of Gynecology and Obstetrics Stage I and II were used. HPV DNA was detected by polymerase chain reaction (PCR) using a general primer set that targets the L1 region and synthesizes a product of only 65 base pairs. The HPV types were determined by direct sequencing and compared with known HPV types. All 159 carcinomas were positive for HPV. HPV 16 (64.8%) was most frequently found, followed by HPV 18 (10.7%) and HPV 45 (8.2%). In 6 patients (3.8%), HPV types could not been further classified, and these cases were therefore categorized as HPV X. Although a trend was noted toward poorer prognosis for women with carcinomas harboring HPV types 16, 18, and 45 than for patients with carcinomas harboring HPV types 31, 33, 35, 52, 56, 58, and 68, the differences were not statistically significant. The prevalence of adenocarcinoma and adenosquamous carcinoma was higher among HPV 18 positive patients than among patients with the other known HPV types (P = 0.0002). The rate of HPV positivity in these 159 cervical carcinomas was 100%. These findings challenge the assumption that HPV negative cervical carcinomas exist. This high rate might be attributed to the use of a new broad-spectrum HPV PCR test. HPV typing in cervical carcinoma was not significantly related to clinical outcome. HPV 18 was significantly more frequently found in adenocarcinoma and adenosquamous carcinoma. The possibility of classifying HPV 45 as an oncogenic high risk type should be considered. Cancer 1999;85:2011–6. © 1999 American Cancer Society.

Due to the high variability of the epidemiology, genetics, morphology, and biologic behavior of gastric carcinoma, many classification systems are in use, e.g., the World Health Organization (WHO) classification; tumor differentiation; the criteria of Ming, Mulligan, and Laurén; and the recently introduced Goseki classification. In the authors' opinion, the TNM staging is the most valuable classification system, with a prognostic value for survival. To assess the reproducibility and usefulness of these systems in clinical practice, material from 285 gastric carcinoma patients entered in the Dutch Gastric Cancer Trial was analyzed by a panel of 5 experienced gastrointestinal pathologists. The presence of eosinophilic and lymphocytic infiltrates was analyzed in addition to the TNM staging. Of the analyzed classification systems, only TNM stage, tumor differentiation, eosinophilic infiltrate, and the Goseki system contained information associated with the survival of patients with gastric carcinoma. The reproducibility was perfect for tumor differentiation (Kappa 1.00), nearly perfect for the WHO and Goseki classifications (Kappa 0.86 and 0.87, respectively), reasonably good for Laurén and lymphocytic infiltrate (Kappa 0.70), and reasonably good for eosinophilic infiltrate (Kappa 0.42). Of all these systems, the Goseki classification was the only system with prognostic value that is additional to TNM staging. Cancer 1999;85:2114–8. © 1999 American Cancer Society.

The spleen‐liver model, as a predictor for contrast‐to‐noise ratio (C/N) in liver metastases, was verified for seven sequences in 22 patients with 70 colorectal metastases. Optimization of conventional spin‐echo, T1‐magnetization‐prepared gradient‐echo and fat frequency‐selective presaturation inversion‐recovery fast spin echo can be done using the spleen‐liver model. C/N of liver‐spleen and liver‐metastases, however, differed significantly on our T1 gradient‐echo and T2‐weighted fast spin‐echo images, with and without fat‐selective saturation. J. Magn. Reson. Imaging 1999;9:369–372. © 1999 Wiley‐Liss, Inc.

OBJECTIVE: To study early motor and cognitive symptoms in Huntington disease. DESIGN: A follow-up cohort study after a DNA test procedure in which gene carriers and noncarriers were identified among people genetically at risk for Huntington disease. SETTING: Leiden University Medical Center, Department of Neurology, Leiden, the Netherlands, in cooperation with the Clinical Genetics Center Leiden and the Department of Medical Psychology and Psychotherapy, Erasmus University Rotterdam, Rotterdam, the Netherlands. PARTICIPANTS: Thirty-three individuals: 9 unaffected gene carriers, 6 gene carriers with motor symptoms, and 18 noncarriers of the gene for Huntington disease. MAIN OUTCOME MEASURES: A neuropsychologic examination covering a broad area of cognitive functioning, reaction time procedures, and motor tasks. RESULTS: The neuropsychologic assessment showed no significant differences between presymptomatic gene carriers and noncarriers. Three motor tasks differentiated between these 2 groups on a liberal.05 P level (analysis of variance followed by the Student t test). The affected gene carriers performed less well than the presymptomatic gene carriers and the noncarriers in 10 motor tasks and 7 cognitive tasks. These differences were significant at P&lt;.05. CONCLUSION: Motor symptoms play a more prominent and unequivocal role than cognitive symptoms in early stages of Huntington disease.

• To identify clinical and laboratory risk factors for the susceptibility to infections in Felty's syndrome, 46 patients were studied prospectively during a total number of 431 periods of three months ("patient-quarters"). The incidence of infections increased significantly with polymorphonuclear leukocyte (PMN) counts below 0.1×103/mm3 (&lt;0.1 ×109/L). At PMN levels over 0.1 × 103/mm3 (>0.1 ×109/L), no association was found between PMN counts and the incidence of infections. Other factors found to be associated with an increased incidence of infections were severe disability, skin ulcers, glucocorticosteroid dose, monocyte counts, hypocomplementemia, and high levels of circulating immune complexes. The activity of the rheumatoid arthritis, erythrocyte sedimentation rate, hemoglobin concentrations, and lymphocyte counts were not associated with increased incidence of infections.(Arch Intern Med 1987;147:915-920)

• Since 1961,14 patients at the University Hospital of Leiden, the Netherlands, have undergone reconstructive surgery for treatment of chronic mesenteric vascular syndrome. Of the 42 mesenteric arteries, 31 were severely obstructed (mean, 2.2 stenotic arteries per patient). A total of 23 mesenteric arteries were repaired. Long-term follow-up data were available for all 13 surviving patients (mean follow-up, 11.8 years). Symptoms were relieved immediately after surgery, and relief was maintained during follow-up. Digital subtraction angiography at long-term follow-up evaluation was performed in eight patients (13 reconstructions) with these results: 11 (85%) of the 13 reconstructions were patent and severe stenoses were found in eight (33%) of the 24 mesenteric arteries (mean, 1.0 stenotic artery per patient). We conclude that reconstructive surgery for patients with chronic mesenteric vascular syndrome promptly relieves symptoms, provides excellent patency, and has long-lasting beneficial results.(Arch Surg. 1991;126:1101-1106)

Aims - To assess the prevalence of depression in elderly patients presenting in general practice, and to assess which patient characteristics and presenting symptoms are useful clues for predicting depression.Design - Cross-sectional survey based on data collected at the presenting consultation and at a subsequent domiciliary interview.Subjects and setting - 580 of 706 consecutive patients aged 65+ years consulting 13 general practitioners in the Netherlands.Method - GPs entered data on presenting symptoms and their assessment of psychological state during the consultation. Formal psychiatric assessment was subsequently done at home using the Diagnostic Interview Schedule (plus additional questions to assess minor depression according to ICHPPC-2-Defined). Major depression and dysthymia were assessed with the Diagnostic Interview Schedule. Results - The estimated prevalence of depression (both major and minor plus dysthymia) was 7.9%, and was very similar whether based on GP assessment or formal validated interview schedule, but the GPs did not identify the same patients as the formal psychiatric assessment. GPs identified only 26% (95% CI 4-71%) of patients with major depression. Clinical clues which could help the GP to suspect underlying depression were female gender, the presentation of vague symptoms, and gastrointestinal symptoms.Conclusions - Although presentation of symptoms does provide some clues about the likelihood of underlying depression, the sensitivity of GP diagnosis remains low and needs to be improved.

Objective - To obtain information on the course of complaints and restrictions in daily activities of patients with acute bronchitis.Design - Prospective study.Setting - General practice.Subjects - Otherwise healthy persons over 16, who visited their GP with an acute cough with purulent sputum and/or auscultatory abnormalities.Main outcome measurements - Recordings by patients on reasons for encounter, symptoms and restrictions in daily activities at entry, and one and two weeks after entry.Results - 99 Patients were included, of whom 79 were suitable for further analysis. Discomfort caused by coughing and concern in the patient and his/her social environment were the main reasons why patients visited their general practitioner. Counting from the onset of the disease it took three to four weeks before most patients were well and able to perform all their usual daily activities again.Conclusion - in most cases acute bronchitis has considerable impact on patients' well-being and daily activities for some weeks.

The aim of this study was to investigate the generation of DNA ploidy diversity in different stages of colorectal carcinoma development. DNA flow cytometry was performed on tissue samples from 20 colorectal adenomas, 38 colorectal carcinomas, 30 lymph node metastases, and 70 hematogenous metastases. DNA aneuploidy was detected in 30% of the adenomas, 82% of the primary colorectal tumors, 57% of the lymph node metastases, 92% of the liver metastases, and 100% of the other distant hematogenous metastases. Multiple DNA tumor stemlines were found in 10%, 39%, 29%, 24%, and 40%, respectively. Sixty-two percent of the DNA tumor stemlines detected in the lymph node or liver metastases were also present in the primary tumors. In primary carcinomas and lymph node metastases, the DNA index distribution had a bimodal shape with a minimum at the 1.2-1.4 region. In the hematogenous metastases, a higher percentage of hypertetraploid stemlines was found. The emergence of DNA aneuploidy as well as clonal divergence seems to take place during the transition from adenoma to carcinoma. The DNA aneuploid stemlines formed during this phase remain relatively stable over time, although ongoing clonal evolution at distant metastatic tumor sites cannot be completely ruled out. Cancer 1997; 79:1304-14. © 1997 American Cancer Society.

Non-Hodgkin's lymphoma (NHL) originating in mucosa-associated lymphoid tissue (MALT) is supposed to have different clinical behavior from lymph node NHL. To test this hypothesis, the authors compared data of gastric NHL patients with lymph node NHL patients in a population-based registry for differences in clinical presentation and prognosis. Data from 1981-1989 on patients with primary gastric NHL (n = 109) and patients with primary lymph node NHL (n = 658) were retrieved from a Dutch population-based NHL registry. Patients were compared for stage distribution, involved sites, and survival. The prognostic value of grading lymphomas according to the malignancy grades of the Working Formulation for Clinical Usage was compared with the value of grading MALT NHLs as either low grade or high grade malignancies. Patients with gastric NHL presented more often with localized disease. Stage IV patients had a higher rate of dissemination to other non-lymph node sites but less frequent localization in the bone marrow. The restricted pattern of dissemination was reflected in a significantly lower recurrence rate for gastric NHL. Gastric NHL patients had significantly better disease free survival than lymph node NHL patients (80% and 44% at 5 years, respectively; P &lt; 0.001). In contrast, overall survival did not significantly differ between the two groups, and it appeared to depend on disease stage. Grading MALT lymphoma as either low grade (26%) or high grade (70%) malignancies did not provide better prognostic information than grading according to the Working Formulation for Clinical Usage (low 8%, intermediate 75%, high 9%). Primary gastric NHL shows a restricted dissemination pattern, which gives support to the MALT lymphoma concept. Although this might explain the superior disease free survival observed for gastric NHL patients, it does not translate into better overall survival for these patients. Cancer 1997; 79:390-7. © 1997 American Cancer Society.

In this study we have investigated the prevalence of p53 overexpression in various vulvar lesions and its significance as a prognostic parameter in patients with vulvar carcinoma. Overexpression of p53 was studied in 66 patients with squamous cell carcinoma of the vulva and in the following synchronous epithelial lesions: intraepithelial neoplasia grade I (VIN I) (n = 33), VIN II (n = 11), VIN III (n = 16), lichen sclerosus (n = 30), squamous cell hyperplasia (n = 37), normal vulvar skin of patients with vulvar carcinoma (n = 55), and in 18 samples of normal skin from healthy controls. Survival curves of the p53-positive and p53-negative patients were compared using the log-rank test. The use of DO7, an anti-p53 monoclonal antibody, showed p53 overexpression in 35 (53) specimens of carcinoma, in eight (27) of lichen sclerosus, in five (14) of squamous cell hyperplasia, in six (18) of VIN I, in two (18) of VIN II, in two (13) of VIN III, and in seven (13) specimens of normal vulvar skin. Staining of normal skin from healthy controls showed no p53 positive specimens. No relationship between expression of p53 and disease-free survival in patients with vulvar carcinoma was present. In malignant, synchronous premalignant and non-neoplastic epithelial disorders of the vulva, p53 overexpression is a frequent observation, indicating that the latter two groups have characteristics of premalignant lesions. In addition, p53 overexpression was not a useful prognostic parameter for patients with vulvar carcinoma.

Our goal was to assess the value of MRA for detecting stenoses in the celiac (CA) and superior mesenteric (SMA) arteries in patients suspected of having chronic mesenteric ischemia, using an optimized systolically gated 3D phase contrast technique.

Similarities between the nitrogen-fixing systems of the archaebacteriumMethanosarcina barkeri (strain Fusaro) and a number of eubacteria were investigated. Using antibodies againstRhizobium leguminosarum nitrogenase and a probe of clonednif-HDK genes of this species, homology withM. barkeri was demonstrated on the protein level and to a greater extent on the DNA level.

RATIONALE AND OBJECTIVES. Measurements of segmental contraction of the left ventricle by standard magnetic resonance imaging (MRI) and two-dimensional echocardiography involve the comparison of diastolic and systolic timeframes acquired from the same imaging plane in space. As the coneshaped left ventricle shortens along its long axis during systole, the observed contraction may differ from the true myocardial contraction.

A prospective study was performed to establish the objective response of brain metastases after radiotherapy. Twenty-five patients with a total of 53 metastatic lesions were evaluated approximately 6 weeks after completing the treatment (30 Gy/2, 5 weeks). Clinical response was seen more often than objective response, due probably to concomitant use of corticosteroids and to most patients having multiple metastases. Clinical response, although important for the patient, does not well reflect the objective response. In 48% of the cases there was agreement between the clinical and the radiodiagnos-tic findings. The tumor size was an important prognostic factor for prediction of complete response. The majority of patients who achieved complete remission of at least one of the metastatic lesions, did not show recurrence of the neurological symptoms.

Hairy cell leukemia (HCL) is a usually chronic B cell lymphoproliferative disorder. To evaluate the prognostic significance of the various heavy and light chain determinants of the surface immunoglobulins (sIg), we analyzed the clinical data and immunologic phenotype of 64 patients with HCL. Sixty-two of the 64 patients showed sIg, which was invariably of only one light chain type (κ33, λ29). The actuarial survival of the cases expressing κ-light chains was significantly better than those with λ-light chains (p< 0.002). This difference persisted when only cases with γ or αγ heavy chains were considered. No differences between the κ and λ-subgroups were discovered with respect to parameters of clinical importance. The various heavy chain classes of sIg did not correlate significantly with the survival time. These results suggest that the immunologic phenotype, in particular the light chain type, may be a prognostic factor in patients with HCL.

The relative importance of prognostic factors in papillary and follicular thyroid cancer was studied in 113 patients using Cox's proportional hazards model. Prognostic factors studied were: histology, tumor grade, extrathyroidal growth, nodal involvement, distant métastases at diagnosis, nuclear DNA content, age at diagnosis, and sex. Nuclear DNA content was measured in primary tumors by flow cytometry. Total thyroidectomy and postoperative131I ablation was the standard treatment. The results showed that nuclear DNA content correlated significantly with histologic type and, in papillary cancer, also with tumor grade. The presence of distant metastases at diagnosis was, by far, the most important prognostic factor. In the patient group without distant metastases (n=91), multiploidy (i.e., presence of 2 or more aberrant stemlines) was the only significant prognostic factor for overall survival. With respect to diseasefree survival, multiploidy was second only to the age factor. In the patient group with distant métastases (n=22), all 6 patients with multiploid tumors died compared to 8 (50%) of 16 of those with other ploidy tumors. However, the small number in this group precluded significant results. The present study demonstrates that nuclear DNA content is a prognostic factor in those patients with papillary and follicular thyroid cancer without distant metastases at diagnosis.

During the period 1974-1986, 107 consecutive 1-9 month-old children with late-diagnosed congenital dislocation of the hip (CDH) were treated with a Frejka pillow primarily, followed by a Becker device. Treatment was initially successful in 96 cases with 2 not reduced, 4 failed stabilization, 4 persisting dysplasia, and 1 avascular necrosis. No correlation was found between age at the time of diagnosis or the severity of the dislocation and the duration or the result of treatment.In those initially successful, 14 percent had slight dysplasia 6 months later. The last follow-up, at the mean age of 7 years, excluding the 11 children needing supplementary treatment, showed that 84 percent had normal hips on radiography, based on measurements of the acetabular angles and the center-edge angles. The clinical findings were normal.

Forin vitroevaluation of functional properties of endothelial cells seeded on synthetic vascular prostheses accurate and reproducible quantification of cells is mandatory. Comparison of these properties with those resulting from other studies requires correlation of the functional parameters to reliably counted cell numbers. The accuracy of methods of quantification currently being used is unknown due to the lack of a “gold standard” method to which these methods can be compared. To determine the accuracy and reproducibility of four widely used methods, we have developed a “gold standard” model, using a flow cytometer (FACS). Endothelial cells, attached to collagen-coated Dacron vascular prostheses, were counted by four conventional methods and a new method of quantification after the attached number of cells had been determined with 99% accuracy by FACS. Subsequently, ratios were computed by dividing the cell numbers determined by the methods under investigation by those determined by FACS (×100%). The four conventional methods investigated were (1) removal and subsequent counting of cells from substrata by trypsin (T), (2) digestion of cells by citric acid and counting of crystal violet-stained cell nuclei (CV), (3) light microscopy after hematoxylin staining (LM), and (4) scanning electron microscopy (SEM). The new method consists of the measurement of cell fluorescence after labeling with fluorescein–diacetate (FDA). T and CV had average accuracy ratios of 127 ± 58% and 96 ± 48%, respectively (± standard deviation). The ratios for LM and SEM were 116 ± 101% and 44 ± 10% (respectively). FDA had a ratio of 99 ± 7%. Reproducibility of cell quantification by T and CV was significantly less than that of quantification by LM, SEM, and FDA, as expressed by data on inter- and intraobserver agreement. Our results indicate that the investigated conventional methods of quantification failed to meet criteria ofbothhigh accuracy and reproducibility. Light microscopy and scanning microscopy methods were inaccurate but yielded reproducible countings. We conclude that the FACS method can serve as a “gold standard” to compare the accuracy and reproducibility of cell quantification methods. Moreover, the FDA method results in both accurate and reproducible quantification of endothelial cells attached to vascular prosthetic material.

BACKGROUND: Regional metastasis is an important factor in the treatment and prognosis of patients with head and neck squamous cell carcinoma. Although in recent years imaging techniques have improved, it is still impossible to detect small metastatic deposits. Metastasis is mainly determined by properties of the primary tumor and its interaction with surrounding structures. OBJECTIVE: To identify markers that predict the presence of metastasis based on the features of the primary tumor. DESIGN: Correlation of the results of histological, immunohistochemical, and molecular biological analysis with clinical and histopathological data. MATERIALS AND METHODS: Several histological features and biological markers were examined in 31 laryngeal carcinomas. The following markers were selected on their putative role in the process of metastasis and were studied using immunohistochemical and/or Southern blot techniques: proliferating cell nuclear antigen (PCNA),p53, retinoblastoma tumor-suppressor gene (Rb), myc, bcl-2 (inhibitor of apoptosis), epidermal growth factor (EGF), EGF-receptor (EGFR), neu, nm23 (also known as NME1, putative metastasis suppressor), desmoplakin, neuron cell-adhesion molecule (N-CAM), epithelial cell-adhesion molecule (Ep-CAM), E-cadherin, cyclin D1 (CCND1), and EMS1. RESULTS: The presence of an inflammatory reaction surrounding the tumor (P=.07), eosinophilic infiltration (P=.16), positive immunostaining for Rb (P=.02), negative immunostaining for Ep-CAM (P=.13), and amplification of CCND1 and EMS1 (P=.05) correlated with nodal metastasis. The combination of an inflammatory reaction, eosinophilic infiltration, and staining for Rb and Ep-CAM resulted in a superior accuracy in assessing nodal metastasis. CONCLUSIONS: These results indicate that it is possible to predict and exclude lymph node metastasis by studying the features of the primary tumor only. When these results are confirmed in a larger series, biological markers may be powerful diagnostic tools with great impact on clinical decision making.Arch Otolaryngol Head Neck Surg. 1997;123:412-419

Human papillomavirus (HPV) infection and p53 abnormalities might both play a role in the carcinogenesis of subtypes of squamous cell carcinoma of the vulva. In this study, the authors investigated the prevalence of and the relationship between p53 overexpression and HPV infection in patients with vulvar carcinoma. Immunohistochemical methods for the detection of p53 protein and consensus primer polymerase chain reaction (PCR) were used, followed by direct sequencing of the PCR product for the evaluation of HPV subtype infection. Sixty-six patients with squamous cell carcinoma of the vulva were available for this study. DO7, an anti-p53 monoclonal antibody, showed p53 overexpression in 35 carcinomas (53%). Consensus primer PCR showed HPV infection in 12 carcinomas (18%). No significant association was observed between p53 overexpression or HPV infection and tumor subtype. Approximately 57% of the HPV negative carcinomas and 33% of the HPV positive carcinomas had p53 overexpression. With regard to the patients with DO7 positivity in ≥50% of the nuclei only, significantly more HPV negative carcinomas were DO7 positive compared with HPV positive carcinomas (41% vs. 0%, respectively; P = 0.018). No relation was found between either HPV infection or p53 overexpression and disease free survival. p53 overexpression is common in both HPV positive and HPV negative carcinomas of the vulva. These findings indicate that these two both play a role in the pathogenesis of vulvar carcinoma, but do not influence disease free survival. Cancer 1997; 80:1228-33. © 1997 American Cancer Society.

Objective.To investigate the prevalence of human papillomavirus (HPV) infection in various vulvar lesions.

To find a clinical staging system for patients with hairy cell leukemia, 391 patients contributed by 22 centers were analyzed using the proportional hazard survival model. Attention was paid to nonsplenectomized patients to find a staging system to predict the survival length at the time of diagnosis. On the basis of hemoglobin level and spleen size at the time of diagnosis, 3 stages could be distinguished with significantly different prognoses (stages I–III). In addition, we addressed the question of splenectomy to identify those patients who benefit from the operation. Using arbitrary, but clinically relevant, criteria to call the operation beneficial, splenectomy appears to be indicated for patients with large spleens (>4 cm under costal margin) or with smaller, but palpable, spleens when anemia (Hb < 12 g /dl) is present. The third question concerned the splenectomized patients. To indicate the patients who have a poor postsplenectomy survival, a staging system was developed on the basis of hemoglobin level and number of neutrophils at 2-3 mo after the operation (stages A–C). The validity of the two staging systems was supported by the results of an analysis of an independent test series of patients. These staging systems may be helpful for the choice of therapy and in the planning of clinical trials in patients with hairy-cell leukemia.

Intestinal contents (gas and food particles) are well known to cause problems in abdominal ultrasonography by inducing confusing and inconclusive images. We prospectively studied the effect on the combination of a 2‐day low‐calorie, low gasforming diet with laxatives on abdominal sonographic image quality. For a total group of 100 consecutive outpatients, 50 patients (diet‐laxative or DL group) were randomly assigned to follow the preparation of a diet and laxatives, and 50 patients (control or C group) served as a control group without any special preparation. The sonographic imaging quality of abdominal organs and retroperitoneal structures was assessed without knowledge of which group the patients were assigned to. The DL group patients showed a significant improvement in visibility of the extrahepatic common bile duct (p= 0.009), head and body of the pancreas (p= 0.015 and 0.004, respectively), para‐aortic region (p= 0.001), and the iliac vessels (p= 0.0005). The combined use of a low‐calorie, low gas‐forming diet and laxatives improves the abdominal sonographic image quality of the above‐mentioned structures to such an extent that the sonographer will be able to make more pertinent statements about the presence or absence of pathology.

• One hundred eighty-three patients with psoriasis were treated with UV-B irradiation or oral methoxsalen plus longwave UV light (PUVA). Patients treated with PUVA, in the initial and maintenance period, achieved in general a higher therapeutic score (95% to 100% clearance) than those receiving UV-B therapy. However, taking 80% to 100% improvement as criterion, no difference was found between initial UV-B and PUVA therapy, if less than 50% of the skin surface was affected by psoriasis. If more than 50% of the skin was involved, PUVA was better than UV-B therapy. The maintenance treatment frequency for the UV-B—treated patients for more than a year seemed to be higher than for PUVA-treated patients. A positive correlation was found between response to sunbathing (questionnaire survey) and the response to UV-B phototherapy. An extra UV-B treatment to the leg lesions appeared useless.(Arch Dermatol 1984;120:52-57)

In the past, Huntington's disease was diagnosed when movement disturbances were present in concordance with a positive family history. Early motor signs, however, are often not found in a standard neurologic examination, and their expression is variable. Not until later stages of the disease could one be sure about the diagnosis. Since genetic diagnosis became available, the onset of symptoms and signs could be studied in the earliest phase. The aim of the study was to evaluate observer agreement of the assessment of early motor signs in Huntington's disease. A total of 17 gene carriers, 22 noncarriers, and eight partners were recorded on video performing several facial movements after instruction and engaging in a 5‐minute conversation. Three experienced neurologists, unaware of the genetic status of the participants, judged and classified the video recordings independently. The cases with disagreement were judged a second time after the neurologists discussed these cases. The observer agreement after the first judgment is poor (kappas 0.09, 0.24, 0.45) and after the second judgment satisfactory (kappas 0.79, 0.90, 0.78). Consequences for clinical practice and research programs into early symptoms and signs are discussed.

Experimental studies have been made of the lesion detectability in myocardial perfusion studies using thallium-201. A series of images (AP-view) was generated using a convolution of a mathematical model of the left ventricular myocardium and an experimentally determined point spread function. Background was added. Images were simulated with 100k, 200k, and 300k counts for the complete image. Each image contained a lesion with either 0% or 50% of the normal tracer concentration. All images were interpreted by five experienced observers, independently of each other. Their interpretations were analysed using the Kolmogorov-Smirnov two sample test. The true positive fraction (TPF) was hardly affected by changes in count density. The TPF decreased significantly if the lesion tracer concentration changed from 0% to 50% of the normal myocardial tracer concentration. The decrease was independent of the count density. The false positive fraction (FPF) decreased significantly if the count density increased; no difference in FPF was found for a change in lesion tracer concentration. In addition, plots were generated with the TPF and the FPF versus lesion location and of the TPF versus lesion volume. The TPF was lowest for locations far from the camera; FPF was high for these segments. Increase of the count density mainly improved the FPF in these segments. Small lesion were more difficult to detect.

Pancreas graft survival is influenced by various donor and recipient factors. Factors that have posed serious problems to pancreas transplantation have included the limited cold ischemia time, early graft thrombosis, and rejection. A limited cold ischemia time not only causes problems in terms of logistics but also implies limitations with regard to HLA matching and organ exchange. Between August 1988 and August 1989 we performed a prospective, nonrandomized European multicenter study to evaluate the effect of University of Wisconsin (UW) solution on pancreas graft survival. In addition, donor and recipient factors were collected and their influence on graft survival analyzed. Overall pancreas graft survival at 1 and 4 years was 67% and 59%, respectively (n=62). When only simultaneous pancreas and kidney transplants were included, the graft survival was 70% and 63% at 1 and 4 years, respectively. The incidence of pancreas graft thrombosis was 8%. Cold ischemia time was not found to significantly influence pancreas graft survival even when it exceeded 12h. Factors that did were HLA-DR matching, simultaneous pancreas and kidney transplantation versus pancreas transplantation alone, and ABO blood group matching. We feel that the use of UW solution for pancreas preservation has contributed to improved pancreas graft survival and has reduced early graft thrombosis despite much longer cold ischemia times of over 12 h. Given this and the significant effect of HLA and blood group matching, we conclude that more attention should be paid to preoperative matching and organ exchange in order to further improve pancreas graft survival.