Positive urinary cytology in patients with lung cancer in the absence of obvious urine tract metastases.

PURPOSE: To study the phenomenon of positive urine cytology in patients with lung cancer in the absence of obvious urothelial metastases. PATIENTS AND METHODS: 150 patients with small (SCLC) and non-small cell lung cancer (NSCLC) of all stages and 3 control groups were prospectively studied. Immunocytochemical study (cytokeratins 7-20, TTF1) in all positive urine specimens and chemokine profile (CXCR4, CCL21) study of the primary tumor in selected positive patients was performed. In experimental study, C57Bl/6 BALB/C mice injected with LLC lung and 4T1 mammary cancer cells were used for the detection of positive urine cytology. RESULTS: 11% of patients with NSCLC, 7% of patients with SCLC and none of the control group had positive urine cytology. In NSCLC, metastatic disease and high tumor burden positively correlated (p=0.01 and 0.03 respectively) with the phenomenon. In SCLC, correlation with extensive disease and multiple metastatic sites (p=0.02 and 0.04 respectively) was found. No correlation was found in either group with: age, gender, histology, performance status, line of chemotherapy, previous platinum-based chemotherapy, adrenal metastases, renal function, abnormal urinary sediment, response to chemotherapy and overall survival (p=0.9). Distinctive chemokine expression was identified in positive patients studied and was not observed in negative patients (×2 p=0.008). In the experimental study, only the LLC lung cancer cells were detected in the urine cytology of mice. CONCLUSION: This phenomenon, carrying undefined pathophysiological mechanisms, seems to characterize only patients with metastatic/extensive disease and high tumor burden. Further studies are needed to validate our preliminary chemokine expression results.

Early, intracoronary growth hormone administration attenuates ventricular remodeling in a porcine model of myocardial infarction.

OBJECTIVE: Ventricular remodeling is a common corollary of myocardial infarction. We hypothesized that this process may be attenuated by growth hormone, administered as a single high-dose, selectively in the infarct zone, early postmyocardial infarction. DESIGN: In 35 pigs (29+/-4 kg), myocardial infarction was generated by inflation of an over-the-wire angioplasty balloon in the circumflex artery for 60 min and 5 further pigs were sham-operated. Ten minutes after reperfusion, the pigs were randomized (2:1) to either growth hormone (1 IU/kg) (n=23) or normal saline (n=12), delivered via the balloon catheter. All survivors were treated with captopril and were sacrificed 4 weeks after myocardial infarction. RESULTS: Compared to controls, growth hormone-treated animals displayed lower heart weight (4.1+/-0.5 g/kg body weight, versus 3.4+/-0.4 g/kg, respectively, p=0.003) and dimensions (left ventricular short axis diameter 46+/-7 mm versus 37+/-6 mm, p=0.01; right ventricular short axis diameter 38+/-7 mm versus 30+/-5 mm p=0.001). Growth hormone increased wall thickness in the infarct (6.0+/-1.8 in controls versus 9.9+/-3.7 in treated animals, p=0.004) and non-infarct zones (10.6+/-1.8 in controls versus 15.5+/-3.8 in treated animals, p=0.0006) and produced higher (p<0.05) microvascular density in both zones. CONCLUSION: Intracoronary administration of growth hormone attenuates left and right ventricular remodeling by inducing hypertrophy and by enhancing angiogenesis.

Factors affecting outcome after incomplete excision of cervical intraepithelial neoplasia.

PURPOSE: Conservative treatment for cervical intraepithelial neoplasia (CIN) by ablative or excisional techniques is widely used. However, women with incomplete excision have a variable risk of CIN recurrence. The aim of this study was to identify possible risk factors for recurrence of CIN after large loop excision of the transformation zone (LLETZ) with involved margins of excision. METHODS: All cases of women treated with LLETZ for CIN between 1989-2000, in whom histological evaluation of the excised specimen revealed extension of CIN to the excision margins, were retrospectively studied. A woman was considered to have recurrence when she had histologically confirmed CIN following a second LLETZ or hysterectomy during the follow-up period. The characteristics that were examined as possible risk factors were age, parity, smoking habit, grade of initial lesion and extension to the endo- or ectocervical margin. RESULTS: Treatment failure was diagnosed in 18 out of 65 (27.7%) women with involved margins. The only characteristic that reached statistical significance was age. The mean age of women with recurrence was 35.8 years, whereas the mean age of women without recurrence was 32.8 years (p = 0.044). Also, a trend was evident in women with high-grade initial lesions (CIN II-III) (p = 0.168) and involvement of the endocervical margins (p = 0.149). No differences were observed between the two groups regarding parity and smoking habit. CONCLUSIONS: Increased age is a risk factor for recurrence in women with incomplete excision of CIN after LLETZ. Larger studies are required for definite conclusions.

An observational study of women with positive HPV-DNA tests and normal cytology and colposcopy.

PURPOSE: High risk human papillomaviruses (HPV) are implicated in the aetiology of malignant cervical disease. The usefulness of HPV DNA tests in identifying women at risk of cervical cancer as an adjunct to cervical cytology is under evaluation. PATIENTS AND METHODS: This is a retrospective analysis of 47 women positive for high risk HPV but with negative cytology and negative colposcopy at the start of the study. Women were observed for three years or more (in 96% cases) using six-monthly combined HPV DNA tests, cytological and colposcopic evaluation. RESULTS: At the end of follow-up, 29/47 (62%) women were still positive for high risk HPV, 45/47 (96%) women had normal cytology and 47/47 (100%) women continued to have normal colposcopy. CONCLUSIONS: Normal colposcopy has an excellent negative predictive value for HPV positive women with normal cytology. These women can be safely screened cytologically on a three-yearly basis.

Screening transvaginal uterine ultrasonography for identifying endometrial pathology in postmenopausal women.

BACKGROUND: During the last decade, transvaginal ultrasonography (TVS) has become a widely-used technique for the evaluation of endometrial histology. The purposes of this study were to compare transvaginal sonographic evaluation of the endometrium with histology obtained by endometrial biopsy in asymptomatic postmenopausal women and to determine whether screening transvaginal sonography might be useful in the evaluation of postmenopausal women. MATERIALS AND METHODS: The study included 59 unselected asymptomatic postmenopausal women who attended the outpatients' clinic for annual cervical cytology at Ioannina University Hospital, Greece. The women were evaluated by transvaginal scans, performed immediately before endometrial biopsy. RESULTS: In the 43 women with a histopathological diagnosis of normal endometrium/inadequate for assessment/atrophy, the mean endometrial thickness was 5.1 +/- 3.3 mm (range 0.8-13.8 mm) whereas the corresponding value in the 16 women with abnormal findings was 17.6 +/- 4.3 mm (range 9.4-24.6 mm) (p<0.001). If a 9-mm cut-off limit was used for endometrial thickness, the sensitivity, specificity and positive predictive value were 100%, 90.69% and 80%, respectively. CONCLUSION: TVS is a sensitive test for determining endometrial disease in asymptomatic postmenopausal women. However, well-designed studies should be conducted, completed, analysed and validated before a mass-screening program using TVS is implemented.

Transvaginal uterine ultrasonography compared with endometrial biopsy for the detection of endometrial disease in perimenopausal women with uterine bleeding.

BACKGROUND: Almost 70% of all gynecological consultations in perimenopausal women are related to irregular uterine bleeding. In this prospective study, we compared endometrial assessment by transvaginal ultrasonography (TVS) in perimenopausal women with irregular uterine bleeding to histological assessment and tested whether the TVS was effective as a diagnostic tool for the detection of endometrial pathology in these women. MATERIALS AND METHODS: Eighty consecutive perimenopausal women complaining of irregular uterine bleeding participated in the study. The women were evaluated by transvaginal scans, performed immediately before endometrial biopsy. The ultrasonographic results were compared with the histological diagnosis obtained from the endometrial biopsy. RESULTS: Sixty-seven out of 80 women (83.7%) had normal histological findings, whereas 13 (16.3%) had abnormal findings. No endometrial cancer was diagnosed in this cohort of women. In the 67 women with a histological diagnosis of normal endometrium, mean+/-SD endometrial thickness was 10.5+/-4.0 mm (range 4.0-18.5 mm), whereas the corresponding value in the 13 women with abnormal findings was 18.7+/-3.8 mm (range 13.5-22.5 mm). If a 13 mm cut-off limit was used for endometrial thickness, which would include all abnormal cases, the sensitivity, specificity and positive predictive values were 100%, 71.64% and 40.62%, respectively. CONCLUSION: TVS can identify women with perimenopausal bleeding in which the likelihood of endometrial pathology is high and in which tissue sampling should be performed. Thus, TVS can be a primary method of selecting women with perimenopausal bleeding who must be further investigated with more invasive methods such as endometrial biopsy.

Screening transvaginal uterine ultrasonography for identifying endometrial pathology in postmenopausal women.

BACKGROUND: During the last decade, transvaginal ultrasonography (TVS) has become a widely-used technique for the evaluation of endometrial histology. The purposes of this study were to compare transvaginal sonographic evaluation of the endometrium with histology obtained by endometrial biopsy in asymptomatic postmenopausal women and to determine whether screening transvaginal sonography might be useful in the evaluation of postmenopausal women. MATERIALS AND METHODS: The study included 59 unselected asymptomatic postmenopausal women who attended the outpatient clinic for annual cervical cytology at Ioannina University Hospital Greece. The women were evaluated by transvaginal scans, performed immediately before endometrial biopsy. RESULTS: In the 43 women with a histopathological diagnosis of normal endometrium/inadequate for assessment/atrophy, the mean endometrial thickness was 5.1 +/- 3.3 mm (range 0.8-13.8 mm) whereas the corresponding value in the 16 women with abnormal findings was 17.6 +/- 4.3 mm (range 9.4-24.6 mm) (p<0.001). If a 9 mm cut-off limit was used for endometrial thickness, the sensitivity, specificity and positive predictive value were 100%, 90.69% and 80%, respectively. CONCLUSION: TVS is a sensitive test for determining endometrial disease in asymptomatic postmenopausal women. However, well-designed studies should be conducted, completed, analysed and validated before a mass-screening program using TVS is implemented.

The presence of proprioceptive mechanoreceptors in the remnants of the ruptured ACL as a possible source of re-innervation of the ACL autograft.

This study investigated the presence of neural mechanoreceptors in the remnants of the ruptured ACL as a possible source of reinnervation of the ACL autologous graft. The remainder of the torn ACL was selected for further histological investigation from 17 patients during ACL reconstruction 3 months to 3.5 years after injury. Perioperatively two types of ACL remnant were identified. Fifteen patients had portions of ACL adapted at the PCL. In all of these patients we found mechanoreceptors (I and II). In five patients we found mushroomlike remnants which included either none or small numbers of mechanoreceptors. Free neural ends were found in both patient groups. There was a significant difference between the groups in regard to the mean number of mechanoreceptors I and II per slice. In conclusion, in patients with an ACL remnant adapted to the PCL, mechanoreceptors exist even 3 years after injury. If we accept that restoration of proprioception is the result of reinnervation of the ACL, leaving the ACL remnants as a source, if this is surgically possible without risk of Cyclop's lesion, may be of potential benefit to the patient.

Large loop excision of the transformation zone for treating cervical intraepithelial neoplasia: a 12-year experience.

BACKGROUND: Although the existing evidence suggests that there is no obviously superior conservative method for treating cervical intraepithelial neoplasia (CIN), one of the most widely used is the large loop excision of the transformation zone (LLETZ). MATERIALS AND METHODS: A total of 897 women who were treated with LLETZ at our colposcopy clinic from 1989 to 2000 were retrospectively studied. RESULTS: Forty women did not have significant cervical pathology (4.5% over-treatment rate). Clear margins of excision were obtained in 748 (88.5%) of the 845 cases of CIN or microinvasive cancers. Treatment failure rates were 4.7% for clear margins and 26.8% for involved or uncertain. CONCLUSION: LLETZ is a fast and reliable method of treating CIN and microinvasive carcinoma. Generalized cauterization of the resulting crater should be avoided and satellite HPV lesions ablated. Involved margins have a higher treatmentfailure rate, therefore a larger excision is recommended as cervical craters regenerate. Treatment in pregnant women can be delayed until postpartum provided they have adequate surveillance during pregnancy.

Expanded cytological referral criteria for colposcopy in cervical screening: comparison with human papillomavirus testing.

OBJECTIVE: The goal of this study was to investigate whether expanded cytologic referral criteria for colposcopy or the addition of human papillomavirus (HPV) testing on cervical screening could improve the rates of detection of cervical intraepithelial neoplasia (CIN). METHODS: HPV testing by semiquantitative polymerase chain reaction/ELISA was performed in 1000 women who were self-referred for routine Pap smear. They underwent colposcopy following an abnormal smear result or a positive HPV test. As abnormal smear results were considered reports of low- or high-grade squamous intraepithelial lesion, atypical squamous cells of undetermined significance, and even HPV-associated reactive cellular changes (mild koilocytosis, mild dyskeratocytosis, hyperchromatic nuclei, bimultinucleation, and cleared cytoplasm). Loop excision of the transformation zone was performed in women with cytology and colposcopy indicative of CIN, as well as in women with normal cytology but positive HPV test and colposcopic impression of CIN. RESULTS: The Pap test was abnormal in 89% of the cases of CIN 1 (34/38) and 96% of CIN 2/3 (27/28) diagnosed in our population. HPV testing picked up four additional cases of CIN 1 (11%) and one case of CIN 2/3 (4%). Overall the HPV test detected 95% of the cases of CIN 1 (36/38) and 89% of the cases of CIN 2/3 (25/28). CONCLUSION: HPV testing does not appear to add significantly to cytology in terms of positive predictive value or detection rate, if extended cytologic indications for colposcopy are used.

Contribution of exfoliative cytology to the diagnosis of laryngeal lesions.

OBJECTIVE: To estimate the diagnostic accuracy and reliability of exfoliative laryngeal cytology. STUDY DESIGN: Over three years (1996-1999) cytologic smears were obtained from clinically suspicious laryngeal lesions during laryngoscopy in a total of 31 selected patients (28 males and 3 females with an age range from 28-90 years). The cytologic diagnoses were analyzed and correlated with the histologic and final clinical diagnoses in 17 and 14 cases, respectively. Cytologic identification of the exact histologic type of the lesion was evaluated in 17 patients from whom both cytologic smears and biopsy material were obtained. RESULTS: The overall specificity was 100%, with no false positive diagnoses. The overall sensitivity was 93.3%, with one false negative cytologic diagnosis, in a case of non-Hodgkin's lymphoma. Cytohistologic correlation showed complete agreement between cytologic and histologic diagnoses in five of six benign lesions, in four cases of dysplasia and in six cases of squamous cell carcinoma. The overall diagnostic accuracy of cytology was 96.7% CONCLUSION: Exfoliative cytology by the smear technique is a reliable and accurate method in clinically suspected laryngeal lesions. Moreover, exfoliative cytology may be applied as the only alternative diagnostic method, especially in elderly patients with coexistent cardiorespiratory problems, when biopsy is not advisable or indicated.

Spontaneous evolution of human papillomavirus infection in the uterine cervix.

BACKGROUND: Little is known about the natural history and the malignant potential of low-grade cervical intraepithelial neoplasia associated with human papillomavirus (HPV) infection. Cervical cancer remains the second most frequent cause of death in women across the world. Epidemiologic and molecular studies have shown that human papillomavirus (HPV) is associated with cervical carcinogenesis. In this prospective study we examined the behavior of low-grade cervical intraepithelial lesions associated with HPV infection over a 6-year period. MATERIAL AND METHODS: During 1992, women with Papanicolaou smears reporting koilocytotic atypia (HPV effect) with or without grade 1 cervical intraepithelial neoplasia (HPV +/- CINI, low grade squamous intraepithelial lesions, LgSIL), along with colposcopic impression of LgSIL were included to the study. Between 1992 and 1998 all women underwent repeat Papanicolaou smears, colposcopic evaluation and HPV DNA testing every six months. HPV typing of cervical scrapes was done by PCR. RESULTS: A total of 330 women completed at least 6 years of follow up. Among women with high-risk HPV types (16/18), the presence of dysplasia (grade 1 cervical intraepithelial neoplasia) was significantly correlated with the progression of the lesion; 29% of cases with HPV + CINI (15 out of 75) progressed to more severe lesions versus only 9% of cases with HPV infection (18 out of 225), P < 0.001, chi-square test. The incidence of histologically confirmed progressive lesions was significantly greater in women with mild dysplasia (18 out of 75, 24%) compared to women without dysplasia (13 out of 255, 5%), P < 0.001, chi-square test. CONCLUSIONS: In our study HPV typing was not predictive of the evolution of low-grade intraepithelial lesions associated with HPV infection. Standard cytologic screening and colposcopy are the most effective means of monitoring low-grade lesions.

Antiproliferative activity of interferon gamma in superficial bladder cancer.

BACKGROUND: Although the antiproliferative activity of interferon gamma has been reported in various tumours, this has not been studied in bladder cancer. Proliferative cell nuclear antigen and Ki67 growth fractions were estimated in this study in superficial bladder cancer, as a measure of the antiproliferative effect of interferon gamma. MATERIALS AND METHODS: Superficial bladder cancer samples before and after four weekly intravesical instillations of 0.7 mg IFN gamma were studied immunohistochemically for proliferative cell nuclear (PCNA) and Ki67 antigens in 25 evaluable patients. RESULTS: Ki67 growth fraction decreased from median 5% preoperatively to 1% postoperatively (p = 0.0015) and proliferating cell nuclear antigen from 20% to 5% respectively (p = 0.0001). Net reductions of both indices after the interferon instillations were significantly higher in T1 than in Ta tumours (p = 0.0431 for Ki67, and p = 0.0350 for PCNA). CONCLUSIONS: The intravesical instillations of the present dose of interferon gamma have a significant cytostatic effect on superficial bladder cancer cells as this is evidenced by the significant decrease of the growth fractions measured by means of the proliferating cell nuclear and the Ki67 antigens.

Local immune response after intravesical interferon gamma in superficial bladder cancer.

OBJECTIVE: To investigate the lymphocyte subpopulations (T4, T8 and macrophages) and major histocompatibility (MHC) II antigens in patients with superficial bladder cancer before and after intravesical instillations of recombinant interferon-gamma (IFN-gamma). PATIENTS AND METHODS: Four intravesical weekly instillations of either 1.3 mg (20 patients, group A) or 0.7 mg (11 patients, group B) IFN-gamma were administered in 31 evaluable patients (28 men and three women, mean age 68.5 years). The CD4+, CD8+, CD68+ and HLA-DR antigens were detected immunohistochemically in tumours and a marker tumour before and after intravesical instillations. RESULTS: The median number of T4 lymphocytes increased from 15 per high-power field (HPF) to 27.5 in group A (P = 0.0029) and to 45 in group B (P = 0.0117). Macrophages increased from 6 cells/HPF to 15 cells/HPF in group A (P = 0.0029) and from 2 to 8.75 cells/HPF in group B (P = 0.0117). The T8 lymphocyte subpopulation decreased from 4 to 3 cells/HPF (P = 0.0231) in group A and from 5 to 2 cells/HPF (P = 0.0759) in group B. The median percentage of HLA-DR antigens increased from 1.5% to 18% in general, (P < 0.001), from 2.5% to 15% in group A (P = 0.0064) and from 0% to 20% in group B (P = 0.0077). The induction of HLA-DR antigens was statistically significant in those receiving the lower dose (from 0% before instillation to 20% afterward, P = 0.0277), while it was not with the higher dose (from 0% to 5%, P = 0.068). Irrespective of the dose of IFN used. T4 lymphocytes and macrophages increased significantly after treatment in patients in whom the tumour HLA-DR antigens were either up-regulated or remained stable. The median net increase in T4 cells was 17.5 and 30 cells/HPF for groups A and B, respectively (P = 0.0429). CONCLUSION: T4 lymphocytes, macrophages and HLA-DR antigens increased after intravesical IFN-gamma in patients with superficial bladder cancer, but T8 lymphocytes decreased. Irrespective of the drug dose used, patients with either upregulated or stable HLA-DR antigens after treatment showed the same pattern of changes in the lymphocyte subpopulations. The two doses generally had the same effect on the immunological variables assessed but the lower dose was more effective in inducing HLA-DR antigens and in increasing the number of T4 lymphocytes in the tumours.