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L Di Bonito

Publications and source records attributed to L Di Bonito.

At least 19 recordsLinked to original sources
PubMed2006

Up-regulation of proliferating cell nuclear antigen (PCNA) is closely associated with high-risk human papillomavirus (HPV) and progression of cervical intraepithelial neoplasia (CIN), but does not predict disease outcome in cervical cancer.

OBJECTIVE: Proliferating cell nuclear antigen (PCNA) is essential for DNA replication of mammalian cells and their small DNA tumour viruses. The E7 oncoprotein of high-risk human papillomavirus (HPV) is known to activate PCNA, shown to be up-regulated in CIN and cervical cancer (CC), but still incompletely studied as an intermediate endpoint marker in this disease. MATERIAL AND METHODS: As part of our HPV-PathogenISS study, a series of 150 CCs and 152 CIN lesions were examined using immunohistochemical (IHC) staining for PCNA, and tested for HPV using PCR with three primer sets (MY09/11, GP5+/GP6+, SPF). Follow-up data were available from all SCC patients, and 67 of the CIN lesions had been monitored with serial PCR for HPV after cone treatment. RESULTS: Expression of PCNA increased in parallel with the grade of CIN, with major up-regulation upon transition to CIN3 (OR 21.77; 95%CI 6.59-71.94) (p = 0.0001). Intense PCNA expression was 100% specific indicator of CIN, with 100% PPV, but suffers from low sensitivity (34.8%) and NPV (10.8%). PCNA expression was also significantly associated to HR-HPV with OR 3.02 (95%CI 1.71-5.34) (p = 0.0001), and this association was not confounded by the histological grade (Mantel-Haenszel common OR = 2.03; 95%CI 1.06-3.89) (p = 0.033). Expression of PCNA did not predict clearance/persistence of HR-HPV after treatment of CIN, and it was not a prognostic predictor in CC in univariate or in multivariate analysis. CONCLUSIONS: Up-regulation of PCNA was closely associated with HR-HPV and progressive CIN, most feasibly explained by the abrogation of normal cell cycle control by the E7 ongogene, reverting the p21(Cip1)-mediated inhibition of PCNA. However, the fact that PCNA is also expressed in normal squamous epithelium precludes the use of this marker as a potential screening tool for CC.

Adolescent↗
PubMed2006

Down-regulated nucleoside diphosphate kinase nm23-H1 expression is unrelated to high-risk human papillomavirus but associated with progression of cervical intraepithelial neoplasia and unfavourable prognosis in cervical cancer.

OBJECTIVE: One of the factors leading to an invasive phenotype is the nm23 family of metastases-associated genes. Of the six known members, nm23-H1 is the most frequently studied potential anti-metastatic gene in cervical cancer. However, the possible molecular links to oncogenic human papillomavirus (HPV) are completely unexplored as yet. MATERIALS AND METHODS: As a part of the HPV-Pathogen Istituto Superiore di Sanità study, a series of 150 squamous cell carcinomas (SCCs) and 152 cervical intraepithelial neoplasia (CIN) lesions were examined by immunohistochemical staining for nm23-H1, and tested for HPV by polymerase chain reaction (PCR) with three sets of primers (MY09/11, GP5(+)/GP6(+) and short PCR fragment). Follow-up data were available on all patients with SCC, and 67 CIN lesions were monitored by serial PCR for clearance or persistence of HPV after cone treatment. RESULTS: A linear decrease (p = 0.001) was observed in nm23-H1 expression, starting from CIN1 (85% with normal expression), with the most dramatic down regulation on transition from CIN2 (70% normal) to CIN3 (39%) and further to SCC (25%). Reduced expression was associated with CIN3 or cancer at an odds ratio 8.72 (95% confidence interval 4.13 to 18.41). Nm23-H1 was of no use as a marker of the high-risk human papillomavirus (HR-HPV) type, and it did not predict clearance or persistence of HR-HPV after treatment of CIN. Importantly, nm23-H1 expression was a significant prognostic factor in cervical cancer, reduced expression being associated with lower survival (p = 0.022) in univariate analysis. In the multivariate (Cox) regression model, however, only the International Federation of Gynecology and Obstetrics stage (p = 0.001) and age (p = 0.011) remained independent prognostic predictors. CONCLUSIONS: Down-regulated nm23-H1 expression is markedly associated with progression from CIN2 to CIN3, and predicts poor prognosis in cervical cancer. Nm23-H1 down regulation is probably orchestrated by mechanisms independent of HR-HPV oncoproteins and is possibly related to the emergence of a proteolytic phenotype.

Adolescent↗
PubMed2006

Upregulation of nuclear factor-kappaB (NF-kappaB) is related to the grade of cervical intraepithelial neoplasia, but is not an independent predictor of high-risk human papillomavirus or disease outcome in cervical cancer.

Nuclear factor-kappaB (NF-kappaB) has a pivotal function in controlling a wide variety of gene functions, and has shown to be constitutively activated in many human cancers. The molecular links of NF-kappaB to oncogenic human papillomavirus (HPV) in cervical intraepithelial neoplasia (CIN) lesions and its prognostic value in cervical cancer (CC) are incompletely understood. As part of our HPV-PathogenISS study, a series of 150 squamous-cell carcinomas (SCCs) and 152 CIN lesions were examined using immunohistochemical staining for NF-kappaB, and tested for HPV using PCR with three primer sets (MY09/11, GP5+/GP6+, and SPF). Follow-up data were available from all SCC patients, and 67 CIN lesions had been monitored with serial PCR for HPV clearance/persistence after cone treatment. Cytoplasmic NF-kappaB expression was associated with CIN3/cancer at OR 3.55 (95% CI, 1.79-7.05), while nuclear NF-kappaB expression had an OR of 21.90 (95% CI, 2.96-161.74) (P = 0.0001). Strong nuclear expression was a rare event (8.8%) also in CC, but it was related to high-risk human papillomavirus (HR-HPV) detection, with OR 2.15 (95% CI, 1.08-4.30) (P = 0.022). This association was confounded, however, by the histological grade (Mantel-Haenszel common OR = 1.46; 95% CI, 0.70-3.03) (P = 0.308). Cytoplasmic or nuclear NF-kappaB expression did not predict clearance/persistence of HR-HPV after treatment of CIN, and neither one proved to be a prognostic predictor in CC. Overexpression of cytoplasmic NF-kappaB is significantly associated with progression to CIN3 and cancer. This is paralleled by only a slight increase in nuclear expression of NF-kappaB, which could be explained by the mechanisms whereby HR-HPVs escape from the transcriptional control of NF-kappaB, i.e., E7-mediated impaired nuclear translocation of cytoplasmic NF-kappaB, and E6-conditioned attenuated NF-kappaB (p65)-dependent transcriptional activity.

Adolescent↗
PubMed2006

Upregulation of telomerase (hTERT) is related to the grade of cervical intraepithelial neoplasia, but is not an independent predictor of high-risk human papillomavirus, virus persistence, or disease outcome in cervical cancer.

Telomerase activation and telomere maintenance are essential for cell immortalization and represent a rate-limiting step in cancer progression. The E6 oncoprotein of high-risk human papillomavirus (HPV) is known to activate telomerase, but its expression in CIN lesions and its prognostic value in cervical cancer (CC) are still incompletely understood. As part of our HPV-PathogenISS study, a series of 150 CCs and 152 CIN lesions were examined using immunohistochemical (IHC) staining for hTERT (telomerase reverse transcriptase), and tested for HPV using PCR with three primer sets (MY09/11, GP5(+)/GP6(+), SPF). Follow-up data were available from all SCC patients, and 67 CIN lesions had been monitored with serial PCR for HPV after cone treatment. Expression of hTERT was increased in parallel with the grade of CIN, with major up-regulation upon transition to CIN3 (OR 18.81; 95% CI 8.48-41.69; P = 0.0001). Positive hTERT expression was 90% specific indicator of CIN, with 98.7% PPV, but suffers from low sensitivity (57.5%) and NPV (14.3%). hTERT expression was also significantly associated to HR-HPV with OR 3.38 (95% CI 1.90-6.02; P = 0.0001), but this association was confounded by the histological grade (Mantel-Haenszel common OR = 1.83; 95% CI 0.92-3.79; P = 0.086). Expression of hTERT did not predict clearance/persistence of HR-HPV after treatment of CIN, and it was not a prognostic predictor in cervical cancer in univariate or multivariate survival analysis. It was concluded that up-regulation of hTERT was closely associated with HR-HPV, due to activation by the E6 oncoprotein. hTERT is a late marker of cervical carcinogenesis, significantly associated with progression to CIN3. Theoretically, a combination of hTERT assay (showing high SP and PPV) with another test showing high SE and high NPV (e.g. Hybrid Capture 2 for HPV), should provide an ideal screening tool capable of high-performance detection of CIN lesions.

Adolescent↗
PubMed2006

Interlaboratory reproducibility of atypical glandular cells of undetermined significance: a national survey.

OBJECTIVE: The aim of this study was to evaluate the inter-laboratory reproducibility for atypical glandular cells (AGC) (The Bethesda System (TBS) 2001) of the laboratories involved in the screening programmes in Italy. METHODS: A set of 35 selected slides were circulated among 167 laboratories involved in local population-based cervical screening programmes. Each laboratory provided one single diagnosis per smear. The smears were read blind to the original diagnosis and to the diagnoses provided by other laboratories. A 'majority' diagnosis was defined for each case and assumed as the reference standard. The diagnosis provided from each laboratory was compared with the majority diagnosis. RESULTS: According to the majority report the 35 slides in the set were classified as negative in nine cases, AGC in eight, adenocarcinoma in eight, and squamous lesion or squamous + glandular lesion in 10. The crude agreement between all pairs of laboratories was 49.43%. K-values were 0.46, 0.21, 0.34, 0.36 and 0.32 for negative, AGC/AIS (adenocarcinoma in situ of endocervix), AdenoCa, Sq/Sq + Gl and all reporting categories respectively. Concordance according to overall K was moderate to substantial in 77% of the participating laboratories. CONCLUSIONS: The present study shows that the AGC category is not easily reproducible. The data confirmed the importance, in a screening scenario, of AGC/AIS diagnoses, but also presented difficulties in differentiating between the two diagnoses. In addition to the results obtained from the circulation of the slides, laboratories which had annually a low number of cervical smears were able to gain experience focused on particular morphological pictures.

Adenocarcinoma↗
PubMed2006

Aberrant expression of VEGF-C is related to grade of cervical intraepithelial neoplasia (CIN) and high risk HPV, but does not predict virus clearance after treatment of CIN or prognosis of cervical cancer.

AIMS: Increased angiogenesis leads to invasion in cervical cancer. Vascular endothelial growth factors (VEGFs) are involved in angiogenesis, but molecular links to the most important aetiological agent, human papillomavirus (HPV), need clarifying. MATERIAL/METHODS: Archival samples-150 squamous cell carcinomas (SCCs) and 152 cervical intraepithelial neoplasia (CIN) lesions-were examined immunohistochemically for anti-VEGF-C antibody and for HPV by polymerase chain reaction (PCR). Follow up data were available for all SCC cases, and 67 CIN lesions were monitored with serial PCR to assess HPV clearance/persistence after treatment. RESULTS: High risk (HR) HPV types were closely associated with CIN (odds ratio, 19.12; 95% confidence interval, 2.31 to 157.81) and SCC (27.25; 3.28 to 226.09). There was a linear increase of VEGF-C expression-weak in CIN1 and intense in CIN3 and SCC (20.49; 8.69 to 48.26). VEGF-C upregulation was a sensitive (93.5%; 95% CI, 90.1% to 96.9%) marker of HR-HPV type (4.70; 2.17 to 10.21), but lost its significance in multivariate regression-p16(INK4a) and survivin were equally strong independent predictors of HR-HPV. Aberrant expression of VEGF-C did not predict clearance/persistence of HR-HPV after treatment of CIN. In cervical cancer, VEGF-C had no prognostic value in univariate or multivariate survival analysis. After adjustment for HR-HPV, FIGO stage, age, and tumour grade, only FIGO stage and age remained independent prognostic predictors. CONCLUSIONS: VEGF-C is an early marker of cervical carcinogenesis, with linearly increasing expression starting from low grade CIN. VEGF-C expression is closely related to HR-HPV in cervical lesions, probably because of its p53 independent upregulation by the E6 oncoprotein of HR-HPV.

Adolescent↗
PubMed2006

Down-regulation of E-cadherin is closely associated with progression of cervical intraepithelial neoplasia (CIN), but not with high-risk human papillomavirus (HPV) or disease outcome in cervical cancer.

OBJECTIVE: E-cadherin plays a pivotal role in maintenance of normal adhesion in epithelial cells but has also been shown to suppress tumour invasion and participate in cell signalling. Known to be capable of reversing the invasive phenotype of high-risk human papillomavirus (HPV)-transformed keratinocytes, E-cadherin is down-regulated in CIN and cervical cancer (CC), but still incompletely studied as an intermediate endpoint marker in this disease. MATERIAL AND METHODS: As part of our HPV-PathogenISS study, a series of 150 CCs and 152 CIN lesions were examined using immunohistochemical (IHC) staining for E-cadherin, and tested for HPV using PCR with three primer sets (MY09/11, GP5+/GP6, SPF). Follow-up data were available from all squamous cell carcinoma (SCC) patients, and 67 CIN lesions were monitored with serial PCR for HPV after cone treatment. RESULTS: Expression of E-cadherin was reduced in parallel with the increasing grade of CIN, with major down-regulation upon transition to CIN3 and further to invasive cancer (OR 6.95; 95% CI 2.67-18.09) (p = 0.0001). Negative markedly reduced E-cadherin expression was a 90.9% specific indicator of CIN, with 97.4% PPV, but suffered from low sensitivity (27.0%) and NPV (9.1%). E-cadherin expression was completely unrelated to HR-HPV (p = 0.982), and did not predict clearance/persistence of HR-HPV after treatment of CIN. Similarly, E-cadherin expression was not a prognostic predictor of CC in univariate or multivariate analysis. CONCLUSIONS: Down-regulation of E-cadherin was closely associated with progressive CIN and cell proliferation. It is tempting to speculate that part of this cell proliferation is mediated through the canonic Wnt signalling pathway, after liberation of transcriptionally competent beta-catenin from the E-cadherin/catenin complex, most notably orchestrated by E6 and E7 oncoproteins of HR-HPV. Such a liberation of beta-catenin would abrogate the negative transcriptional control of E-cadherin on the Lef/TCF/beta-catenin responsive genes. The exact role of HR-HPV oncoproteins E6 and E7 in this process remains to be seen in future studies.

Adolescent↗
PubMed2004

p16(INK4A) expression is related to grade of cin and high-risk human papillomavirus but does not predict virus clearance after conization or disease outcome.

The role of p16(INK4A) as a marker of HR-HPV and in the diagnosis of CIN has been well established, but its predictive value in the clearance of the virus after CIN treatment and its use as a prognostic marker of cervical cancer has not been studied. A series of 302 archival samples, including 150 squamous cell carcinomas (SCCs) and 152 CIN lesions, were subjected to immunohistochemical staining for p16(INK4A) and HPV testing using PCR with three primer sets (MY09/11, GP5/GP6, SPF). Follow-up data were available of 88 SCC patients, and 67 of the CIN lesions had been followed-up with serial PCR after conization. HR-HPV types were closely associated with CIN (OR 19.12; 95%CI 2.31-157.81) and SCC (OR 27.25; 95%CI 3.28-226.09). There was a significant linear relationship between the lesion grade and intensity of p16(INK4A) staining (p = 0.0001). The expression of p16(INK4A) was also closely related to HR-HPV (p = 0.0001). p16(INK4A) staining was a 100% specific indicator of CIN, with 100% PPV, and showed 83.5% sensitivity and 80.1% PPV in detecting HR-HPV. However, p16(INK4A) staining did not predict clearance/persistence of HR-HPV after treatment of CIN. Similarly, despite a slightly more favorable survival in women with strong/intense p16(INK4A) staining in univariate analysis, p16(INK4A) expression was not an independent prognostic predictor in multivariate survival (Cox) analysis. After adjustment for p16(INK4A) staining, HR-HPV, histological grade, International Federation of Gynecology and Obstetrics (FIGO) stage, and age, only the last two were significant prognostic predictors (p = 0.0001 and p = 0.003, respectively). The present data confirm the role of p16(INK4A) as a highly specific marker of CIN and HR-HPV type, but expression of this protein does not seem to be of any prognostic value in cervical cancer or in predicting the clearance of HR-HPV after treatment of CIN. We speculate that different subgroups of cervical cancer are characterized by aberrant p16(INK4A)/cyclin D/Rb pathways that are due to different mechanisms that can be mutually exclusive.

Adolescent↗
PubMed2002

Papnet-assisted cytological diagnosis intensifies the already marked variability among cytological laboratories.

OBJECTIVE: The main objective was to assess the sensitivity, specificity and reliability of PAPNET-assisted diagnosis in comparison with conventional screening. SETTING: Seven Italian and one English University or Research Institutes, and a random sample of an other 20 Italian Laboratories of the Italian National Health Service (INHS) provided the cervical smears. METHODS: During the training phase every center examined in rotation four sets of slides for a total of 300 representative slides. Afterwards, 900 "positive" slides were added to the 3,100 slides which were collected consecutively without any selection or exclusion. The eight main centers were divided into four couples and each couple of centers examined 775 slides with the PAPNET system, "blindly" to the original diagnosis. An expert cytopathologist (M.A.) of the National Institute of Health (NIH) reassessed 40% of the slides with an original negative diagnosis to evaluate the false negative rate. Two expert NIH cytopathologists (M.A., G.M.) re-examined all slides where a disagreement had been observed between the original and one or both of the study diagnoses. The main analyses concerned the following three main categories: WNL and unsatisfactory for evaluation; ASCUS, AGUS and LSIL; HSIL and carcinoma. A special algorithm was devised to define the reference diagnosis for sensitivity and specificity assessment. RESULTS: Laboratories, even belonging to the same couple, classified as "no review" a very different proportion of slides ranging from 35% to 74%. The index of kappa agreement between the members of couples examining the same sets of slides was low or very low, ranging from 0.30 to 0.03. The sensitivity of the review classification was particularly low in some laboratories. Surprisingly, only a small correlation was observed between the sensitivity of the review classification and the proportion of slides classified as "review". The "tentative" diagnosis on PAPNET tiles of the "review" slides was almost as reliable as the microscopic diagnosis. In the overall performance, there were many significant differences among the eight laboratories. The best laboratory had a sensitivity of 95% and a specificity of 96%. At least three laboratories displayed unacceptably low sensitivity and one a very low specificity. CONCLUSION: Altogether these results seem to confirm that there are wide differences among cytological laboratories per se, and that these differences are intensified by the use of an instrument like PAPNET. The huge variation in performance may be explained by differences in basic skills and by different training, but it is difficult to understand exactly what could have been done to reduce it.

Autoanalysis↗
PubMed2000

Role of fine-needle aspiration cytology in nonpalpable mammary lesions: a comparative cytohistologic study based on 308 cases.

We retrospectively evaluated the accuracy of fine-needle aspiration cytology (FNAC) in nonpalpable breast lesions detected by imaging techniques between 1995-1997. A total number of 308 lesions was investigated: 273 had been studied by means of either FNAC obtained under ultrasound (175 cases) or stereotactic guidance (98 cases). The overall sensitivity rate was 87.8%; specificity was 95.3%; the positive predictive value was 76.6%; the negative predictive value was 97.8%. Our results confirm that FNAC is quite effective in the approach to patients with nonpalpable breast lesions. It is particularly accurate in diagnosing malignancy, although a lower yield may be encountered in tumor types producing a desmoplastic stroma (tubular carcinoma, infiltrating lobular carcinoma) or in noncomedonic in situ ductal carcinoma. Discrepancy between a suspicious cytology and a negative histology is more frequent with benign lesions usually because of sampling mistake or technically inadequate smears. In particular, when smears are adequate, FNAC safely assists in ruling out the malignant lesions.

Adenocarcinoma↗
PubMed1998

Expression of HMGI(Y) proteins in squamous intraepithelial and invasive lesions of the uterine cervix.

The expression of nuclear proteins high mobility group (HMG) I and HMGY was investigated in intraepithelial and invasive lesions of the uterine cervix. Human carcinoma cell lines C-41, ME-180, and CaSki were used for testing protein expression in neoplastic cells from the cervix. Morphological grading of the dysplasias (CIN 1, CIN 2, and CIN 3) and invasive carcinomas from formalin-fixed paraffin-embedded samples parallels the degree of nuclear immunostaining obtained using a polyclonal antibody raised against the amino-terminal region of HMGI(Y) proteins. The immunostaining obtained with HMGI(Y) antibody was compared with that observed using the antibody Ki-67, and the results were similar. We suggest the use of HMGI(Y) antibody in clinical oncology as a useful marker of intraepithelial lesions and invasive carcinomas.

Antibodies, Monoclonal↗
PubMed1997

Gestational squamous cell carcinoma of the breast: an unusual mammary tumor associated with aggressive clinical course.

We report two cases of squamous carcinoma of the breast detected during the gestational period. One woman was post-partum and lactating; one was in the first trimester of pregnancy. The lesions were clinically palpable, multifocal, and measured more than 5 cm in their largest dimension; both had a cystic appearance. They were treated with radical mastectomy. One patient received pre-operatory chemotherapy. Histologically, the tumors were poorly differentiated squamous cell carcinomas. No areas of ordinary duct differentiation were seen. Lymph nodes contained metastatic squamous carcinoma in both cases. Tumor cells were negative for estrogen and progesterone receptors. Also, they expressed a high proliferative index and several markers of tumor progression, including cErb-B2, p53 protein, bcl-2, and epidermal growth factor receptor. One patient died of tumor 5 months following breast surgery and had extensive metastases proven at autopsy. The other patient had evidence of pulmonary metastases: following cisplatin therapy, she underwent clinical remission. This study shows that squamous carcinoma of the breast may occur in pregnant or lactating women: it appears clinically distinguishable from the non-gestational type that is usually associated with a better prognosis and occurs in peri- or postmenopausal women.

Adult↗
PubMed1996

Inflammatory fibrosarcoma: another imitator of Hodgkin's disease?

We report a case of inflammatory fibrosarcoma occurring in a 49 year-old man, that manifested with distinct multinodular masses in the mesentery. Histologically, the lesion was characterized by spindle fibroblast-like cells, histiocytes, pool of lymphocytes and eosinophils, abundant fibrous to hyaline stroma, and numerous "ganglion" cells. Of special interest was the presence of large multinucleated tumor cells which displayed optically clear nuclei and prominent nucleoli, bearing a deceitful resemblance to the diagnostic Reed Sternberg cells of Hodgkin's disease. The differential diagnosis between the two conditions rests on the evaluation of the appropriate clinical background, as well as on an in-depth assessment of the basic pathologic features. Immunohistochemical reactivity of spindle and ganglion cells for actin along to complementary negativity for CD15, and CD30 further assists in separating the two conditions.

Abdominal Neoplasms↗
PubMed1996

Histopathology of the frozen prostate. The microscopic bases of prostatic carcinoma cryoablation.

In the last few years percutaneous cryoablation surgery of the prostate has been re-introduced as an alternative means to treat prostatic carcinoma. Advantages of the technique include local effectiveness in eradicating tumors, minimal morbidity rate and lower costs when compared to radical surgery. We report a study documenting the histopathological changes seen in 317 biopsy specimens obtained from 30 patients (age range 59-83 years, median 73 years) treated with cryosurgical ablation for prostate cancer. Pre- and postoperatory assessment was inclusive of plain clinical, laboratory and instrumental data (digital rectal examination, transrectal ultrasound scan, serum prostatic specific antigen concentration) and systematic biopsies obtained from conventional and modified prostate sextants. Fifteen patients had tumors extending through the prostate capsule (pT3 and pT4). Six patients had stage PT1 tumors and 9 had stage pT2. Tissues were sampled at 3, 6 and between 12-18 months postoperatively. The histologic findings, in decreasing order of frequency, were: full core fibrosis, necrosis, granulation tissue, basal cell hyperplasia, cell swelling, hemosiderin deposits, chronic inflammation, thick nerves and prostatic hyperplasia. Necrosis was of the coagulative type, sometimes associated with nuclear debris, and seen at relatively short interval from cryotherapy. Fibrosis with hyaline qualities was seen especially at 12-18 month interval. The presence of necrosis, as well as granulation tissue, hemosiderin deposits and cell swelling, strongly correlate to intervals from cryosurgical ablation. Residual tumor tissue was focal (0.5-1 mm) and recognizable in 9 cores from 4 patients (13.3%) sampled especially from the prostatic apex. Incipient tumor necrosis was seen in 11 cores, without particular distribution. These findings indicate that cryosurgery results in distinctive changes in both tumoral and non-tumoral prostate tissue. Knowledge of the histopathologic patterns is important since it provides the clinicians with information on treatment efficacy or failure, and could assist in the selection of larger groups of patients eligible to cryosurgical ablation.

Aged↗