High-grade Premalignant Lesions Research Articles

268 DEGAS: Deep transfer learning reveals cancer-like transcriptional signatures in histologically normal prostate tissue and adjacent-normal tissues in pancreatic cancer

OBJECTIVES/GOALS: Single-cell and spatial transcriptomics have revealed high heterogeneity in the tumor and microenvironment. Identifying populations of cells that impact a patient’s prognosis is an important research goal, so researchers can generate hypotheses and clinicians can provide targeted treatment. METHODS/STUDY POPULATION: DEGAS uses deep-transfer-learning to identify patterns between patient tumor RNA-seq and clinical outcomes and map these associations on to higher-resolution data like spatial and single-cell transcriptomics. We apply DEGAS to prostate and pancreatic cancer spatial transcriptomics samples, as well as one normal sample of prostate tissue. We used the TCGA prostate cancer cohort to with the accompanying survival information and publicly accessible prostate cancer ST data from 10X Genomics to predict survival associations in the ST slides derived from the TCGA patients. Based on these survival associations, we identify higher risk subsections of ST slides which can be further studied. RESULTS/ANTICIPATED RESULTS: We were able to validate our method by comparing it to Scissor and were able to show that the number of high-risk regions in prostate cancer slides increased with the stage of disease. Furthermore, we identify transcriptomic signatures enriched for ontology terms associated with growth regulation and apoptosis, inflammation, immune signaling, and autophagy in histologically normal prostate tissues and adjacent normal pancreatic cancer tissues that were identified as high-risk by DEGAS. The regions highlighted by DEGAS could reflect transcriptional precursors to intraepithelial neoplasia–a well-recognized premalignant morphological change in glandular epithelium. DISCUSSION/SIGNIFICANCE: Identifying biomarkers of tissue stress that precede morphologic diagnosis of high-grade pre-malignant lesions by a pathologist may help triage patients at high risk for future development of cancer, or aid in better understanding whether histologically normal pre-malignant tissues at tumor margins contribute to recurrence.

ROLE OF NARROW BAND IMAGING IN DIAGNOSIS AND DIODE LASER IN MANAGEMENT OF PREMALIGNANT LESIONS OF ORAL CAVITY AND ORO PHARYNX

Head neck tumors are Heterogenous group of cancers arising from different anatomical parts with different predisposing factors prevalence and outcomes. The most common type of cancer in the oral cavity and oropharynx is called squamous cell carcinoma. Narrow band imaging (NBI) is one of the most frequently used optical digital methods of performing non-invasive image-enhanced endoscopy . The gold standard for management of the clinically more suspicious high-grade premalignant lesions is excision or laser ablation. Laser is an advanced technology receiving a lot of attention in research because of its advantages compared to other ablation techniques, such as higher efficacy, safety and precision, and shorter time period treatment needed to achieve the same result

Phylogenetic origin of Helicobacter pylori pathogenicity island and risk of stomach cancer and high-grade premalignant gastric lesions.

Infection by Helicobacter pylori (Hp) has been causally linked to risk of gastric cancer (GC). The coevolution of Hp and humans shaped the risk of GC as our species left Africa and migrated to the other continents. Latin America (LatAm) is a high GC incidence region where Hp evolved uniquely in the 500 years since European colonization. Differential virulence of the Hp cagA -pathogenicity island (cagPAI) by ancestral origin has been reported. We hypothesized that Hp phylogenetic origin might play a role in determining GC risk in LatAm. We used genotypes of 50 Hp genetic variants mapping to the Hp cagPAI, studied in 1220 subjects from Venezuela, Colombia, Mexico and Paraguay, who were infected with cagA-positive Hp, including 150 GC, 177 high-grade premalignant lesions (HGPMLs) and 893 low-grade premalignant lesions. We estimated the phylogenetic origin of Hp cagPAI in all study subjects by use of the STRUCTURE software and principal component analysis (PCA) and tested whether the estimated African ancestry percentage was associated with the risk of GC or HGPML. African ancestral component estimates by STRUCTURE and PCA were highly correlated. STRUCTURE-based African origin estimate was not significantly associated with the risk of HGPML, but it was inversely associated with GC risk: the OR associated with the continuous values of African component was 0.09 (95% CI, 0.01-0.85; P = 0.035). Similar trends were observed for GC with PCA-based estimates, but the association was not statistically significant. These results suggest that Hp ancestral origin may play a role in gastric carcinogenesis.

Abstract 5948: Modeling lung squamous cell carcinoma progression using primary human bronchial basal cells

Abstract Background: Lung squamous cell carcinoma (LUSC) arises from the accumulation of genetic driver alterations in bronchial basal cells. LUSC genomes lack obvious actionable mutations and present with a high degree of inter-tumor heterogeneity. Tractable, patient relevant models are needed to study LUSC pathogenesis and investigate the role of recurrent genomic alterations in driving cancer progression. Therefore, we are developing a tractable human model of LUSC progression to increase our understanding of this disease. Methods: To investigate the contribution and co-operation of frequently mutated genes (TP53 and CDKN2A) and commonly deregulated pathways (SOX2/P63, PI3K/AKT and KEAP1/NRF2 pathways) in driving LUSC progression, we genetically engineered primary human bronchial basal cells. This culminated in eight basal cell mutants harboring ubiquitous LOF alterations in TP53 and CDKN2A combined with additional pathway alterations. To assess the function of the genetic alterations in LUSC progression, we investigated proliferation using cell cycle analysis and colony forming assays. Air-liquid interface organotypic cultures were used to model histological changes in the bronchial epithelium driven by different combinations of mutations. The resultant cultures were analyzed for changes in histology indicative of LUSC progression using immunostaining to evaluate changes to epithelial cell proliferation, and expression of LUSC biomarkers. Results: Increases in proliferation were driven by inactivation of TP53, CDKN2A and PTEN, whereas SOX2 overexpression inhibited mutant basal cell proliferation. LUSC alterations also drove striking phenotypic changes in 3D organotypic cultures of the bronchial epithelium. All mutant cultures displayed thickening of the bronchial epithelium and significantly increased cellularity (p<0.001), indicating hyper-proliferation. SOX2 overexpression inhibited mucociliary differentiation and drove the appearance of a disordered epithelium with clear cellular and nuclear pleomorphism, indicative of high-grade premalignant lesions. Conclusions: We developed a basal cell model of recurrent LUSC genetic alterations. This approach is unique due to [1] the use of primary human cells and [2] the representation of interpatient heterogeneity and developmental stages by introducing different combinations of pathway alterations. Early results indicate that basal cells carrying cumulative alterations display increasingly complex phenotypes with features of low and high-grade premalignant lesions. Further work is required to assess the tumorigenicity of mutant cells. Citation Format: Julia Ogden, Caroline Dive, Carlos Lopez Garcia. Modeling lung squamous cell carcinoma progression using primary human bronchial basal cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5948.

Synbiotic sheep milk ice cream reduces chemically induced mouse colon carcinogenesis

Sheep dairy products containing prebiotic and probiotic ingredients may have health-promoting properties. Thus, this study evaluated the effects of sheep milk ice cream [conventional full-fat (CONV), full-fat enriched with probiotic (PROB, 100 mg % wt/wt of Lacticaseibacillus casei 01), or nonfat synbiotic (SYNB, Lacticaseibacillus casei 01 and inulin, 10% wt/wt)] on carcinogen-induced colonic crypt cytotoxicity and premalignant lesion development. Male Swiss mice received 2 doses of colon carcinogen azoxymethane (AOM, 15 mg/kg of body weight) at wk 3 and 4. Two weeks before and during AOM administrations (4 wk) mice were treated with CONV, PROB, or SYNB by gavage (10 mL/kg). Mice were euthanized at wk 4 or 25 (n = 5 or 10 mice/group, respectively). At wk 4, a significant reduction in micronucleated colonocytes was observed in PROB and SYNB groups, and a significant decrease in both p53 expression and apoptosis indexes in colonic crypts was observed in SYNB group. At wk 25, both PROB and SYNB interventions reduced the mean number of colonic premalignant lesions. However, only SYNB group showed lower incidence and number of high-grade premalignant lesions in the colonic mucosa. These findings indicate that PROB or SYNB sheep milk ice cream, especially SYNB intervention, can reduce chemically induced mouse colon carcinogenesis.

Keratin 17 Expression Predicts Poor Clinical Outcome in Patients With Advanced Esophageal Squamous Cell Carcinoma.

The major roles of keratin 17 (K17) as a prognostic biomarker have been highlighted in a range of human malignancies. However, its relevance to esophageal squamous cell carcinoma (ESCC) remains unexplored. In this study, the relationship between K17 expression and clinicopathologic parameters and survival were determined by RNA sequencing (RNA-Seq) in 90 ESCCs and by immunohistochemistry (IHC) in 68 ESCCs. K17 expression was significantly higher in ESCC than in paired normal tissues at both the messenger RNA and protein levels. K17 messenger RNA and staining by IHC were significantly correlated with aggressive characteristics, including advanced clinical stage, invasion depth, and lymph node metastases; and were predictive of poor prognosis in advanced disease patients. Furthermore, K17 expression was detected by IHC in high-grade premalignant lesions of the esophageal mucosa, suggesting that K17 could also be a biomarker of dysplasia of the esophageal mucosa. Overall, this study established that K17 is a negative prognostic biomarker for the most common subtype of esophageal cancer.

Abstract B18: The carcinogen-induced NTCU model: A preclinical mouse model for lung cancer interception

Abstract Lung cancer is the leading cause of cancer mortality due in part to an inability to diagnose and intercept the disease at its earliest and potentially most curable stage. In order to improve lung cancer prevention and early detection, a detailed understanding of both the genomic alterations driving carcinogenesis and the mechanisms by which altered cells escape immune surveillance is required. Toward this goal, our group is profiling RNA and DNA from bronchial premalignant lesions (PMLs), precursors of lung squamous cell carcinoma (LUSCC), to identify alterations associated with their development and progression. Results from the analysis of 197 human endobronchial biopsies representing all histologic grades profiled by RNA-Seq, identified a class of high-grade PMLs with high activity of pathways associated with epithelial proliferation and differentiation. Among this class of PMLs, progression-associated pathways included immunoproteasome, antigen processing, immune inhibition, and macrophage activation. Further elucidation of the epithelial and immune changes that characterize progression of PMLs and testing of interception strategies based on these human findings require a preclinical model with similar histology and molecular alterations. The N-nitrosotris-(2-choroethyl)urea (NTCU) mouse model of LUSCC is a promising preclinical model that develops histologically comparable PMLs to those found in humans; however, the molecular alterations associated with these histologic changes have not yet been characterized. In order to establish molecular concordance between NTCU-treated mouse and human PMLs, we isolated RNA from 40 fresh-frozen whole lung sections and laser capture microdissected (LCM) tissue from SWR/J and A/J mice treated with NTCU. We profiled by RNA-Seq tissue that represented a range of histologic grades including normal (n=9), metaplasia/mild dysplasia (n=8), moderate/severe dysplasia (n=19), and carcinoma in situ/SCC (n=4). RNA-Seq data was aligned to mm9 and gene-level counts were summarized using Ensembl annotation. After removing samples of low quality, linear modeling adjusting for sample quality, sample type, and mouse strain was used to identify differentially expressed genes associated with histologic grade. Immune cell abundance was estimated using CIBERSORT and EnrichR was used to identify pathways associated with histologic grade. Concordance between the mouse data and human data was established using GSEA and GSVA. We identified 596 genes differentially expressed with increasing histologic severity across all mouse samples (FDR<0.05). The genes are involved in cancer signaling including protein processing, DNA damage, and p53 signaling as well as immune regulation including interferon signaling and lymphocyte and myeloid cell regulation (FDR<0.05). Upon further investigations of the immune-associated changes, we observed increases in T-cell populations in moderate dysplasia samples that declined in more severe lesions. Comparing the mouse strains, the SWR/J strain had more variability in immune cell content and types of immune cells, and the A/J strain had a more prominent macrophage polarization with increasing histologic severity. We also identified significant concordance of gene expression differences associated with histology between mouse and human (FDR<0.05). Concordant enrichment included alterations in DNA damage, cell cycle, and mitochondrial respiration in addition to immune modulation associated with progression of PMLs in human lesions. The results suggest that molecular changes and immune modulation in the NTCU model are similar to those observed in human PMLs. This work indicates that the NTCU mouse model may be a relevant preclinical model for investigating targeted agents to halt or reverse PML progression to reverse or delay lung cancer development in the damaged epithelium. Citation Format: Sarah Mazzilli, Sherry Zhang, Gang Liu, Marc Lenburg, Avrum Spira, Jennifer Beane. The carcinogen-induced NTCU model: A preclinical mouse model for lung cancer interception [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B18.

HPV 16 E2 binding sites 1 and 2 become more methylated than E2 binding site 4 during cervical carcinogenesis.

E2 protein binding to the four E2 binding sites (E2BSs) at the long control region of Human Papillomavirus (HPV) 16/18 genome may exert either transcriptional activation/repression on E6 and E7 oncoproteins. Methylation status at the E2BSs may affect the relative binding of E2 protein to them. In this study, methylation percentage at E2BS 1, 2 (promoter-proximal), and 4 (promoter-distal) were assessed by pyrosequencing and compared among HPV 16/18-positive cervical cancer, high-grade, and low-grade Cervical Intraepithelial Neoplasia, Atypical Squamous Cells of Undetermined Significance, and normal cervical epithelium. HPV 16 E2BS1&2 were more methylated than HPV 16 E2BS4 in cervical cancer whereas in cervical premalignant lesions and normal epithelium, HPV 16 E2BS1&2 were less methylated than HPV 16 E2BS4. HPV 18 E2BS1&2 remained more methylated than E2BS4 in all histological groups. HPV 16 E2BS1&2 methylation increased from high-grade lesions to cervical cancer (P < 0.001). HPV 16 E2BS4 methylation increased from low-grade to high-grade premalignant lesions (P = 0.041). Both HPV 18 E2BS1&2 and E2BS4 methylation increased from low-grade to high-grade Cervical Intraepithelial Neoplasia (P = 0.019 and 0.001 respectively) and further increased form high-grade lesions to cervical cancer (P < 0.001 and 0.005 respectively). Conclusively, HPV 16 E2BS1&2 (for transcriptional repression of E6/E7 oncoproteins) became more heavily methylated than E2BS4 (for transcriptional activation of E6/E7) in cervical cancer, favouring the differential binding of E2 protein to E2BS4. Increasing methylation at HPV 16/18 E2BSs are potentially useful adjunctive molecular markers for predicting progression from low-grade to high-grade cervical premalignant lesions and from high-grade lesions to cervical cancer.

Precursors of Breast Cancer

It has become apparent that estrogen receptor (ER) - positive and - negative breast lesions are completely distinct diseases. Precursors of low-grade breast cancer are low-grade premalignant lesions, usually ER and progesterone receptor (PR) positive and HER2 negative. On the other hand, precursors of high-grade breast cancer are high-grade premalignant lesions, usually ER and PR negative and HER2 positive. Lobular neoplasia (LN) and ductal carcinoma in situ (DCIS) are important from the clinical point of view. LN increases the risk of bilateral breast cancer. This is why the recommendation for the treatment of LN is very different - from just following up up to bilateral mastectomy. The complete surgical excision of the lesion with negative margins is the usual treatment of DCIS. Several big randomized clinical trials showed the benefit of adjuvant radiotherapy (RT). Some of them suppose that there is a group of patients who do not need adjuvant treatment. The benefit of adjuvant tamoxifen is clear only for patients with ER positive disease. The UK/ ANZ study showed the benefit of tamoxifen only in patients without RT.

Chromosomal gains and losses in human papillomavirus-associated neoplasia of the lower genital tract – A systematic review and meta-analysis

BackgroundOverexpression of the human papillomavirus (HPV) oncogenes E6 and E7 is necessary for the development of distinct lower genital tract cancers. However, secondary cellular genomic alterations are mandatory to promote progression of HPV-induced premalignant stages. We aimed at identifying the chromosomal regions most frequently gained and lost and the disease stage at which the latter occurs. These regions might be relevant for carcinogenesis and could serve as diagnostic markers to identify premalignant lesions with high progression risk towards invasive cancer. MethodsWe performed a systematic literature review and meta-analysis of studies listed in PubMed that analysed chromosomal copy number alterations by comparative genomic hybridisation (CGH) in HPV-positive and -negative cancers or premalignant lesions of the anogenital tract (cervix, anus, vagina, penis and vulva). FindingsData were extracted and analysed from 32 studies. The most common alterations in cervical squamous cell carcinoma (SCC) (12 studies, 293 samples) were gains at 3q with a rate of 0.55 (95% confidence interval (CI) 0.43–0.70), losses at 3p (0.36, 95%CI 0.27–0.48) and losses at 11q (0.33, 95%CI 0.26–0.43). Gains at 3q were particularly frequent in HPV16-positive cervical SCC (0.84, 95%CI 0.78–0.90). Also more than one quarter of high grade cervical intraepithelial neoplasia (CIN) harboured gains of 3q (0.27, 95%CI 0.20–0.36), but the rate in low grade CIN was low (0.02, 95%CI 0.00–0.09). For HPV-associated vulvar SCC (four studies, 30 samples) the same common alterations as in cervical SCC were reported. Studies on non-cervical and non-vulvar SCC and premalignant lesions of the lower genital tract are scarce. Interpretation3q gains were most frequently found in HPV16-positive cervical SCC. The results suggest the selection of HPV-transformed cell clones harbouring 3q gains in high grade premalignant lesions, while alterations in low grade lesions are rare.

A phase II trial of cetuximab in high-risk premalignant lesions of the upper aerodigestive tract.

5528 Background: High risk head and neck premalignancy includes patients with prior HNSCC and loss of heterozygosity (LOH). These patients demonstrate 30-60% rates of progression to malignancy despite conventional surgical excision. We performed a phase II trial using short term therapy with cetuximab, a humanized monoclonal antibody directed against EGFR, in the treatment of high risk premalignant lesions of the UADT. Methods: Inclusion criteria required; 1) presence of 3p, 9p21, or 17p LOH, and/or 2) surgically unresectable high grade premalignant lesions, and/or 3) high grade premalignancy after curative therapy for HNSCC. Patients received cetuximab 400 mg/m2 on week one followed by 250 mg/m2 on week 2-8 or observation, with the option for crossover to cetuximab for patients originally randomized to the observation arm. Histologic grade (1=benign, 2=mild dysplasia, 3=moderate dysplasia, 4=severe dysplasia/carcinoma in situ, 5=invasive cancer) and change in grade of dysplasia was evaluated. Results: 19 patients were enrolled. Two patients discontinued therapy due to toxicity. We noted a decrease in grade of dysplasia in the cetuximab treated group (-1.0) vs. the observation group (-0.2), (Wilcoxon test p value = 0.18). In the observation group, 0/5 patients (0%) underwent complete resolution of dysplasia; while 4/12 (33.3%) treated patients had no remaining dysplasia after therapy (p = 0.26), three of these patients had complete resolution of dysplastic changes after cetuximab therapy alone. Of these three patients, two have had no recurrence of leukoplakia or dysplasia at 1.5 and 2 years. One patient treated with oral cavity dysplasia has had no recurrence of dysplasia or lesions within the oral cavity, but developed a hypopharyngeal cancer at 1.5 years after trial completion. Of 5 patients randomized to observation, three underwent crossover to cetuximab therapy, and two of these three patients had complete resolution of dysplasia. Conclusions: EGFR blockade with cetuximab alone can result in significant, durable, and complete clinical and histological resolution of moderate to severe dysplasia in at least a subset of high risk patients.

Follow-up after LLETZ: a study of 682 cases of CIN 2–CIN 3 in a single institution

To evaluate the importance of resection margins in the risk of persistent/recurrent lesions and to investigate other factors such as detection of high-risk HPV, which could potentially predict persistent/recurrent disease before patients engage in follow-up. 682 women with a histologically confirmed diagnosis of CIN 2-3 treated by loop electrosurgical excision procedure (LEEP) were included, between January 2000 and December 2006. Age, high-risk HPV detection determined by Hybrid Capture II and cone margins were evaluated as possible predictors of persistent/recurrent disease. The mean age at diagnosis was 37.8 years (range 18-73). The mean follow-up period was 39.9 months (SD 25.8). 6.6% of patients (45/682) were lost to follow-up. 64.7% of patients (441/682) had clear margins in the specimen and 20.1% of patients had positive surgical margins (137/682). In 8.6% of patients (59/682) the resection margins were uncertain. Positive endocervical sweep was found in 10.8% of cases (73/682). Residual/recurrent disease was demonstrated by colposcopy-guided biopsy in 13.9% of patients (88/637); 77.3% (68/88) of them developed CIN 1 while only 22.7% (20/88) developed high-grade premalignant lesions or carcinomas during the follow-up. We found significant differences in the frequency of persistent/recurrent disease depending on the status of margins: 24.8% of cases with positive margins vs 11.1% of cases with negative margins (p<0.0001). Multivariate analysis showed that only post-treatment high-risk HPV detection and status of the cone margins were significantly predictive of persistent/recurrent disease (OR 4.1, 95%CI 2.4-7.3, p<0.0001 and OR 2.7, 95%CI 1.5-4.7, p=0.001; respectively). The combination of histological examination of resection margins plus post-treatment tests for HPV detection would help to classify LEEP-treated patients into categories at different risk of recurrence.

Immunotherapy for persistent viral infections and associated disease

Persistent viral infections reflect a failure of the host's immune system to control infection, and in many cases, they are associated with the development of malignancies. So far, vaccines designed to boost viral immunity during chronic infection have not been successful. Infections with high-risk human papilloma viruses (e.g. HPV16) are acquired by a large segment of the population and persist in 5-10% of infected individuals, which causes the development of high-grade pre-malignant lesions. Recently we succeeded in causing regression of HPV16-induced disease in ∼50% of chronically infected patients by a novel therapeutic vaccine. Here, we summarize the parallels in immunity against HPV and other chronic viruses and discuss the general implications of our findings for the immunotherapy of chronic infections.

Increased expression of cellular RNA‐binding proteins in HPV‐induced neoplasia and cervical cancer

The expression profile of a panel of RNA-binding proteins (heterogeneous ribonucleoprotein (hnRNP) A1, hnRNP C1/C2, hnRNP H, hnRNP I, ASF/SF2, SR proteins, HuR and U2AF(65)) and markers of differentiation, proliferation and neoplasia (cytokeratin (CK) 13, CK-14, proliferating cell nuclear antigen (PCNA), Syndecan-1 and p16INK4a) were analyzed in 50 formalin fixed paraffin embedded cervical tissues using immunohistochemistry. The samples included histologically normal cervical epithelium, human papillomavirus (HPV) induced low-grade and high-grade pre-malignant lesions and cervical cancers. All samples were tested for HPV DNA using nested PCR. Forty-nine of the 50 tissue samples tested positive for HPV, 27 tissue samples (54%) were HPV-16 positive and 4 samples (8%) were HPV-18 positive. The immunohistochemistry results detected different expression levels of the various proteins in basal epithelial cells in histologically normal epithelium followed by an increase in expression in the intermediate layers, whereas the superficial layers remained negative for all tested RNA-binding proteins. Expression of all RNA-binding proteins increased in neoplastic lesions and highest expression was detected in cervical cancers. p16INK4a had a stronger association with high-grade lesions when compared with the RNA-binding proteins. The expression profile of the RNA-binding proteins is similar to PCNA expression in histologically normal epithelium as well as in lesions (low-grade and high-grade) and cervical cancers. As PCNA expression has been suggested to mimic HPV E6/E7 expression in cervical epithelium, the results suggest the RNA-binding protein analyzed here regulate HPV early gene expression directly and late gene expression indirectly.

Clinical role of cervical cancer vaccination: When and whom to vaccinate?

The recent development of two highly effective vaccines against persistent infection by the 2 most important types of human papillomavirus (HPV) (16 and 18) and against high grade premalignant lesions (CIN2+) has opened a new scenario for the primary prevention of cervical cancer. The optimum target population for vaccination should be individually defined taking the following into account: 1) the efficacy of the vaccine, 2) the epidemiological context and 3) the vaccination programs available in each country. To achieve the maximum preventive benefits, the vaccine should be administered before the initiation of sexual relations. So, the HPV vaccine should be integrated in the school vaccination programs of adolescents together with other vaccines. The vaccination of sexually active women may considerably increase the speed with which results in the fight against this disease will be achieved. Developed countries will probably consider the vaccination of these women, although vaccination strategies and the efforts to reach this population will be conditioned by the resources of each country and by the estimations of the cost-efficacy relationship in each situation. Women with a previous history of premalignant cervical disease or with an abnormal screening test should not be excluded from the potential benefits which the vaccine may provide. There is no contraindication for the administration of the vaccine in immunosupressed women. However, it is still unknown under what specific circumstances of immunosuppression the immunogenicity of the vaccine may be affected and there are currently ongoing studies for an answer to this question.

P73 is over-expressed in vulval cancer principally as the Δ2 isoform

p73 was studied in squamous cancers and precursor lesions of the vulva. Over-expression of p73 occurred commonly in both human papillomavirus (HPV)-positive and -negative squamous cell cancers (SCC) and high-grade premalignant lesions. Whereas expression in normal vulval epithelium was detected only in the basal and supra-basal layers, expression in neoplastic epithelium increased with grade of neoplasia, being maximal at both protein and RNA levels in SCC. p73 Δ2 was the principal over-expressed isoform in the majority of cases of vulval SCC and often the sole form expressed in SCC. Over-expression of p73 was associated with expression of HPV-encoded E7 or with hypermethylation or mutation of p16INK4a in HPV-negative cases. There was a close correlation between expression of p73 and p14ARF in cancers with loss of p53 function. The frequent over-expression of p73 Δ2 in neoplastic but not normal vulval epithelium, and its co-ordinate deregulation with other E2F-1 responsive genes suggests a role in the oncogenic process. © 2001 Cancer Research Campaign http://www.bjcancer.com

Report on consensus conference on cervical cancer screening and management A meeting of the International Network on Control of Gynaecological Cancers (INCGC) was held in Tunis, January 28–31, 1999. This was a follow-up to a World Health Organization (WHO) Consultation on the Control of Cervical Cancer In Developing Countries held in 1994 at which the Network had been formed (Memorandum,

Report on consensus conference on cervical cancer screening and management A meeting of the International Network on Control of Gynaecological Cancers (INCGC) was held in Tunis, January 28–31, 1999. This was a follow-up to a World Health Organization (WHO) Consultation on the Control of Cervical Cancer In Developing Countries held in 1994 at which the Network had been formed (Memorandum,