The impact of mammography screening programmes on incidence of advanced breast cancer in Europe: a literature review.

BACKGROUND: Observational studies have reported conflicting results on the impact of mammography service screening programmes on the advanced breast cancer rate (ABCR), a correlation that was firmly established in randomized controlled trials. We reviewed and summarized studies of the effect of service screening programmes in the European Union on ABCR and discussed their limitations. METHODS: The PubMed database was searched for English language studies published between 01-01-2000 and 01-06-2018. After inspection of titles and abstracts, 220 of the 8644 potentially eligible papers were considered relevant. Their abstracts were reviewed by groups of two authors using predefined criteria. Fifty studies were selected for full paper review, and 22 of these were eligible. A theoretical framework for their review was developed. Review was performed using a ten-point checklist of the methodological caveats in the analysis of studies of ABCR and a standardised assessment form designed to extract quantitative and qualitative information. RESULTS: Most of the evaluable studies support a reduction in ABCR following the introduction of screening. However, all studies were challenged by issues of design and analysis which could at least potentially cause bias, and showed considerable variation in the estimated effect. Problems were observed in duration of follow-up time, availability of reliable reference ABCR, definition of advanced stage, temporal variation in the proportion of unknown-stage cancers, and statistical approach. CONCLUSIONS: We conclude that much of the current controversy on the impact of service screening programmes on ABCR is due to observational data that were gathered and/or analysed with methodological approaches which could not capture stage effects in full. Future research on this important early indicator of screening effectiveness should focus on establishing consensus in the correct methodology.

Strategies for delivery of faecal occult blood test kits and participation to colorectal cancer screening in the Emilia-Romagna Region of Italy.

There is a lack of agreement about which routine invitation strategy should be adopted in colorectal cancer screening. We conducted an observational study to assess the impact of three invitation strategies on participation. Invitation records for the years 2005-2009 were evaluated. There were 2,234,276 invitations from 1,230,683 individuals. Among first invitations, participation associated with direct mailing of the faecal occult blood test kits was slightly lower (relative risk, RR 0.985; 95% confidence interval 0.979-0.990) than that of the reference invitation strategy, that is, the distribution of the test kits by pharmacies. In repeated invitations/previous non-responders, the participation associated with the direct mailing of the test kits was even lower (RR 0.914; 95% confidence interval 0.895-0.933) and this was also the case for the distribution of the test kits by primary care centres (RR 0.983; 95% confidence interval 0.971-0.995). In contrast, in repeated invitations/previous responders, the impact of primary care centres and direct mailing of the test kits was greater than the use of pharmacies, showing only modest RRs: 1.021 (95% confidence interval 1.019-1.023) and 1.029 (95% confidence interval 1.025-1.033) respectively. The faecal occult blood test mailing strategy modestly increased participation in previous responders.

Combining cytology, TRAP assay, and FISH analysis for the detection of bladder cancer in symptomatic patients.

BACKGROUND: There is a need to improve the performance of urine cytology in bladder cancer diagnosis. We assessed the diagnostic performance of (i) telomerase activity detected by telomeric repeat amplification protocol (TRAP) assay, (ii) cytology and TRAP assay in parallel, (iii) cytology in parallel with the in-series combination of TRAP assay and FISH analysis, and (iv) the in-series combination of TRAP assay and FISH analysis. PATIENTS AND METHODS: Cross-sectional study of 289 consecutive patients who presented with urinary symptoms at a north Italian hospital between 2007 and 2008. All underwent cystoscopy and cytology evaluation, and conclusive results were available for TRAP assay and FISH analysis. RESULTS: Sensitivity and specificity were 0.39 and 0.83, respectively, for cytology; 0.66 and 0.72 for TRAP; 0.78 and 0.60 for the combination of cytology and TRAP; 0.78 and 0.78 for the combination of cytology, TRAP, and FISH; and 0.65 and 0.93 for the combination of TRAP and FISH. All differences versus cytology alone were significant (P ≤ 0.011). CONCLUSION: Compared with cytology alone, the combination of cytology, TRAP, and FISH provided the best trade-off between increase in sensitivity and loss in specificity, especially among non-bleeding patients, low-grade cancers, and early-stage cancers.

The influence of endoscopic biliary stents on the accuracy of endoscopic ultrasound for pancreatic head cancer staging.

BACKGROUND AND STUDY AIMS: Biliary stents have been found to interfere with endoscopic ultrasound (EUS) tumor (T) and nodal (N) staging in patients with periampullary cancer. Our aim was to determine whether this also occurs in patients with pancreatic head cancer. PATIENTS AND METHODS: We studied a consecutive series of patients who were undergoing preoperative EUS for diagnosis and staging of suspected pancreatic cancer, some of whom had biliary stents in situ and some of whom did not. The main end point was the uni- and multivariate association of biliary stenting with T and N mis-staging by EUS. The surgical T and N stages were used as gold standards. RESULTS: A total of 65 patients were identified (19 with biliary stents in situ and 46 without). Surgical stage T4 was found more frequently in patients with stents (53% vs. 22%, P = 0.014). The T stage by EUS was correct in 85% of the patients without biliary stents and in 47% of the patients with stents. The frequency of mis-staging by EUS was significant only among patients with a biliary stent. The distribution by EUS N stage did not differ significantly from the surgical N-stage distribution in the two groups of patients. According to the multivariate analysis, patients with stents were 6.55 times more likely to be incorrectly T staged (95% confidence interval [CI] 1.69-25.49) and 3.71 times more likely to be incorrectly N staged (95% CI 1.11-12.45) than patients without stents. CONCLUSIONS: The results add support to the recommendation that EUS staging of pancreatic head neoplasms should be performed prior to stent placement.

Relative and absolute cancer mortality of women in agriculture in northern Italy.

Most studies of cancer risk related to agricultural exposures have focused on male operators. Cancer mortality in a cohort of 38 962 women engaged in agriculture (Province of Forlì, 1969-1993) was compared with that of the rest of the female residents using the ratio of age-standardized (Europe) mortality rates (ASR) with 95% confidence interval (CI). Moreover, mortality time trends in both subsets of the population were evaluated. The cohort yielded 798 439 person-years with 2397 cancer deaths. Total ASR ratio was 0.86 (95% CI 0.80-0.92). Only gastric cancer was associated with a significant but declining excess mortality (ASR ratio 1.26; 95% CI 1.11-1.43). Total ASR ratio decreased from 1.07 (95% CI 0.95-1.20) in 1969-1976 to 0.74 (95% CI 0.66-0.82) in 1985-1993. This resulted from a downward mortality trend restricted to the cohort. In particular, mortality from cancers of the oesophagus, stomach and colon/rectum decreased more steeply in the cohort. Mortality from liver cancer decreased only in the cohort. Mortality from cancers of the pancreas, lung, breast, bladder and skin melanoma remained stable in the cohort whilst increasing in the rest of the population. In conclusion, risk excesses previously reported were not confirmed. Agricultural workers qualified as a subset of the female population with atypical, favourable epidemiologic characteristics.

Screen-detected vs clinical breast cancer: the advantage in the relative risk of lymph node metastases decreases with increasing tumour size.

Screen-detected (SD) breast cancers are smaller and biologically more indolent than clinically presenting cancers. An often debated question is: if left undiagnosed during their preclinical phase, would they become more aggressive or would they only increase in size? This study considered a registry-based series (1988-1999) of 3329 unifocal, pT1a-pT3 breast cancer cases aged 50-70 years, of which 994 were SD cases and 2335 clinical cases. The rationale was that (1) the average risk of lymph node involvement (N+) is lower for SD cases, (2) nodal status is the product of biological aggressiveness and chronological age of the disease, (3) for any breast cancer, tumour size is an indicator of chronological age, and (4) for SD cases, tumour size is specifically an indicator of the duration of the preclinical phase, that is, an inverse indicator of lead time. The hypothesis was that the relative protection of SD cases from the risk of N+ and, thus, their relative biological indolence decrease with increasing tumour size. The odds ratio (OR) estimate of the risk of N+ was obtained from a multiple logistic regression model that included terms for detection modality, tumour size category, patient age, histological type, and number of lymph nodes recovered. A term for the detection modality-by-tumour size category interaction was entered, and the OR for the main effect of detection by screening vs clinical diagnosis was calculated. This increased linearly from 0.05 (95% confidence interval: 0.01-0.39) in the 2-7 mm size category to 0.95 (0.64-1.40) in the 18-22 mm category. This trend is compatible with the view that biological aggressiveness of breast cancer increases during the preclinical phase.

Integrating self-referral for mammography into organised screening: results from an Italian experience.

OBJECTIVE: To compare self-referred screenees with respondents to invitation for main performance indicators of mammography screening. SETTING: First round of an organised, population-based screening programme in six districts of northern Italy. METHODS: The screening test was a two-view mammography. Eligible women aged 50-69 years were invited. Self-referred attendees were accepted if they were eligible for screening and had not yet been invited or had been invited >6 months before presentation. Age-specific performance indicators were compared with the calculation of their ratio and 95% confidence intervals (CIs). Total ratios were age standardised. In situ carcinomas were excluded. RESULTS: The eligible population was 183 542 women. There were 112 188 respondents to invitation and 20 280 self-referred attendees. Self-referral rate was inversely related to age. Performance indicators were as follows: recall rate, 5.6% for self-referred attendees vs 5.5% for respondents (ratio 1.02, 95% CI 0.96 to 1.08); total aspiration cytology rate, 37.3% vs 28.3% (1.37, 1.24 to 1.51); biopsy rate, 17.0 vs 12.6 x 1000 (1.51, 1.35 to 1.67); total detection rate, 10.7 vs 7.5 x 1000 (1.70, 1.48 to 1.94); detection rate of pT1 carcinoma, 7.0 vs 6.1 x 1000 (1.35, 1.14 to 1.59); detection rate of pT2-4 carcinoma, 3.5 vs 1.2 x 1000 (3.51, 2.75 to 4.43); false-positive rate, 4.5% vs 4.7% (0.93, 0.87 to 0.99); positive predictive value (PPV) of mammography, 19.1% vs 13.5% (1.59, 1.39 to 1.82); PPV of biopsy, 63.7% vs 60.6% (1.13, 0.98 to 1.29); detected:expected ratio, 5.02 vs 3.37 (1.49, 1.28 to 1.74). All differences were more pronounced among or restricted to women aged 50-54 years. CONCLUSIONS: Self-referred screenees were similar to respondents to invitation in main indicators of screening feasibility such as recall rate and PPV of biopsy, while showing important increases in detection rates and detected:expected ratios, especially among women aged 50-54 years.

The impact of organised screening programmes on the stage-specific incidence of breast cancer in some Italian areas.

The aim of this study was to examine the effects of mammographic screening programmes on stage-specific incidence of breast cancer. The study compared prescreening and screening periods in seven areas in Italy, primarily evaluating the first screening round. All 17617 breast cancers (16554 invasive, 1063 in situ) registered in women aged 40-79 years between 1988 and 1999 were analysed through age-standardised rates and Poisson regression models. For all areas, independent of the baseline rates, the introduction of screening increased incidence for invasive cancers overall and, more markedly, for early cancers (screening/prescreening ratio: range 1.07-1.47 and 1.23-1.82, respectively), modifying the pattern of age-specific rates. The multiple regression analysis showed that the percentage of cases diagnosed at screening explained most of the increase; a residual effect of diagnosis period (screening versus prescreening) suggested a role for 'spontaneous' early detection in ages outside of the screening programme. Advanced cases did not show consistent variations across the registries for those aged 40-79 years (range: 0.91-1.21), whereas a more coherent picture was observed for those aged 50-69 years. In one area, a moderate reduction in the number of 'advanced' cases in the second screening period was observed. For all stages, the age-specific incidence rates of cases diagnosed outside of the screening programme for the age groups 50-69 years were lower than the corresponding rates in the prescreening period, suggesting a shift from the usual clinical services to the screening programme. Our results confirmed the increase in early-stage cancers occurring at the start of screening, and substantially explained the rise in breast cancer incidence. In addition, our study confirms the importance of cancer registries in monitoring the effect of breast cancer screening and the validity, for this purpose, of the linkage between cancer registries and screening programme databases.

Performance indicators of organized cervical screening in Romagna (Italy).

The availability of published data from organized cervical screening programmes in southern Europe is scant. In the Italian area of Romagna, a first round of organized screening (based on a 3-yearly Pap smear for women aged 25-64 years) was initiated between December 1995 and January 1997 and was completed in an average of 42 months (range 36-48 months). The target population included 305 478 women. Of these, 253 949 were eligible and received a personal letter of invitation. Age-specific screening performance indicators were calculated according to standard methods. The response rate within 6 months of invitation was 49.1% (n=124 621). The total participation rate including women who presented later was 61.7% (n=156 735). The recall rate was 35.2 per 1000 of participants (n=5514). Positive cytology results were distributed as follows: atypical squamous cells of un-determined significance/atypical glandular cells of undetermined significance (ASCUS/AGUS) 40.1%, low-grade squamous intraepithelial neoplasia (LGSIL) 48.6%, high-grade squamous intraepithelial neoplasia (HGSIL) 10.7% and carcinoma 0.7%. Compliance to colposcopy follow-up was 93.4% (n=5149). The biopsy rate was 52.4% (n=2696) of patients undergoing colposcopy. The detection rate was 4.5 per 1000 of participants (n=707) for CIN2-3 and 0.5 (n=75) for invasive carcinoma. The proportion of microinvasive carcinomas was 36.0% (n=27). The positive predictive value for CIN2-3/carcinoma was 5.8% for the cytology reports of ASCUS/AGUS, 7.6% for those of LGSIL, 76.5% for those of HGSIL, and 100.0% for those of carcinoma (80.4% for combined HGSIL/carcinoma). The ratio of observed to expected (or prevalent to incident) cases of invasive carcinoma was 2.35 (95% confidence interval (CI) 1.85-2.95). In conclusion, most early results of the programme were compatible with an acceptable performance.

[Computerized monitoring for integrated cervical screening. Rationale, methods and indicators of participation]. / Monitoraggio informatizzato dello screening cervicale integrato. Razionale, metodi e indicatori di partecipazione.

This paper presents a computerised system for the monitoring of integrated cervical screening, i.e. the integration of spontaneous Pap smear practice into organised screening. The general characteristics of the system are described, including background and rationale (integrated cervical screening in European countries, impact of integration on monitoring, decentralised organization of screening and levels of monitoring), general methods (definitions, sections, software description, and setting of application), and indicators of participation (distribution by time interval since previous Pap smear, distribution by screening sector--organised screening centres vs public and private clinical settings--, distribution by time interval between the last two Pap smears, and movement of women between the two screening sectors). Also, the paper reports the results of the application of these indicators in the general database of the Pathology Department of Imola Health District in northern Italy.

[Computerised monitoring of integrated cervical screening. Indicators of diagnostic performance]. / Monitoraggio informatizzato dello screening cervicale integrato. Indicatori di diagnosi.

In a previous issue of this journal, we presented the background, rationale, general methods, and indicators of participation of a computerised system for the monitoring of integrated cervical screening, i.e. the integration of spontaneous Pap smear practice into organised screening. We also reported the results of the application of those indicators in the general database of the Pathology Department of Imola Health District in northern Italy. In the current paper, we present the rationale and definitions of indicators of diagnostic performance (total Pap smears and rate of unsatisfactory Pap smears, distribution by cytology class reported, rate of patients without timely follow-up, detection rate, positive predictive value, distribution of cytology classes reported by histology diagnosis, and distribution of cases of CIN and carcinoma registered by detection modality) as well as the results of their application in the same database as above.

Overall mortality structure for the calculation of relative survival.

This article analyses the mortality data used for the calculation of relative survival, within the survival study of the cases incident in 1990-1994. The mortality data used in the 14 cancer registries come from ISTAT or other official sources. Results show higher death risk for all causes of death in men and lower in women. Risk increases with age, values are generally higher in the North and lower in the Centre and the South of the country. Consistently with mortality trends, the difference between observed and relative survival is higher in older age groups, and in men rather than women, with an increasing difference the further from the date of diagnosis.

Frequency and determinants of lymphadenectomy in endometrial carcinoma: a population-based study from northern Italy.

BACKGROUND: The diffusion of pelvic and para-aortic lymphadenectomy for the surgical pathological staging of endometrial carcinoma into clinical practice has been evaluated only with questionnaire surveys of gynecological oncologists. No population-based information is available. METHODS: In this study of operable endometrial carcinoma cases registered by the population-based Romagna Cancer Registry (northern Italy) between 1987 and 1994, the association of demographic (age, time period, place of birth, place of residence, place of treatment, and marital status) and pathological factors (histological type, tumor grade, myoinvasion, and extension of disease to cervix, serosa, adnexa, and vagina) with the probability of lymphadenectomy was evaluated by multiple logistic regression analysis. RESULTS: Of the 300 potentially eligible cases, sufficient information was obtained for 276 (92%; median age, 63 years; range, 33-87 years). No case of para-aortic lymphadenectomy was observed. Pelvic lymphadenectomy was performed in 86 (31%) cases. The probability of pelvic lymphadenectomy was related to tumor grade (positive association), place of treatment, and marital status. All other variables, including myoinvasion and extension of disease to the cervix and beyond the uterus, had no effect whatsoever. CONCLUSIONS: The most likely interpretations of results include poor acceptance of current surgical pathological staging criteria and insufficient use of standard diagnostic techniques for preoperative and intraoperative assessment of myoinvasion and extrauterine spread.

Epidemiology of digital epiluminescence microscopy features of acquired melanocytic naevi.

This study addressed the independent association of past and recent sun exposure indicators and other host factors with the prevalence of major digital epiluminescence microscopy (D-ELM) features such as the pigment network (PN), brown globules (BGs), and pigment dots (PDs) in acquired melanocytic naevi. In a consecutive series of 189 patients (median age 28 years; range 10-73 years) with one or more naevi as diagnosed on D-ELM, we evaluated 35 solitary lesions and one naevus randomly selected from each of the 154 patients with multiple lesions. D-ELM images were classified for the presence or absence of PN, BGs and PDs on two blind readings. Data analysis was based on multiple logistic regression. Patient age was positively associated with PN and inversely associated with BGs. The probability of PN increased with more than 110 days since last exposure to the sun, whereas a rapid decrease for BGs and PDs was observed after approximately 1 month. PDs were significantly more likely among lesions with 6-10 h/day of recent exposure. Sex, total lifetime hours of exposure, sunbed use, skin type and colour of hair exerted no effect. In conclusion, major D-ELM features appeared to differ in their relationship with sun exposure indicators.

Epiluminescence microscopy features of melanoma in relation to tumor thickness. Current concepts and clinical examples.

Based on current information, the expression of ELM features as a function of tumor thickness seems to be consistent not only with the definition of main ELM features but also with the model of histogenesis of the disease. The published data and observations, however, are insufficient. The relationship between tumor thickness and the ELM picture needs to be the subject of further research.

Cervical screening behavior of women with atypical squamous cells of undetermined significance (ASCUS).

Expectant follow-up based on early repeat Papanicolaou (Pap) smear(s) is the most commonly recommended management of patients with atypical squamous cells of undetermined significance (ASCUS). In a cervical cytology laboratory in northern Italy, a retrospective study of 1,087 ASCUS patients aged 25-64 was conducted. The primary aim was to assess the actual probability of early repeat Pap smear and associated factors. Univariate comparisons were based on the actuarial method. Multivariate associations were evaluated by Cox regression analysis. The cumulative probability of early repeat Pap smear was 0.11 at 6 mo, 0.29 at 12 mo, and 0.41 at 24 mo, with a multivariate association with screening sector (relative hazard, 3.0 for public offices and 2.8 for private offices vs. organized screening) and previous Pap smear history. Laboratory recommendation, patient age, place of birth, place of residence, marital status, and occupation exerted no independent effect. In conclusion, the probability of early repeat Pap smear was poor and independent of demographic and social factors. The frequency of follow-up failures emerged as a major problem with ASCUS management.

Probability of early repeat Pap smear in an integrated cervical screening programme.

The integration of routine Pap smear practice based on self-referral into an organized programme based on personal invitation is the recommended approach to cervical cancer screening. In this study, the cytology archive of the integrated cervical screening programme implemented in the Faenza district (northern Italy) was used to compare the population of women responding to invitation with that of self-referred women for the cumulative probability of early (< 36 months) repeat Pap smear after a negative result. Between 1995 and 1998, women aged 25-64 living in five municipalities of the district were targeted by the first round of the programme. Eligible for the study were 2356 women responding to invitation for screening and 2221 women not invited because of self-referral for Pap smear at any other setting. The probability of early repeat Pap smear was estimated by the life table method. Differences were evaluated by the Gehan test. Multivariate determinants were assessed by the Cox regression analysis. At 36 months' follow-up, the cumulative probability of early repeat Pap smear was 44% among self-referred women and 6% among women responding to invitation (relative hazard = 4.8). For self-referred women, the probability was related to age (with a peak at 35-44 years), previous Pap smear history and municipality of residence. Among women responding to invitation, only an inverse association with age was demonstrated. In conclusion, the observed differences in overall probability and determinants of early repeat Pap smear between the two screening populations provided important information on Pap smear usage in the total target population.

Factors associated with cone margin involvement in CIN patients undergoing conization-equivalent electrosurgical procedure.

BACKGROUND: Most studies of cervical conization have considered the frequency of complications and the outcome of follow-up. The determinants of cone margin positivity have been inadequately described. In a series of CIN patients undergoing conization-equivalent electrosurgical procedure, we evaluated the factors associated with (i) any cone margin involvement, and (ii) endocervical margin involvement (with or without other locations) as contrasted with all other conditions. METHODS: Study population included 718 patients. Potential determinants of margin involvement were or were treated as categorical. Univariate analysis was based on the chi-square test. Multivariate associations were estimated by multiple logistic regression models. RESULTS: Cone margin involvement was observed in a total of 195 patients (27%). In univariate analysis, the frequency was positively related to histologic grade, time period, lesion size, and cone width and depth. In multivariate analysis, histology diagnosis and time period retained a strong association. The effect of lesion size was of borderline significance. The endocervical location emerged as a multivariate determinant of margin positivity. The effect of cone width and depth was not confirmed. Endocervical margin involvement was observed in 98 cases (14%). In univariate analysis, the frequency was positively associated with histologic grade, time period, and age, and inversely related to the visibility of the squamous-columnar junction. Multivariate analysis confirmed the strong effect of histology diagnosis and time period. The association with age and visibility of the squamous-columnar junction was weaker. CONCLUSIONS: Histology diagnosis and time period were the strongest determinants of cone margin involvement. Endocervical margin positivity was also related to patient age and visibility of the squamous-columnar junction. Cone width and depth had no protective effect.

Diagnosis of pigmented skin lesions by epiluminescence microscopy: determinants of accuracy improvement in a nationwide training programme for practical dermatologists.

BACKGROUND: The poor accuracy of the clinical examination of pigmented skin lesions (PSLs) is a major limitation of secondary prevention strategies for cutaneous melanoma (CMM). In the last few years, the epiluminescence microscopy (ELM) technique has been used increasingly as an adjunct to clinical examination in the dermatology practice. Although the question of training has emerged as a priority, the diffusion, the effects, and the correlates of educational programmes in ELM have seldom been studied. METHODS: Thirty ELM images of PSLs (11 CMMs, 14 melanocytic nevi (MN), and 5 nonmelanocytic lesions (NMLs) each matched with the corresponding clinical or plain photographic image were independently diagnosed before and after a one-day workshop by 83 Italian dermatologists participating in a nationwide educational programme on ELM. The original histology diagnosis was assumed as a gold standard. The overall effect of training on a set of accuracy measures by PSL type was evaluated. The association of the professional sector (public/private), number of years of general experience in dermatology (1-10/>10), average weekly number of PSLs seen (< or =10/11-20/>20), routine use of ELM (no/yes), and area of residence (northern/southern Italy) with the mean number of PSLs correctly diagnosed before and after training was evaluated with the general factorial analysis of variance. The factors associated with improvement between the two tests were evaluated with the analysis of variance for repeated measures. RESULTS: Compared with pretraining data, the average percentage of exact diagnosis increased significantly for all PSLs (CMMs, 72% vs 55%; MN, 68% vs 64%; NMLs, 67% vs 58%; total lesions combined, 69% vs 60%). Baseline as well as final accuracy were independent from the professional sector and the years of experience but were greater among those subjects who reported >20 PSLs per week compared with the reference group (< or =10 PSLs). The routine use of ELM was associated with a slight advantage in pretraining accuracy. The area of residence was the strongest determinant of baseline as well as final accuracy. The effect of training was independent from all factors studied with the exception of the area of residence with a 13% increase in the frequency of exact diagnosis in northern Italy (from 66-79%) and 6% in southern Italy (from 55-61%). CONCLUSIONS: Though insufficient in absolute terms, a measurable increase in ELM accuracy can be achieved even with intense training sessions of short duration. Medical education to ELM in southern Italy should be a priority.