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The Barcelona clinic liver cancer (BCLC) algorithm is the most widely accepted staging system form hepatocellular carcinoma (HCC). Liver resection is traditionally proposed to early stage HCC (BCLC-0/A), even if recent reports have shown that surgical resection could provide a safe and effective treatment also for intermediate-stage HCC (BCLC-B). In this study, we focused on surgical and oncological outcomes of hepatic resection in BLCB-B patients. Patients who received hepatic resection for early- (BCLC-0/A) or intermediate-stage (BCLC-B) HCC in two tertiary hepatobiliary centers between January 2003 and December 2016 were included in study. Four-hundred and twenty-nine patients were included in the analysis. At the time of resection, 298 patients were classified as BCLC-A/0 and 131 as BCLC-B. Despite a higher complication rate in BCLC-B group (49.6% vs 32.9%; p = 0.001), the incidence of clinically relevant complications did not differ significantly between the two groups (16.0% vs 10.1%; p = 0.079); moreover, postoperative mortality (4.6% vs 2.7%; p = 0.309) and relapse-free survival (RFS) were similar between BCLC-0/A and BCLC-B group (1-, 3-, and 5-year RFS: 74, 43, and 31% vs 59, 38, and 34%; p = 0.180). Overall survival was slightly worse in BCLC-B group (1-, 3-, and 5-year overall survival of 89, 70, and 52% vs. 77, 51, and 44%; p = 0.004). Focusing on BCLC-B group, a Child–Pugh score B (HR 2.47; p = 0.003), growing number of nodules (HR 3.04; p = 0.003), and R1 resection (HR 2.43; p = 0.005) beard a higher risk of tumor recurrence, while overall survival was negatively affected by the presence of more than two nodules (HR 3.66; p = 0.0001) and R1 resection (HR 3.06; p = 0.0001); patients presenting single-large HCC experienced a better overall survival (HR 0.53; p = 0.014) and lower recurrence-rate (HR 0.60; p = 0.046). Hepatic resection for intermediate-stage HCC shows acceptable results in terms of perioperative morbidity and mortality, with better oncological outcomes in patients with lower number of lesions despite of their size.

Aim: The primary aim of the study was to assess the association between risk of recurrence and HER2 equivocal gene status through immunohistochemistry in patients with early breast cancer. Patients and Methods: We retrospectively analyzed clinical and pathological data of 455 consecutive patients with early breast cancer (BC) who were HER2+ and had a HER2/CEP17 ratio

Purpose Oncoplastic surgery is a well-established discipline that combines conserving treatment for breast cancer with immediate plastic reconstruction. Although widely practiced, the oncologic outcomes of this combined approach are reported only in small series. The aim of the present paper is to assess the safety of oncoplastic surgery for invasive primary breast cancer. Methods We compared 454 consecutive patients who underwent an oncoplastic approach between 2000 and 2008 for primary invasive breast tumors (study group) with twice the number of patients who received conservation alone in the same interval time (control group). Disease free survival and overall survival were estimated using the Kaplan-Meier method. The log-rank test was used to assess differences between groups. Results The median follow-up was 7.2 years. The overall survival is similar within the two groups, being 91.4% and 91.3% at 10-yr in the study group and in the control group respectively. The disease free survival is slightly lower in the oncoplastic group (69 vs.73.1% at 10-yr). The difference is not statistically significant. Discussion. We have compared a large series of primary breast cancer patients that have undergone oncoplastic surgery (454) with a control group (908) and they were followed for a prolonged period of time. It provides the best available evidence to suggest that oncoplastic surgery is a safe and reliable treatment option for the managing of invasive breast cancer.

Background/Aim: In breast cancer (BC) patients, breast surgery followed by immediate breast reconstruction (IBR) might favour recurrences and metastases due to extensive surgical manipulation. We retrospectively investigated whether IBR after mastectomy and neoadjuvant chemotherapy (NT) influenced the outcome in patients with early and locally advanced oestrogen receptor (ER)-negative BC. Patients and Methods: Between 1995 and 2006, 133 BC patients received NT followed by total mastectomy, 59 of whom underwent IBR. Patients receiving IBR (IBR group) were compared to patients who did not receive IBR (no-IBR group) over a prolonged median follow-up time (8.2 years). Results: Patients receiving IBR were on average younger than patients not receiving IBR (p

Background: Alcohol is capable of traversing the blood-brain barrier and is thus a possible risk factor for brain cancer. Several epidemiological studies have been published on the issue, a number of those during recent years, with inconsistent findings. Materials and methods: We performed a systematic literature search in the Medline and EMBASE databases. We found a total of 19 studies providing risk estimates for total alcohol or specific alcoholic beverages. Pooled estimates of the relative risks (RR) and 95% confidence intervals (CI) were calculated using random-effects models. Results: The pooled RR of brain cancer for alcohol drinkers versus non-drinkers was 0.97 (95% CI 0.82-1.15; based on 12 studies). Moderate (

Background: The role of alcohol consumption as an independent risk factor for lung cancer is controversial. Since drinking and smoking are strongly associated, residual confounding by smoking may bias the estimation of alcohol consumption and lung cancer risk relation. Therefore, we undertook a meta-analysis to quantitatively assess the association between alcohol and risk of lung cancer in never smokers.Methods: After a literature search in Medline, we included all case-control and cohort studies published up to January 2010 that reported an estimate of the association between alcohol intake and lung cancer risk in never smokers.Results: We selected 10 articles, including 1913 never smoker lung cancer cases. The random-effects pooled relative risk (RR) for drinkers versus nondrinkers was 1.21 [95% confidence interval (CI) 0.95-1.55]. The same figure was 1.05 (95% CI 0.89-1.23) after the exclusion of one outlier study. At the dose-response analysis, RR for an increase in alcohol intake of 10 g/day was 1.01 (95% CI 0.92-1.10).Conclusions: Alcohol consumption was not associated with lung cancer risk in never smokers. Even if the synergistic effect of smoking and alcohol cannot be ruled out, our results suggest that alcohol does not play an independent role in lung cancer etiology. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Background: The International Agency for Research on Cancer (IARC) concluded that alcohol consumption is related to colorectal cancer (CRC). However, several issues remain unresolved, including quantification of the association for light (=1 drink/day) and moderate (2-3 drinks/day) alcohol drinking, investigation of the dose-response relationship, and potential heterogeneity of effects by sex, colorectal site, and geographical region. Methods: Twenty-seven cohort and 34 case-control studies presenting results for at least three categories of alcohol intake were identified from a PubMed search of articles published before May 2010. The summary relative risks (RRs) were estimated by the random effects model. Second-order fractional polynomials and random effects metaregression models were used for modeling the dose-risk relation. Results: The RRs were 1.21 [95% confidence interval (CI) 1.13-1.28] for moderate and 1.52 (95% CI 1.27-1.81) for heavy (=4 drinks/day) alcohol drinking. The RR for moderate drinkers, compared with non-/occasional drinkers, was stronger for men (RR = 1.24, 95% CI 1.13-1.37) than for women (RR = 1.08, 95% CI 1.03-1.13; Pheterogeneity = 0.02). For heavy drinkers, the association was stronger in Asian studies (RR = 1.81, 95% CI 1.33-2.46; Pheterogeneity = 0.04). The dose-risk analysis estimated RRs of 1.07 (95% CI 1.04-1.10), 1.38 (95% CI 1.28-1.50), and 1.82 (95% CI 1.41-2.35) for 10, 50, and 100 g/day of alcohol, respectively. Conclusions: This meta-analysis provides strong evidence for an association between alcohol drinking of >1 drink/day and colorectal cancer risk. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Purpose The purpose of the study was to evaluate the toxicity, local control, overall and disease-free survival of elderly breast cancer (BC) patients treated with adjuvant once-weekly ultra-hypofractionated radiotherapy (RT) either with intensity-modulated RT (IMRT) or 3D conformal RT (3DCRT). Methods From July 2011 to July 2018, BC patients receiving 5.7 Gy once a week for 5 weeks to the whole breast after breast-conserving surgery were considered for the study. Inclusion criteria were: T1–T3 invasive BC, no or limited axillary involvement, age ≥ 65 years or women with commuting difficulties or disabling diseases. Results A total of 271 patients were included in the study. Median age was 76 (46–86) years. Most of BC were T1 (77%), while the remaining were T2 (22.2%) and T3 (0.4%). Axillary status was negative in 68.3% of the patients. The only severe acute toxicity (G3) at the end of RT was erythema (0.4%), registered in the 3DCRT group; no G3 edema or epitheliolysis was recorded. With 18 months of median follow-up, severe early–late toxicity (G3) was reported in terms of fibrosis and breast retraction, both with an incidence of 1.4%, mostly in the 3DCRT group. Oncological outcomes at a median follow-up of 2.9 years reported 249/271 (91.9%) patients alive and free from any event and 5 (1.8%) isolated locoregional recurrences. At 3 years, disease-free survival and overall survival were 94.9% and 97.8%, respectively. Breast volume > 500 cm3 was reported as predictive for moderate–severe (≥ G2) acute toxicity. Conclusions Weekly ultra-hypofractionated whole breast RT seems feasible and effective. Toxicity was mild, local control was acceptable, and overall survival was 97.8% at 3 years. Rates of severe toxicity were reduced with the IMRT technique. Supplementary Information The online version contains supplementary material available at 10.1007/s00432-021-03907-w.

Despite several studies support a positive association between heavy alcohol consumption and liver cancer risk, a consistent dose-risk relationship has not yet been established. We carried out a systematic review and a meta-analysis of the association between alcohol intake and liver cancer occurrence, following the Meta-analysis Of Observational Studies in Epidemiology guidelines. We searched for cohort and nested case-control studies on the general population published before April 2013, using PubMed and EMBASE. Summary meta-analytic relative risks (RRs) were estimated using random-effect models. We included 16 articles (19 cohorts) for a total of 4445 incident cases and 5550 deaths from liver cancer. Compared with non-drinking, the pooled RRs were 0.91 (95% confidence interval, CI, 0.81-1.02) for moderate drinking (

It has been suggested that alcohol intake increases sunburn severity, a major risk factor for cutaneous melanoma (CM). Several epidemiological studies have investigated the relationship between alcohol consumption and CM, but the evidence is inconsistent. Therefore, we aimed to quantify this relationship better, using a meta-analytical approach. The dose-risk relationship was also modelled through a class of flexible nonlinear meta-regression random effects models. The present meta-analysis included 16 studies (14 case-control and two cohort investigations) with a total of 6251 cases of CM. The pooled relative risk (RR) for any alcohol drinking compared with no/occasional drinking was 1·20 [95% confidence interval (CI) 1·06-1·37]. The risk estimate was similar in case-control (RR 1·20, 95% CI 1·01-1·44) and cohort studies (RR 1·26, 95% CI 1·19-1·35). The pooled RR was 1·10 (95% CI 0·96-1·26) for light alcohol drinking (≤ 1 drink per day) and 1·18 (95% CI 1·01-1·40) for moderate-to-heavy drinking. The pooled RR from 10 studies adjusting for sun exposure was 1·15 (95% CI 0·94-1·41), while the RR from six unadjusted studies was 1·27 (95% CI 1·20-1·35). No evidence of publication bias was detected. This meta-analysis of published data reveals that alcohol consumption is positively associated with the risk of CM. However, caution in interpreting these results is required, as residual confounding by sun exposure cannot be ruled out. What's already known about this topic? Alcohol drinking increases sunburn severity, a major risk factor for cutaneous melanoma. Several epidemiological studies have investigated the relationship between alcohol consumption and cutaneous melanoma, but the evidence is inconsistent. What does this study add? We found a 20% increased risk of cutaneous melanoma with regular alcohol drinking. © 2014 British Association of Dermatologists.

Background Postmastectomy radiotherapy (PMRT) with TomoHelical™ (TH) or TomoDirect™ (TD) allows a uniform target coverage. In this study, we compare treatment plans using TD and TH in the setting of hypofractionated PMRT and immediate breast reconstruction. Material and methods The TD-treatment plans of breast cancer patients treated between May 2016 and August 2019 were retrospectively selected. All the TD plans were re-planned on TH with the same prescription dose (40.05 Gy/15 fractions) and according to our dose/volume constraints. Data about the 2 treatment plans were compared with a focus on PTV coverage and all the organs at risk (OARs) constraints. Results Fifty patients for a total number of 100 treatment plans (50 with TD and 50 re-planned with TH) were analyzed. All the median value in the TD PTV CHEST WALL plans fulfilled the predefined planning objectives, even though TH emerged as best for target coverage with statistically significant difference for V90%. TD provided the lowest V95% for the PTV SVC, but the median value was near to the recommended value of 90% (89.8 % vs 98.6% for TD and TH, respectively). Overall, TD reached the best OARs sparing. The main statistically significant differences with TH were for contralateral breast, ipsilateral and contralateral lung. All the other dose values for TH were higher than TD, but they fulfilled the recommended/acceptable predefined planning objectives. Conclusions In the setting of PMRT, TD compared to TH reached an acceptable target volume coverage, with an optimal sparing of OARs.

Background Specific data regarding coronavirus disease 2019 (COVID-19) in patients with neuroendocrine neoplasms (NENs) are lacking. The aim of this study is to describe the characteristics of patients with NENs who tested severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive. Material and methods This is a worldwide study collecting cases of patients with NENs along with a positive nasopharyngeal swab reverse transcriptase-polymerase chain reaction (RT-PCR) test for SARS-CoV-2 between June 1, 2020, and March 31, 2021. Centres treating patients with NENs were directly contacted by the principal investigator. Patients with NENs of any primary site, grade and stage were included, excluding small-cell lung carcinoma and mixed adenoneuroendocrine carcinoma. Results Among 81 centres directly contacted, 88.8% responded and 48.6% of them declined due to lack of cases or interest. On March 31st, 2021, eight recruiting centres enrolled 89 patients. The median age was 64 years at the time of COVID-19 diagnosis. Most patients had metastatic, non-functioning, low-/intermediate-grade gastroenteropancreatic NENs on treatment with somatostatin analogues and radioligand therapy. Most of them had comorbidities. Only 8% of patients had high-grade NENs and 12% were receiving chemotherapy. Most patients had symptoms or signs of COVID-19, mainly fever and cough. Only 3 patients underwent sub-intensive treatment, whereas most of them received medical therapies, mostly antibiotics. In two third of cases, no changes occurred for the anti-NEN therapy. More than 80% of patients completely recovered without sequelae, whereas 7.8% patients died due to COVID-19. Conclusions Patients included in this study reflect the typical NEN population regardless of SARS-CoV-2. In most cases, they overcome COVID-19 without need of intensive care, short-term sequelae and discontinuation of systemic oncological therapy.

Background We report here for the first time, a comprehensive characterization of biological and clinical features of early-stage triple negative Invasive Lobular Carcinomas(TN-ILCs) Methods We analyzed all consecutive patients with early-stage TN-ILC operated at two reference cancer-centers between 1994 and 2012. Primary objective was to assess the invasive disease-free survival(iDFS). Co-primary objective was to assess biological features of TN-ILCs, including molecular intrinsic subtypes based on PAM-50 assay, expression of androgen receptor (AR) and mutational status of ERBB2-gene. Additionally, DNA mutational status of an independent cohort of 45 TN-ILCs from three databases were analyzed, to confirm mutations in ERBB2-gene and to identify other recurrently mutated genes. Results Among 4152 ILCs, 74(1.8%) were TN and were analyzed. The iDFS at 5 and 10 years of FUP were 50.4%(95%CI,38.0–61.6) and 37.2%(95%CI,25.5–48.8), respectively. The molecular subtype was defined through PAM50-classifier for 31 out of 74 TN-ILCs: 48% were Luminal-A(15/31), 3% luminal-B(1/31), 32% HER2-enriched (10/31), and only 16% basal-like(5/31). Luminal tumors expressed AR more frequently than non-luminal tumors (AR≥1% in 94% of luminal tumors versus 53% in non-luminal tumors; p-value = 0.001). 20% of TN-ILCs analyzed(7/35), harbored a pathogenetic and actionable mutation in the ERBB2-gene. Analysis of the independent cohort of 45 TN-ILCs from three different databases, confirmed similar percentage of pathogenetic and actionable mutations in ERBB2-gene(20%; 9/45). Among the top 10 molecular pathways significantly enriched for recurrently mutated genes in TN-ILCs(FDR, Highlights • Triple-negative ILCs are distinct from both TN-IDCs and endocrine-responsive ILC. • TN-ILCs are enriched for actionable mutations in ErbB2 gene and DNA Damage Response genes. • The Luminal Androgen Receptor (LAR) is the most prevalent subtype in TN-ILCs.

The role of alcohol intake in the risk of Hodgkin lymphoma (HL) is still largely unclear. To summarize the evidence on the issue, we carried out a meta-analysis of the available studies. We identified eight case-control and two cohort studies, including a total of 1488 cases of HL. We derived meta-analytic estimates using random-effects models, taking into account the correlation between estimates, and carried out a dose-risk analysis using nonlinear random-effects metaregression models. Compared with nondrinkers, the relative risk for alcohol consumers was 0.70 [95% confidence interval (CI), 0.60-0.81] overall, 0.66 (95% CI, 0.56-0.78) among case-control, and 0.92 (95% CI, 0.63-1.33) among cohort studies. Compared with nondrinkers, the pooled relative risks were 0.71 (95% CI, 0.57-0.89) for light (i.e. =1 drink/day) and 0.73 (95% CI, 0.60-0.87) for moderate-to-heavy (i.e. >1 drink/day) alcohol drinking. This meta-analysis suggests a favourable effect of alcohol on HL, in the absence, however, of a dose-risk relationship. The inverse association was restricted to - or greater in - case-control as compared with cohort studies. This indicates caution in the interpretation of results. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Objective: In order to provide an updated quantification of the association between alcohol drinking and epithelial ovarian cancer risk, we conducted a meta-analysis of published observational studies. Methods: Using PubMed, we performed a literature search of all case-control and cohort studies published as original articles in English up to September 2011. We included 27 observational studies, of which 23 were case-control studies, 3 cohort studies and one pooled analysis of prospective cohort studies, including a total of 16,554 epithelial ovarian cancer cases. We derived pooled meta-analytic estimates using random-effects models. Results: The pooled relative risk (RR) for any alcohol drinking compared with non/occasional drinking was 1.00 [95% confidence interval (CI), 0.95-1.05]. The RRs were 0.97 (95% CI, 0.92-1.02), 1.03 (95% CI, 0.96-1.11) and 1.09 (95% CI, 0.80-1.50) for light (= 1 drink/day), moderate (> 1 to < 3 drinks) and heavy drinking (= 3 drinks/day), respectively. In particular, the pooled RR for invasive epithelial ovarian cancers was 1.00 (95% CI, 0.95-1.06), while for borderline cancers was 0.96 (95% CI, 0.74-1.26). Stratified analyses across cancer histotypes revealed a modest protective effect of alcohol on endometrioid epithelial ovarian tumors (RR = 0.82, 95% CI, 0.70-0.96), while no association was found for serous (RR = 1.00, 95% CI, 0.84-1.19), mucinous (RR = 0.91, 95% CI, 0.78-1.08) and clear cell (RR = 0.93, 95% CI, 0.76-1.14) cancers. There was no evidence of publication bias. Conclusions: This comprehensive meta-analysis provided no evidence of a material association between alcohol drinking and epithelial ovarian cancer risk. © 2012 Elsevier Inc. All rights reserved.

Tramacere, I Pelucchi, C Bagnardi, V Rota, M Scotti, L Islami, F Corrao, G Boffetta, P La Vecchia, C Negri, E eng Meta-Analysis Research Support, Non-U.S. Gov't Review England 2011/05/10 06:00 Ann Oncol. 2012 Feb;23(2):287-97. doi: 10.1093/annonc/mdr136. Epub 2011 May 5.; International audience; BACKGROUND: In order to provide a precise quantification of the association between alcohol drinking and esophageal and gastric cardia adenocarcinoma risk, we conducted a meta-analysis of available data. PATIENTS AND METHODS: We identified 20 case-control and 4 cohort studies, including a total of 5500 cases. We derived meta-analytic estimates using random-effects models, taking into account correlation between estimates, and we carried out a dose-risk analysis using nonlinear random-effects meta-regression models. RESULTS: The relative risk (RR) for drinkers versus nondrinkers was 0.96 [95% confidence interval (CI) 0.85-1.09] overall, 0.87 (95% CI 0.74-1.01) for esophageal adenocarcinoma and 0.89 (95% CI 0.76-1.03) for gastric cardia adenocarcinoma. Compared with nondrinkers, the pooled RRs were 0.86 for light (/= 4 drinks per day) alcohol drinking. The dose-risk model found a minimum at 25 g/day, and the curve was < 1 up to 70 g/day. CONCLUSIONS: This meta-analysis provides definite evidence of an absence of association between alcohol drinking and esophageal and gastric cardia adenocarcinoma risk, even at higher doses of consumption.

Tramacere, I Negri, E Pelucchi, C Bagnardi, V Rota, M Scotti, L Islami, F Corrao, G La Vecchia, C Boffetta, P eng Meta-Analysis Research Support, Non-U.S. Gov't England 2011/05/04 06:00 Ann Oncol. 2012 Jan;23(1):28-36. doi: 10.1093/annonc/mdr135. Epub 2011 May 2.; International audience; BACKGROUND: Whether an association between alcohol drinking and gastric cancer risk exists is an open question. In order to provide a definite quantification of the association between alcohol drinking and gastric cancer risk, we conducted a meta-analysis of available data. PATIENTS AND METHODS: We carried out a PubMed search of articles published up to June 2010 and identified 44 case-control and 15 cohort studies, including a total of 34 557 gastric cancer cases. We derived meta-analytic estimates using random-effects models, taking into account correlation between estimates. We carried out a dose-risk analysis using nonlinear random-effects meta-regression models. RESULTS: Compared with nondrinkers, the pooled relative risk (RR) was 1.07 [95% confidence interval (CI) 1.01-1.13] for alcohol drinkers and 1.20 (95% CI 1.01-1.44) for heavy alcohol drinkers (>/=4 drinks per day). The pooled estimates were apparently higher for gastric noncardia (RR for heavy drinkers=1.17, 95% CI 0.78-1.75) than for gastric cardia (RR=0.99, 95% CI 0.67-1.47) adenocarcinoma. The dose-risk model estimated a RR of 0.95 (95% CI 0.91-0.99) for 10 g/day and 1.14 (95% CI 1.08-1.21) for 50 g/day. CONCLUSIONS: This meta-analysis provides definite evidence of a lack of association between moderate alcohol drinking and gastric cancer risk. There was, however, a positive association with heavy alcohol drinking.

Background: Alcohol intake is an established risk factor for colorectal cancer (CRC); however, there is limited knowledge on whether changing alcohol drinking habits during adulthood modifies CRC risk.Objective: Leveraging longitudinal exposure assessments on alcohol intake at different ages, we examined the relationship between change in alcohol intake and subsequent CRC risk.Methods: Within the European Prospective Investigation into Cancer and Nutrition, changes in alcohol intake comparing follow-up with baseline assessments were investigated in relation to CRC risk. The analysis included 191,180, participants and 1530 incident CRC cases, with exclusion of the first three years of follow-up to minimize reverse causation. Trajectory profiles of alcohol intake, assessed at ages 20, 30, 40, 50years, at baseline and during follow-up, were estimated using latent class mixed models and related to CRC risk, including 407,605 participants and 5,008 incident CRC cases.Results: Mean age at baseline was 50.2years and the follow-up assessment occurred on average 7.1 years later. Compared to stable intake, a 12 g/day increase in alcohol intake during follow-up was positively associated with CRC risk (HR = 1.15, 95%CI 1.04, 1.25), while a 12 g/day reduction was inversely associated with CRC risk (HR = 0.86, 95%CI 0.78, 0.95). Trajectory analysis showed that compared to low alcohol intake, men who increased their alcohol intake from early- to mid- and late-adulthood by up to 30 g/day on average had significantly increased CRC risk (HR = 1.24; 95%CI 1.08, 1.42), while no associations were observed in women. Results were consistent by anatomical subsite.Conclusions: Increasing alcohol intake during mid-to-late adulthood raised CRC risk, while reduction lowered risk

Alcohol drinking is a known risk factor for laryngeal cancer. However, little information is available on the risk associated with light alcohol drinking. To address this issue, we conducted a meta-analysis using two methods: (i) random-effects models with reconstruction of alcohol consumption categories and calculation of risk estimates associated with predefined consumption levels using Hamling method and (ii) random-effects meta-regression models. The PubMed database was searched for all case-control or cohort studies published in the English language on the association between alcohol consumption and risk of laryngeal cancer. Forty studies (38 case-control, 2 cohort) reporting on at least three levels of consumption were included. Overall, alcohol drinking versus non-drinking was associated with an approximately 2-fold increase in risk of laryngeal cancer (RR = 1.90; 95% CI: 1.59-2.28). While light alcohol drinking (=1 drink/day) did not show any significant association with risk of laryngeal cancer (12 studies. RR = 0.88; 95% CI: 0.71-1.08), moderate drinking (>1 to

Oral and pharyngeal cancers are strongly related to alcohol drinking. We combined findings from all case-control and cohort studies published up to September 2009 and presented analyses by subsites, using a meta-analytic approach. Summary measures were obtained using random-effects models, and taking into account the correlation between estimates from the same study. We also performed a dose-risk analysis, using a random-effects meta-regression model. Compared to non- or occasional drinkers, the overall relative risks (RR) for light drinkers were 1.17 (95% confidence interval, CI, 1.01-1.35) for oral (nine studies) and 1.23 (95% CI, 0.87-1.73) for pharyngeal (five studies) cancer, with no significant heterogeneity between the two sites (p = 0.793). RRs for heavy drinkers were 4.64 (95% CI, 3.78-5.70) for oral (17 studies) and 6.62 (95% CI, 4.72-9.29) for pharyngeal (17 studies) cancer (p of heterogeneity between the two sites = 0.075). The summary RRs for heavy drinkers were 4.11 (95% CI, 2.46-6.87) for tongue (five studies), 7.76 (95% CI, 4.77-12.62) for oropharyngeal (four studies), and 9.03 (95% CI, 4.46-18.27) for hypopharyngeal (four studies) cancer. In conclusion, the alcohol-related RRs are higher for pharyngeal than for oral cancer, particularly at higher doses, while the association with cancer of the tongue was similar to that for oral cancer. © 2010 Elsevier Ltd. All rights reserved.

In the last few years, ultrasound-guided vacuum-assisted breast biopsy (US-VABB) has replaced surgical biopsy due to higher diagnostic accuracy and lower patient discomfort, and, at present, an even greater possibility is represented by the new wireless ultrasound-guided VAB device (Wi-UVAB). The purpose of our study is to determine the diagnostic accuracy of this new device in a sizeable representative number of patients. From January 2014 to June 2018, 168 biopsies were performed in our institution using the new Wi-UVAB device. We analyzed sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of biopsies obtained with the new device using surgical results as reference point, following patients for at least one year. In our cohort, we obtained a complete sensitivity of 97.5%, an absolute sensitivity of 94.3%, a complete specificity of 98%, and an absolute specificity of 98%. The positive predictive value of the procedure was 97.5% while the negative predictive value was 98%. The diagnostic accuracy was 98%. The Wi-UVAB is a safe procedure with high diagnostic accuracy, comparable to that of the traditional vacuum-assisted breast biopsy and even higher than that of core needle biopsy (CNB). Moreover, the Wi-UVAB is easy to use and shows low costs as core needle biopsy (CNB).

Purpose: The careful evaluation of MDCT is an essential step for the treatment planning in pre-treatment imaging work-up for Trans-Arterial Radio Embolization (TARE). It may provide unique volumetric data (CTVs), which are information useful for an effective and safe TARE. The purpose of this study is to demonstrate that the radiographer is able to calculate CTVs of TARE simulation with the same precision as the interventional radiologist. Methods: This study retrospectively considers 17 consecutive patients (8 males, 9 females; mean age 66.3 ± 13.2 years) who underwent pre-treatment work-up for TARE, between May 2019 and February 2020 (trial ID:2234 - protocol). For each patient, four specific parameters are evaluated from MDCT achieved during treatment simulation: healthy liver volume (HLV), the whole hepatic parenchyma (THV = healthy liver and TTV = tumour) involved by TARE, and whole liver volume (WLV). Four independent observers—R1 (expert interventional radiologist), T1, T2, and T3 (radiographers, with different experiences in the field of interventional radiology)—are involved in the imaging analysed. Results: All the 4 observers detected the same number of hepatic lesion(s) per patient. Regarding the three radiographers, the intra-observer reliability for CTVs is very high 0.997 to 1.000 (95%CI). Also inter-observer reproducibility between radiographers is excellent regarding CTVs, 0.965 to 0.999 (95%CI). The accuracy of radiographer evaluation is very high 0.964 to 0.999 (95%CI). Conclusions and implications for practice: The high intra- and inter-observer reproducibility shows that a properly trained radiographers might have the same accuracy as interventional radiologists, in assessing liver CTV data for planning TARE.

Aims: To report toxicity of a hypofractionated scheme of whole-breast (WB) intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) to the tumor bed (TB) using Tomotherapy® with Direct modality. Methods: Patients with early breast cancer, undergoing radiotherapy (RT) in 15 daily fractions to WB (prescription dose 40.05 Gy) and SIB to the TB (48 Gy), between 2013 and 2017, was analyzed. Primary endpoint was acute and intermediate toxicity assessed at the end and within 6 months from RT, according to Radiation Therapy Oncology Group (RTOG) scale. Secondary endpoints included early chronic toxicity at 12-months follow-up, using the Late Effects Normal Tissue Task Subjective, Objective, Management, and Analytic (LENT-SOMA) scale, and cosmesis using Harvard criteria. Results: The study population was of 287 patients. Acute and intermediate toxicity was collected among 183 patients with data available at the end of RT and within 6 months, 85 (46%) experienced G2 toxicity and 84 (46%) G1 toxicity, while 14 (8%) did not report toxicity at any time. A significant reduction of any grade toxicity was observed between the two time points, with the majority of patients reporting no clinically relevant toxicity at 6 months. At univariate analysis, age < 40 years, breast volume > 1000 cm3 and Dmax ≤ 115% of prescription dose were predictive factors of clinically relevant acute toxicity (G ≥ 2) at any time. At multivariable analysis, only age and breast volume were confirmed as predictive factors, with Relative Risks (95% Confidence Intervals): 2.02 (1.13–3.63) and 1.84 (1.26–2.67), respectively. At 12-month follow-up, 113 patients had complete information on any toxicity with 53% of toxicity G < 2, while cosmetic evaluation, available for 102 patients, reported a good–excellent result for 86% of patients. Conclusions: Hypofractionated WB IMRT with a SIB to the TB, delivered with TomoDirect modality, is safe and well-tolerated. Most patients reported no toxicity after 6 months and good–excellent cosmesis. Predictive factors of clinically relevant toxicity might be considered during treatment planning in order to further reduce side effects.

Introduction The aim of this study was to provide the most comprehensive and up-to-date evidence on the association between cigarette smoking and colorectal cancer (CRC) risk. Methods We conducted a systematic review and meta-analysis of epidemiological studies on the association between cigarette smoking and CRC risk published up to September 2018. We calculated relative risk (RR) of CRC according to smoking status, intensity, duration, pack-years, and time since quitting, with a focus on molecular subtypes of CRC. Results The meta-analysis summarizes the evidence from 188 original studies. Compared with never smokers, the pooled RR for CRC was 1.14 (95% confidence interval [CI] 1.10-1.18) for current smokers and 1.17 (95% CI 1.15-1.20) for former smokers. CRC risk increased linearly with smoking intensity and duration. Former smokers who had quit smoking for more than 25 years had significantly decreased risk of CRC compared with current smokers. Smoking was strongly associated with the risk of CRC, characterized by high CpG island methylator phenotype (RR 1.42; 95% CI 1.20-1.67; number of studies [n] = 4), BRAF mutation (RR 1.63; 95% CI 1.23-2.16; n = 4), or high microsatellite instability (RR 1.56; 95% CI 1.32-1.85; n = 8), but not characterized by KRAS (RR 1.04; 95% CI 0.90-1.20; n = 5) or TP53 (RR 1.13; 95% CI 0.99-1.29; n = 5) mutations. Discussion Cigarette smoking increases the risk of CRC in a dose-dependent manner with intensity and duration, and quitting smoking reduces CRC risk. Smoking greatly increases the risk of CRC that develops through the microsatellite instability pathway, characterized by microsatellite instability-high, CpG island methylator phenotype positive, and BRAF mutation.

The purpose of this study is the evaluation of clinical and surgical impact of the Z0011 trial criteria on the management of breast cancer (BC) patients undergoing breast conservative surgery (BCS) at the European Institute of Oncology (IEO). We studied 1386 patients who underwent BCS and sentinel lymph node biopsy (SLNB) from July 2016 to July 2018. Clinical evaluation, breast ultrasound, mammogram, and cyto/histological examination were performed for all patients at the time of diagnosis. Frozen sections of the sentinel lymph node (SLN) were not performed for any patient. Patients who underwent neo-adjuvant therapy were excluded. To evaluate the results before and after the introduction of Z0011 criteria, a group of 1425 patients with the same characteristics who underwent BCS and SLNB from July 2013 to July 2015 were analyzed. We studied the characteristics of the patients by nodal status, and we observed that T stage, tumor grade, and lymphovascular invasion were statistically related with the highest rate of positive SLN. Of the 1386 patients who underwent surgery after the introduction of the Z011 trial, 1156 patients (83.4%) had negative SLN, 230 patients (16.6%) had positive SLN. Subsequent axillary lymph node dissection (ALND) was performed in only 7 cases (3.0%). Of the 1425 patients operated before the introduction of the Z0011 trial, 216 patients had subsequent ALND (15%). The reduction in the number of ALND performed after the introduction of Z0011 is statistically significant, and this could result in a remarkable reduction of the comorbidities of our patients.

Objectives Tumor-associated antigens (TAAs) are frequently overexpressed in several cancer types. The aim of this study was to investigate the expression of TAAs in breast cancer. Material and methods A total of 250 selected invasive breast cancers including 50 estrogen receptor (ER)-positive (Luminal B like), 50 triple-negative (TN), 50 ER-positive lobular type, 50 ER- and progesterone receptor (PgR)-positive (Luminal A like) and 50 cerbB2-positive breast cancers, were assessed for New York esophageal squamous cell carcinoma-1 (NY-ESO-1), Wilms tumor antigen (WT-1) and PReferentially expressed Antigen of MElanoma (PRAME) antigen expression by immunohistochemistry (IHC). Results A significantly higher expression of cancer testis (CT)-antigens NY-ESO-1 and WT-1 antigen was detected in TN breast cancers compared with ER-positive tumors. NY-ESO-1 overexpression (score 2 + and 3+) assessed by monoclonal and polyclonal antibodies was detected in 9 (18%) TN cancers as compared to 2 (4%) ER-positive tumors (p = 0.002). WT1 over-expression (score 2 + and 3+) was confirmed in 27 (54%) TN tumor samples as compared to 6 (12%) ER-positive (p, Highlights • Tumor-associated antigens are frequently overexpressed in several cancer types, being also associated with poorer patients’ survival outcomes. • Our study confirmed that NY-ESO-1 and WT1 antigens are higher expressed in triple-negative than in other breast cancer subtypes. • Given the limited therapeutic options for triple-negative breast cancer patients, the assessment of WT1 and NY-ESO-1 antigens expression in breast cancer tissue at surgery may allow to identify patients potentially candidate to adjuvant peptide vaccines, alone or in combination with other systemic therapies.

Background: Limited evidence is available on effectiveness of clinicoradiological follow-up of early-stage NSCLC patients. MAGRIT was a phase III adjuvant RCT conducted in surgically resected stage IB-IIIA NSCLC patients, in which all participants had a prospectively defined intensive clinicoradiological follow-up. Methods: At patient-level data, we analyzed detection modality of disease recurrences and new primary lung cancer (i.e. detected by clinicoradiological scheduled exams versus by interim unscheduled exams), features associated with higher risk of locoregional and/or distant recurrence, and recurrence rates over time. Results: In the 2261 patients studied, there was a significant association between the type of recurrence and the modality of detection: 88.4% (95% CI, 84%–91%) of the locoregional recurrences and 93.2% (95% CI, 84%–99%) of the new primary lung cancers were detected by scheduled exams, whereas this was only 68.7% (95% CI, 65%–73%) for distant metastases (p < 0.001). Survival of patients with locoregional recurrence or new primary lung cancer detected by scheduled exams was significantly better as compared with those detected by unscheduled exams (HR 0.56, 95% CI 0.36–0.87; p = 0.01). Survival was similarly poor in patients with distant recurrences, both with scheduled and unscheduled detection (3-year survival after recurrence 22.0% and 21.8%, respectively). Recurrence rate was the highest in the first 18 months after surgery—with a peak between month 6 and 12—decreasing thereafter. The hazard of a second primary lung cancer was constant over time. Conclusion: Intensive follow-up is effective in detecting locoregional recurrences and second primary lung cancers, with impact on patients’ survival but did not influence the detection of distant recurrences.

Background: To assess the clinical usefulness of serum tumor markers for early detection of distant breast cancer recurrence using FDG-PET/CT. Methods: We retrospectively analyzed 561 consecutive patients who underwent surgery for invasive primary breast cancer and had increased tumor markers (CA 15-3 and CEA) after completion of locoregional therapy. FDG-PET/CT data were reviewed for all cases. CA 15-3 and CEA were evaluated both in a continuous and in a quartile (Q) distribution. The Wilcoxon rank-sum test and logistic regression models were used to evaluate the association between increased tumor marker values and the presence (and type) of distant metastases. Results: The median value of CA 15-3 was 35.0 U/mL (IQR, 29.5–43.0) in cases where no distant metastases were detected, and it was 58.9 U/mL (IQR, 40.0–108.0) in cases where metastases were detected (p < 0.001). The median value of CEA was 6.6 U/mL (IQR, 4.4–10.0) in cases of no metastases and 12.4 U/mL (IQR, 6.9–30.0) in cases of metastases (p < 0.001). Increased levels of both tumor markers (Q3 and Q4) were strongly associated with the presence of distant metastases. The association between CA 15-3 and bone/liver metastases was stronger compared with other types of metastases (p heterogeneity between odds ratios [ORs] = 0.03 for Q3 and Conclusion: Increased tumor marker levels detected in asymptomatic breast cancer patients during adjuvant therapies and follow-up are significantly predictive of distant metastases identified on FDG-PET/CT.

Background The latest National Comprehensive Cancer Network Breast Cancer Guidelines still discourage repeat sentinel node biopsy (SNB) after mastectomy, and the largest multicentric study available reports only 35 cases in the absence of previous axillary dissection (AD). Methods From January 2003 to November 2018, 89 patients of the European Institute of Oncology with local recurrence of breast cancer after mastectomy, free of distant metastases, with a clinically negative axilla and a negative axillary ultrasound, in absence of AD, underwent lymphatic mapping before wide local excision. Results During surgery, SNB was successful for 99% of the patients, with 14% being metastatic. Additional metastatic nodes removed by AD after a positive sentinel node occurred in 82% of cases. After a medium follow-up period of 3.7 years, the overall survival rate was 96.7%, and the disease-free survival rate was 84.4%. No axillary relapse after AD was recorded. One patient who refused human epidermal growth factor receptor 2 (HER2)-targeted treatment experienced ipsilateral axillary recurrence after a negative repeat SNB. The first axillary level was never directly irradiated because all the patients with positive repeat SNB underwent AD. For invasive luminal-like HER2-negative recurrences, the metastatic sentinel node was significantly associated with the choice to prescribe adjuvant chemotherapy (p = 0.003). Conclusions In specialized centers, repeat axillary SNB for patients with local recurrence after mastectomy in the absence of previous AD can represent a safe option for detection and removal of occult axillary disease that would otherwise not be excised/irradiated to achieve better local control and could possibly influence the choice of adjuvant treatments.

Purpose: To compare the accuracy of Contrast-Enhanced Spectral Mammography (CESM), MG, US, and breast MRI in estimating the size of breast lesions requiring surgery. The postoperative histology size of the lesion was used as the gold standard. Material and methods: Two hundred thirty-three non-benign lesions in 189 patients were included in the analyses. All the selected patients underwent CESM and at least one other conventional diagnostic exam (US, MG, or MRI). Subsequently, all the patients underwent surgery preceded by cytological/histological examination. The largest diameter of the lesion at imaging was measured by a radiologist with more than 10years’ experience and then compared with the size of the lesion in the histological sample at the surgery (gold standard). Results: Among the 233 breast lesions, 196 were evaluated with US, 206 with MG and 160 with MRI. We found no statistically significant differences between size measurements using CESM and MRI compared with the measurements at the surgery (p value 0.63 and 0.51), whereas a significant difference was found for MG and US (p < 0.001). Conclusion: CESM is a reliable method for estimating the size of breast lesions: its performance seems superior to US and MG and comparable to MRI.

Aims: The clinical significance of nonvisualized sentinel lymph nodes (non-vSLNs) is unknown. The authors sought to determine the incidence of non-vSLNs on lymphoscintigraphy, the identification rate during surgery, factors associated with non-vSLNs and related axillary management. Patients & methods: A total of 30,508 consecutive SLN procedures performed at a single institution from 2000 to 2017 were retrospectively studied. Associations between clinicopathological factors and the identification of SLNs during surgery were assessed. Results: Non-vSLN occurred in 525 of the procedures (1.7%). In 73.3%, at least one SLN was identified intraoperatively. Nodal involvement was only significantly associated with SLN nonidentification (p

Purpose: Grade 3 neuroendocrine tumor (NET G3) is a novel pathologic category within gastro-entero-pancreatic (GEP) neuroendocrine neoplasms (NENs) but its clinical behavior and therapeutic management still remain challenging. Prognostic and predictive factors aiding NET G3 management are needed. Patients and methods: We performed a retrospective analysis from 2015 to 2020 of all patients with > 20% Ki-67, well-differentiated NETs evaluated within our NEN-dedicated multidisciplinary team. We divided the sample according the timing of NET G3 diagnosis, the radiotracers distribution and Ki-67. We analyzed the correlation between these NET G3 features and clinical outcomes. Results: Among 3238 multidisciplinary discussion reports, we selected 55 patients, 48 from GEP and 7 from an occult GEP origin. In 45 patients, NET G3 diagnosis occurred at the beginning of clinical history (upfront-NET G3), whereas in 10, during the NET G1-G2 clinical history (late-NET G3). Patients with ≤ 30% (34/55) vs. > 30% Ki-67 (21/55) had a better overall survival (OS) (p = 0.042); patients with a homogeneous vs. inhomogeneous/negative 68Gallium(68Ga)-DOTA-Peptide Positron Emission Tomography (PET)/computed tomography (CT) showed a trend to a better OS, and a significant better progression-free survival (PFS) (p = 0.033). A better OS was observed for negative/inhomogeneous vs. homogeneous 18-fluorodeoxyglucose (18FDG)-PET/CT (p = 0.027). A trend to a better OS was reported in late- vs. upfront-NET G3, while the latter showed a significantly better response rate (RR) (p = 0.048). Conclusion: Our findings suggested that Ki-67 cutoff, functional imaging and the timing to NET G3 diagnosis may help clinicians in more accurate selection of NET G3 management. Prospective studies are needed.

The optimal dietary pattern to improve metabolic function remains elusive. In a 21-day randomized controlled inpatient crossover feeding trial of 20 insulin-resistant obese women, we assessed the extent to which two isocaloric dietary interventions—Mediterranean (M) and high protein (HP)—improved metabolic parameters. Obese women were assigned to one of the following dietary sequences: M–HP or HP–M. Cardiometabolic parameters, body weight, glucose monitoring and gut microbiome composition were assessed. Sixteen women completed the study. Compared to the M diet, the HP diet was more effective in (i) reducing insulin resistance (insulin: Beta (95% CI) = −6.98 (−12.30, −1.65) µIU/mL, p = 0.01; HOMA-IR: −1.78 (95% CI: −3.03, −0.52), p = 9 × 10−3); and (ii) improving glycemic variability (−3.13 (−4.60, −1.67) mg/dL, p = 4 × 10−4), a risk factor for T2D development. We then identified a panel of 10 microbial genera predictive of the difference in glycemic variability between the two diets. These include the genera Coprococcus and Lachnoclostridium, previously associated with glucose homeostasis and insulin resistance. Our results suggest that morbidly obese women with insulin resistance can achieve better control of insulin resistance and glycemic variability on a high HP diet compared to an M diet.

Objective Metronomic chemotherapy is a treatment option for metastatic breast cancer (MBC) patients who require prolonged disease control without cumulative toxicity. Data available on the efficacy and tolerability of prolonged usage of metronomic therapy are limited. Methods We analyzed patients with MBC, enrolled in a clinical trial, who obtained a prolonged clinical benefit for a duration of at least 12 months with vinorelbine 30 or 40 mg orally three times a week, cyclophosphamide 50 mg daily and capecitabine 500 mg three times a day (VEX regimen). The patients were treated at the European Institute of Oncology, Milan. Results We identified 67 MBC patients. The median age before starting the VEX regimen was 53 years. There were 59 patients (88%) who had hormone-receptors positive and HER2 negative BC. We had 37 patients who received VEX as the first-line treatment for MBC, while 30 patients were pretreated. The objective response rate was 49% (95% CI, 37-62). The median duration of VEX treatment after the first year was 14 months (min-max range 0.3-81.3 months). The progression-free survival at 3 years was 25.4% (95% CI, 15.7-36.2) and at 4 years was 18.5% (95% CI, 10.1-28.8 time 0 corresponds to 1 year after starting VEX). A total of 25 patients required a dose reduction, 7% of patients experienced G3 hand and foot syndrome. Conclusions Metronomic VEX regimen can induce prolonged clinical benefit in MBC. On the basis of this long-term safety evaluation, there is no evidence of specific cumulative or delayed toxicities with metronomic chemotherapy.

Background: The aim of this work is to evaluate pattern of care and clinical outcome in a large series of patients with in-breast recurrence (IBR), after quadrantectomy and intraoperative radiation therapy with electrons (IOERT) as partial breast irradiation. Patients and Methods: Patients with IBR after IOERT, treated with salvage surgery ± adjuvant reirradiation (re-RT), were selected from a multiinstitution database. Disease-free survival (DFS), overall survival (OS), cumulative incidence of second IBR, and distant metastases (DM) were estimated. Results: A total of 224/267 patients from seven institutions were included. Primary tumors received 21 Gy. Median time to first IBR was 4.3 years (range 2.6–6.1 years). Salvage mastectomy and repeat quadrantectomy were performed in 135 (60.3%) and 89 (39.7%) patients, followed by adjuvant re-RT in 21/135 (15.5%) and 63/89 (70.8%), respectively. Median follow-up after salvage treatment was 4.1 years. Overall, 5- and 8-year outcomes were as follows: cumulative incidence of second IBR: 8.4% and 14.8%; cumulative incidence of DM: 17.1% and 22.5%; DFS: 67.4% and 52.5%; OS: 89.3% and 74.7%. The risk of second IBR was similar in the salvage mastectomy and repeat quadrantectomy + RT groups [hazard ratio (HR) 1.41, p = 0.566], while salvage mastectomy patients had greater risk of DM (HR 3.15, p = 0.019), as well as poorer DFS (HR 2.13, p = 0.016) and a trend towards worse OS (HR 3.27, p = 0.059). Patients who underwent repeat quadrantectomy alone had worse outcomes (second IBR, HR 5.63, p = 0.006; DFS, HR 3.21, p = 0.003; OS, HR 4.38, p = 0.044) than those adding re-RT. Conclusions: Repeat quadrantectomy + RT represents an effective salvage approach and achieved local control comparable to that of salvage mastectomy.

Objectives Most research addressing needs and concerns of young patients with breast cancer (≤40 years) is retrospective. The HOHO European protocol is a prospective multicenter cohort study of young women with newly diagnosed breast cancer, about fertility, psychosocial and quality of life concerns. Here we report the baseline data and focus on predictors of fertility concerns. Materials and methods Patient surveys and medical record review were used. The baseline survey included sociodemographic, medical and treatment data as well as questions on fertility concerns and preservation strategies. Subscales from the CAncer Rehabilitation Evaluation System-Short Form (CARES-SF) were administered to measure specific quality of life aspects. Uni- and multivariable modeling were used to investigate predictors of greater fertility concern. Results Among 297 eligible respondents, 67% discussed fertility issues before starting therapy, 64% were concerned about becoming infertile after treatment, and 15% decided not to follow prescribed therapies. Fifty-four percent of women wished future children before diagnosis; of these, 71% still desired biologic children afterwards. In multivariable analysis, not having children was the only patient characteristic significantly associated with fertility concerns at diagnosis. Twenty-seven percent used fertility preservation strategies. Women who received chemotherapy reported greater physical (p = 0.021) and sexual difficulties (p = 0.039) than women who did not. Women who were married or had a partner reported less psychosocial problems than single women (p = 0.039). Conclusions Young women with newly diagnosed breast cancer have several concerns, including, but not limited to, fertility. The HOHO European study provides valuable information to develop targeted interventions.

BackgroundMicroinvasive breast cancer is an uncommon pathological entity. Owing to the rarity of this condition, its surgical axillary management and overall prognosis remain controversial.MethodsA database was analysed to identify patients with microinvasive ductal carcinoma in situ (DCIS) who had surgery for invasive breast cancer at the European Institute of Oncology, Milan, between 1998 and 2010. Women who had undergone axillary staging by sentinel lymph node biopsy were included in the study.ResultsOf 257 women with microinvasive breast cancer who underwent sentinel lymph node biopsy (SLNB), 226 (87·9 per cent) had negative sentinel lymph nodes (SLNs) and 31 had metastatic SLNs. Twelve patients had isolated tumour cells (ITCs), 14 had micrometastases and five had macrometastases in sentinel nodes. Axillary lymph node dissection was performed in 16 of the 31 patients with positive SLNs. After a median follow-up of 11 years, only one regional first event was observed in the 15 patients with positive SLNs who did not undergo axillary lymph node dissection. There were no regional first events in the 16 patients with positive SLNs who had axillary dissection.ConclusionGood disease-free and overall survival were found in women with positive SLNs and microinvasive DCIS. This study is in line with studies showing that SLNB in microinvasive DCIS may not be useful, and supports the evidence that less surgery can provide the same level of overall survival with better quality of life.

Background Oncoplastic surgery is a well-established approach that combines breast-conserving treatment for breast cancer and plastic surgery techniques. Although this approach already has been described for multicentric and multifocal tumors, no long-term oncologic follow-up evaluation and no comparison with patients undergoing mastectomy have been published. This study aimed to evaluate whether oncoplastic surgery is a safe and reliable treatment for managing invasive primary multicentric and multifocal breast cancer. Methods The study compared a consecutive series of 100 patients with multicentric or multifocal tumors who had undergone oncoplastic surgery (study group) with 100 patients who had multicentric or multifocal tumors and had undergone mastectomy (control group) during a prolonged period. The end points evaluated were disease-free survival (DFS), overall survival (OS), cumulative incidence of local recurrence (CI-L), regional recurrence (CI-R), and distant recurrence (CI-D), all measured from the date of surgery. Results The OS and DFS were similar between the two groups. The incidence of local events was higher in the oncoplastic group, whereas the incidence of regional events was slightly higher in the mastectomy group. These differences were not statistically significant. The cumulative incidence of distant events was similar between the two groups. Conclusions To the authors’ knowledge, the current study provides the best available evidence suggesting that the oncoplastic approach is a safe and reliable treatment for managing invasive multifocal and multicentric breast cancers.

Purpose: We previously demonstrated that sex influences response to immune checkpoint inhibitors. In this article, we investigate sex-based differences in the molecular mechanisms of anticancer immune response and immune evasion in patients with NSCLC. Experimental Design: We analyzed (i) transcriptome data of 2,575 early-stage NSCLCs from seven different datasets; (ii) 327 tumor samples extensively characterized at the molecular level from the TRACERx lung study; (iii) two independent cohorts of 329 and 391 patients, respectively, with advanced NSCLC treated with anti–PD-1/anti–PD-L1 drugs. Results: As compared with men, the tumor microenvironment (TME) of women was significantly enriched for a number of innate and adaptive immune cell types, including specific T-cell subpopulations. NSCLCs of men and women exploited different mechanisms of immune evasion. The TME of females was characterized by significantly greater T-cell dysfunction status, higher expression of inhibitory immune checkpoint molecules, and higher abundance of immune-suppressive cells, including cancer-associated fibroblasts, MDSCs, and regulatory T cells. In contrast, the TME of males was significantly enriched for a T-cell–excluded phenotype. We reported data supporting impaired neoantigens presentation to immune system in tumors of men, as molecular mechanism explaining the findings observed. Finally, in line with our results, we showed significant sex-based differences in the association between TMB and outcome of patients with advanced NSCLC treated with anti–PD-1/PD-L1 drugs. Conclusions: We demonstrated meaningful sex-based differences of anticancer immune response and immune evasion mechanisms, that may be exploited to improve immunotherapy efficacy for both women and men.

Background and objectives The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated that in clinically node-negative women undergoing breast-conserving therapy (BCT) and found to have metastases to 1 or 2 sentinel nodes, sentinel lymph node biopsy (SLNB) alone resulted in rates of local control, disease-free survival, and overall survival equivalent to those seen after axillary lymph node dissection (ALND), but with significantly lower morbidity. Application of the Z0011 guidelines resulted in fewer ALNDs without affecting locoregional recurrence or survival. Changes in practice inevitably affect health care costs. The current study investigated the actual impact of applying the Z0011 guidelines to eligible patients and determined the costs of care at a single institution. Patients and methods We compared axillary nodal management and cost data in breast cancer patients who met the Z0011 criteria and were treated with BCT and SLNB. Patients were allocated into two mutually exclusive cohorts based on the date of surgery: pre-Z0011 (June 2013 to December 2015) and post-Z0011 (June 2016 to December 2018). Results Of 3912 patients, 433 (23%) and 357 (17.6%) patients in the pre- and post-Z0011 era had positive lymph nodes. ALND decreased from 15.3% to 1.57% in the post-Z0011 era. The mean overall cost of SLNB in the pre-Z0011 cohort was €1312 per patient, while that for SLNB with completion ALND was €2613. Intraoperative frozen section (FS) use decreased from 100% to 12%. Omitting the FS decreased mean costs from €247 to €176. The mean total cost in the pre-Z0011 cohort was €1807 per patient, while in the post-Z0011 cohort it was €1498. The application of Z0011 resulted in an overall mean cost savings of €309 for each patient. Conclusions Application of the Z0011 criteria to patients undergoing BCT at our institution results in more than half a million Euro cost savings.

Introduction In patients with positive lymph nodes (cN+) prior to neoadjuvant treatment (NAT), which convert to a clinically negative axilla (cN0) after treatment, the use of sentinel node biopsy (SNB) is still debatable, since the false-negative rate (FNR) is significantly high (12.6–14.2%). The objective of this retrospective mono-institutional study, with a long follow-up, aimed to evaluate the outcome in patients undergoing NAT who remained or converted to cN0 and received SNB independent of target axillary dissection (TAD) or the removal of at least 3 sentinel nodes (SNs). Methods This study analyzed 688 consecutive cT1-3, cN0/1/2 patients, operated at the European Institute of Oncology, Milan, from 2000 to 2015 who became or remained cN0 after NAT and underwent SNB with a least one SN found. Axillary dissection (AD) was not performed if the SN was negative. Nodal radiotherapy (RT) was not mandatory. Results Axillary failure occurred in 1.8% of the initially cN1/2 patients and in 1.5% of the initially cN0 patients. After a median follow-up of 9.2 years (IQR 5.3–12.3), the 5- and 10-year overall survival (OS) were 91.3% (95% CI, 88.8–93.2) and 81.0% (95% CI, 77.2–84.2) in the whole cohort, 92.0% (95% CI, 89.0–94.2) and 81.5% (95% CI, 76.9–85.2) in those initially cN0, 89.8% (95% CI, 85.0–93.2) and 80.1% (95% CI, 72.8–85.7) in those initially cN1/2. Conclusion The 10-year follow-up confirmed our preliminary data that the use of standard SNB is acceptable in cN1/2 patients who become cN0 after NAT and will not translate into a worse outcome.

Background: Adjuvant chemotherapy for Luminal B-like breast cancers usually includes anthracycline-based regimens. However, some patients are reluctant to receive chemotherapy because of side-effects, especially alopecia, and ask for a “less intensive” or personalized approach. Patients and methods: We conducted a phase II feasibility trial to evaluate pegylated liposomal doxorubicin (PLD, Caelyx®) as adjuvant chemotherapy. Patients who received surgery for pT1–3, any N, and luminal B-like early-stage breast cancer (EBC) candidates for adjuvant chemotherapy were included. PLD was administered intravenously at 20 mg/m2 biweekly for eight courses. Endocrine therapy was given according to menopausal status. Trastuzumab was administered in HER2-positive disease. The primary endpoint was to evaluate the feasibility of this regimen, defined as the ability of a patient to achieve a relative dose intensity (RDI) of at least 85% of the eight cycles of treatment. Secondary endpoints included adverse events (AEs), tolerability, breast cancer-free survival, disease-free survival, and overall survival. Results: From March 2016 to July 2018, 63 patients were included in the trial. Median age was 49 years (range: 33–76), with mostly pre- and peri-menopausal (65%) and stage I–II (94%). Only 5% of patients had HER2-positive EBC. Median RDI was 100% (range: 12.5–100%; interquartile range, IQR: 87.5–100%). The proportion of patients meeting the primary endpoint was 84% (95% confidence interval, CI: 73–92%). Overall, 55 out of 63 enrolled patients completed treatment (87%, 95% CI: 77–94%). Most common AEs were palmar-plantar erythrodysesthesia (12.2%), fatigue (10.4%), and mucositis (8.5%). Only 13% of patients had G3 AEs. None had alopecia. After a median follow-up of 3.9 years (range: 0.3–4.7) two distant events were observed, and all patients were alive at the date of last visit. Conclusions: The trial successfully met its primary endpoint: the regimen was feasible and well tolerated and could be considered for further evaluation as a treatment option for patients with contraindications to standard anthracyclines or requiring a personalized, less intensive approach.

Background and objectives cT4 breast cancer (BC) is classified as noninflammatory breast cancer (non-IBC) or inflammatory breast cancer (IBC). The outcome often is considered worse. The purpose of this study was to determine recurrence and outcomes in overall survival (OS), invasive disease-free survival (IDFS), distant disease-free survival (DDFS) according to pathological complete response (pCR), and inflammatory status. Methods From 2000 to 2015 we selected 634 nonmetastatic cT4 BC patients treated with neoadjuvant therapy followed by surgery at the European Institute of Oncology. OS, IDFS, and DDFS were estimated with the Kaplan-Meier method. Results The median follow-up was 9.0 years. Twenty patients underwent only sentinel node biopsy (SNB), 13 SNB + AD, and 601 only AD. Considering the 614 patients with AD, only 2.5% of non-IBC patients reported pCR compared to 15% of IBC cases. Only two axillary recurrences were reported. Ten-year results were 52.3% (95% confidence interval [CI]: 47.8-56.5) for OS, 37.0% (95% CI: 32.6-41.3) for IDFS, and 49.8% (95% CI: 45.0-54.4) for DDFS. OS, IDFS, and DDFS were better in all BC with pCR (irrespective of inflammatory status). Conclusion Our long-term results demonstrated that pCR significantly improves survival, reducing locoregional and distant recurrence risk in cT4 tumors with respect to patients with no pCR and according to inflammatory status of cT4 BC.

Background Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and endocrine therapy (ET) deeply transformed the treatment landscape of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer. Randomized clinical trials suggest that second progression-free survival (PFS2) was not compromised and time to subsequent chemotherapy (TTC) may be delayed. We carried out a meta-analysis to assess the benefit on PFS2 and on delaying the TTC. Methods We conducted a systematic literature search of randomized clinical trials with CDK4/6 inhibitors and ET reporting PFS2 or TTC of HR+/HER2− pre- or postmenopausal metastatic breast cancer. We also reviewed abstracts and presentations from all major conference proceedings. We calculated the pooled hazard ratios (HR) for PFS2 and TTC using random-effects models with 95% confidence intervals (CI). I2 was used to quantify heterogeneity between results of the studies. Results Eight studies (MONALEESA-2/3/7, MONARCH-2/3, PALOMA-1/2/3) were included in this analysis (N = 4580 patients). PFS2 benefit was observed in patients who received CDK4/6 inhibitors plus ET (pooled HR = 0.68, 95% CI = 0.62-0.74, I2 = 0%) and also a delay in subsequent TTC (pooled HR = 0.65, 95% CI = 0.60-0.71, I2 = 0%). A benefit in terms of PFS (pooled HR = 0.55, 95% CI = 0.51-0.59, I2 = 0%) and overall survival (pooled HR = 0.76, 95% CI = 0.69-0.84, I2 = 0%) was also observed. Conclusions CDK4/6 inhibitors plus ET compared with ET alone improve PFS2 and TTC. The delay of chemotherapy may postpone the start of a more toxic treatment option, delaying related toxicities and potentially maintaining a better quality of life for patients, for a longer time. The benefit in PFS2 may postpone the onset of endocrine resistance and help further validate this treatment approach., Highlights • Eight RCTs (MONALEESA-2/3/7, MONARCH-2/3, PALOMA-1/2/3) were included in this analysis on pooled HR for PFS2 and TTC. • Patients who received CDK4/6 inhibitors plus ET had a clear PFS2 benefit and a delay in subsequent TTC. • CDK4/6 inhibitors plus ET compared with ET alone improve PFS2 and TTC.

ObjectiveTo evaluate pathological complete response as a surrogate endpoint for disease-free survival and overall survival in regulatory neoadjuvant trials of early stage breast cancer.DesignSystematic review and meta-analysis.Data sourcesMedline, Embase, and Scopus to 1 December 2020.Eligibility criteria for study selectionRandomised clinical trials that tested neoadjuvant chemotherapy given alone or combined with other treatments, including anti-human epidermal growth factor 2 (anti-HER2) drugs, targeted treatments, antivascular agents, bisphosphonates, and immune checkpoint inhibitors.Data extraction and synthesisTrial level associations between the surrogate endpoint pathological complete response and disease-free survival and overall survival.MethodsA weighted regression analysis was performed on log transformed treatment effect estimates (hazard ratio for disease-free survival and overall survival and relative risk for pathological complete response), and the coefficient of determination (R2) was used to quantify the association. The secondary objective was to explore heterogeneity of results in preplanned subgroups analysis, stratifying trials according treatment type in the experimental arm, definition used for pathological complete response (breast and lymph nodesvbreast only), and biological features of the disease (HER2 positive or triple negative breast cancer). The surrogate threshold effect was also evaluated, indicating the minimum value of the relative risk for pathological complete response necessary to confidently predict a non-null effect on hazard ratio for disease-free survival or overall survival.Results54 randomised clinical trials comprising a total of 32 611 patients were included in the analysis. A weak association was observed between the log(relative risk) for pathological complete response and log(hazard ratio) for both disease-free survival (R2=0.14, 95% confidence interval 0.00 to 0.29) and overall survival (R2=0.08, 0.00 to 0.22). Similar results were found across all subgroups evaluated, independently of the definition used for pathological complete response, treatment type in the experimental arm, and biological features of the disease. The surrogate threshold effect was 5.19 for disease-free survival but was not estimable for overall survival. Consistent results were confirmed in three sensitivity analyses: excluding small trials (ConclusionA lack of surrogacy of pathological complete response was identified at trial level for both disease-free survival and overall survival. The findings suggest that pathological complete response should not be used as primary endpoint in regulatory neoadjuvant trials of early stage breast cancer.

Introduction Metaplastic breast cancer (MBC) is a rare condition of breast tumor with different subtypes, considered a disease with worse prognosis; treatments and survival are often unclear and conflicting. Methods We consecutively collected 153 primary MBCs of different subtypes. Breast surgery, neoadjuvant or adjuvant treatment, clinic-pathological factors, number and type of events during follow-up were considered to evaluate overall survival (OS) and invasive disease-free survival (IDFS). Results The majority of MBC was triple-negative (TN) subtype (88.7%), G3 (95.3%), pN0 (70.6%), and with high levels of Ki-67 (93.5%). For OS and IDFS, no significant associations were seen between the different MBC subtypes. The matched triple-negative MBC (TNMBC) and ductal TNBC cohorts had similar prognosis both in terms of OS (p = .411) and IDFS (p = .981). We observed a positive trend for TNMBC patients treated in the adjuvant setting with the cyclofosfamide, methotrexate, 5-fluorouracil protocol for better OS (p = .090) and IDFS (p = .087). A poor or absent response rate was observed in the neoadjuvant setting. Conclusion Our results demonstrate that metaplastic and ductal breast cancers with TN phenotype are similar in terms of overall and disease-free survival. Metaplastic cancers are poorly responsive to neoadjuvant treatment, and in the absence of novel targeted therapies, surgical treatment remains the first choice.

Purpose: To retrospectively review our experience on 84 patients with squamous cell anal canal cancer (SCAC) within 12 months after combined treatment with intensity-modulated RT (IMRT), in terms of acute and early-late toxicity, overall treatment time and interruptions, colostomy-free survival (CFS), and tumor response. Methods: Acute gastrointestinal (GI), genitourinary (GU), and cutaneous (CU) toxicities were assessed according to Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03. Early-late toxicity was scored using the Radiation Therapy Oncology Group (RTOG) late radiation morbidity scoring system. Tumor response was evaluated with response evaluation criteria in solid tumors (RECIST) v1.1. Results: Acute toxicity for 84 subjects (100%): severe (≥ G3) GI and skin toxicity was observed in 4 (5%) and 19 patients (23%), respectively. Early-late toxicity for 73 subjects (87%): severe (≥ G3) GI and vulvo-vaginal toxicity was observed in 2 (3%) and 2 (3%) patients, respectively. No acute or early-late severe GU toxicity was reported. A treatment interruption occurred in 65 patients (77%). CFS was 96% (95% CI 89–99) at 6 months and 92% (95% CI 83–96) at 12 months. At 6 months complete response (CR), partial response (PR) and progressive disease (PD) was observed in 70 (83%), 3 (4%), and 7 patients (8%), respectively. At 12 months, CR was observed in 60 patients (81%); eleven patients (15%) experienced PD. Conclusion: Our study showed an excellent clinical result and very low acute toxicity rates, confirming the IMRT as standard of care for curative treatment of anal cancer patients. The current trial was registered with the number IEO N87/11

Background Ipsilateral breast cancer recurrence (IBTR) occurs in about 7% of patients with primary invasive breast tumor. Salvage mastectomy and breast reconstruction are often discussed and latissimus dorsi (LD) flap is frequently proposed. Methods We retrospectively investigated 111 consecutive locally relapsing patients who underwent salvage mastectomy and immediate LD reconstruction. All included patients with IBTR previously underwent conserving surgery for BC, and received a postoperative irradiation. Primary endpoints were disease free survival and overall survival. Secondary endpoints were surgical complications and re-interventions. Results Invasive ductal cancer was the most frequent histotype (60.4%) of breast cancer reappearance. rpT1, rpT2 and rpT3 were observed respectively in 50.5%, 20,7% and 3,6% of the patients. rpTis occurred in 11,7% of cases. Positive axillary nodes were observed in 9,9% of patients at reappearance. Post-operative complication other than seroma occurred in 17,1% of patients, while seroma at the donor site was observed in 61.3% of cases. At 5-year after surgery overall survival was 92% (95% CI: 85%–96%) and disease free survival was 78% (95% CI: 69%–85%). Conclusions Immediate latissimus dorsi flap reconstruction in selected patients with isolated breast tumor recurrence, which occurred after breast irradiation, provides an effective treatment with a satisfactory outcome.

The natural history of ductal carcinoma in situ (DCIS) is highly variable and difficult to predict. Biomarkers are needed to stratify patients with DCIS for adjuvant therapy. We investigated the prognostic and predictive relevance of cell cycle progression (CCP) score in women with DCIS. We measured the expression of 23 genes involved in CCP with quantitative RT-PCR on RNA extracted from formalin-fixed paraffin-embedded tumor samples, and assessed the correlation of a predefined score with histopathologic features and recurrence. The signature was analyzed in a cohort of 909 consecutive DCIS with full histopathological features treated in a single institution. The main outcome measure was ipsilateral breast event (IBE) as first event observed, be it in situ or invasive. Median follow-up time was 8.7 years (IQR 6.5-10.5 years). There were 150 ipsilateral IBEs, 84 (56%) of which were invasive. In the first 5 years of follow-up, the score provided statistically different findings (p = 0.009), with IBE rates of 14.7% (95% CI, 10.4-19.7) for the highest quartile of CCP score (Q4) and 8.7% (95% CI, 6.7-11.0) for the lowest quartiles (Q1-3). The prognostic value for IBEs approached significance also in women treated with mastectomy (adjusted hazard ratio [HR] Q4 vs. Q1-3 = 2.60; 95% CI: 0.96-7.08; P = 0.06). Radiotherapy provided a greater benefit in women with higher CCP score. In addition, Q4 predicted a different risk after tamoxifen depending on menopausal status, with a beneficial trend on IBEs in postmenopausal women (HR 0.30; 95% CI, 0.07-1.39), and an opposite trend in premenopausal women (HR 1.68; 95% CI, 0.38-7.44) (P-interaction = 0.03). The results of this study provide for the first time the evidence that CCP score is a prognostic marker, which, after additional validation, could have an important role in personalizing the management of DCIS.

Background Bilateral lung neoplasms are becoming more common, but distinguishing two primary lung cancers from metastatic disease can be difficult and only long-term follow-up after treatment can disclose the real behavior of the disease.The present study aimed to identify the appropriate candidates for bilateral surgical resections from the perspective of short-term postoperative complications and long-term outcomes. Methods Two hundred and fifteen consecutive patients undergoing bilateral pulmonary resection for lung cancers over a 20-year period were analyzed. Preoperative patient characteristics were noted, including demographic information, operative details, pathologic information including histology and tumor stage according to the eighth edition of the tumor nodes metastases staging system, and the use of neoadjuvant or adjuvant treatments. Results Patients receiving the second pulmonary resection more than 24 months from the first procedure as well as patients receiving bilateral lobectomies had higher overall 3-, 5-, and 10-year survival rates compared with the others. Conclusion Patients receiving the second resection more than 24 months from the first procedure have the best long-term results irrespective of the type of resection.