Publications by authors named "Patrick Maisonneuve"

321 Publications

Outcome of Patients With Metastatic Lung Neuroendocrine Tumors Submitted to First Line Monotherapy With Somatostatin Analogs.

Front Endocrinol (Lausanne) 2021 27;12:669484. Epub 2021 Apr 27.

Medical Oncology, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health University of Brescia, ASST-Spedali Civili, Brescia, Italy.

Objective: Antiproliferative activity of somatostatin analogs (SSAs) has been demonstrated in digestive neuroendocrine tumors (NETs), but few data have been published in patients with pulmonary NETs. We therefore conducted a retrospective study to provide additional data on the outcome of patients with metastatic lung NETs submitted to front line SSAs.

Research Design And Methods: Patients with metastatic lung NET treated with first line SSA-monotherapy (octreotide or lanreotide) in two different reference Institutions were reviewed. Outcome measures were progression-free survival (PFS) overall survival (OS), overall response rate and safety. We also explored prognostic factors associated with PFS.

Methods: The outcome of consecutive patients (pts) with metastatic lung NETs, who underwent first-line treatment with SSAs, recruited from 2014 on 2019 in two Italian reference Institutions, was retrospectively evaluated.

Results: Thirty-one patients entered the study: 14 (45.2%) with typical and 17 (54.8%) atypical carcinoid. Six patients (19.4%) had a carcinoid syndrome. 60.0% of patients had Ki-67 ≤ 10%. Two (6.5%) patients obtained a partial response, 24 (77.4%) disease stabilization while 5 (16.1%) had progressive disease. Median progression free survival (PFS) was 28.6 months, median overall survival (OS) was not attained. Ki-67 ≤ 10%, typical carcinoid histotype and non-functioning disease, were associated with a non-significant PFS prolongation. PFS in patients with atypical carcinoids and in those with Ki-67 >10% was greater than 19 months.

Conclusions: The long PFS and OS obtained in this case series suggest that SSAs could be effective as first line approach in the management of patients with progressive, metastatic pulmonary NET.
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http://dx.doi.org/10.3389/fendo.2021.669484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111295PMC
April 2021

Urinary Biomarkers for Early Diagnosis of Lung Cancer.

J Clin Med 2021 Apr 16;10(8). Epub 2021 Apr 16.

Department of Thoracic Surgery, IEO, European Institute of Oncology IRCCS, Via Giuseppe Ripamonti 435, 20141 Milan, Italy.

Lung cancer is the leading cause of cancer deaths worldwide. Its early detection has the potential to significantly impact the burden of the disease. The screening and diagnostic techniques in current use suffer from limited specificity. The need therefore arises for a reliable biomarker to identify the disease earlier, which can be integrated into a test. This test would also allow for the recurrence risk after surgery to be stratified. In this context, urine could represent a non-invasive alternative matrix, with the urinary metabolomic profile offering a potential source for the discovery of diagnostic biomarkers. This paper aims to examine the current state of research and the potential for translation into clinical practice.
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http://dx.doi.org/10.3390/jcm10081723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074220PMC
April 2021

Risk Stratification of Cholangiocarcinoma Patients Presenting with Jaundice: A Retrospective Analysis from a Tertiary Referral Center.

Cancers (Basel) 2021 Apr 25;13(9). Epub 2021 Apr 25.

Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy.

Cholangiocarcinomas (CCAs) are a heterogeneous group of tumors that arise from the biliary tract. Jaundice is a common clinical presentation; however, the prognostic impact of this symptom is poorly understood, and current management recommendations lack solid evidence. We aim to assess the clinical outcomes and predictive factors of CCA patients presenting with jaundice in the Emergency Room (ER). We retrospectively analyzed all consecutive ER cases presenting with jaundice between January 2010 and December 2017. During the study period, 403,766 patients were admitted to the ER, 1217 (0.3%) presented with jaundice, and in 200 (0.049%), the diagnosis was CCA. CCA cases increased during the study period ( for trend 0.026). Most of them presented with advance disease (stage III 46.5%, stage IV 43.5%) and median survival was 4.5 months (95% CI 3.4-6.0). Factors associated with better survival were age, stage of disease, presence of jaundice at the moment of diagnosis, and lack of concomitant viral hepatitis. A nomogram was constructed that significantly predicts 1-month, 6-month, and 1-year survival after patients' admission. In conclusion, the majority of CCA patients presenting with jaundice to the ER have advanced disease and poor prognosis. Risk stratification of these patients can allow tailored management.
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http://dx.doi.org/10.3390/cancers13092070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123266PMC
April 2021

Quality of Life, Postoperative Pain, and Lymph Node Dissection in a Robotic Approach Compared to VATS and OPEN for Early Stage Lung Cancer.

J Clin Med 2021 Apr 14;10(8). Epub 2021 Apr 14.

Division of Thoracic Surgery, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.

We compare the perioperative course, postoperative pain, and quality-of-life (QOL) in patients undergoing anatomic resections of early-stage lung cancer by means of robotic surgery (RATS), video-assisted thoracic surgery (VATS), or muscle-sparing thoracotomy (OPEN); 169 consecutive patients with known/suspected lung cancer, candidates to anatomic resection, were enrolled in a single-center prospective study from April 2016 to December 2018. EORTC QLQ-C30 and QLQ-LC13 scores were obtained preoperatively and, at three time points, postoperatively. RATS and VATS groups were matched for ASA scores, while RATS and open surgery were matched for gender, ASA score, cancer stage, and tumor size; 58 patients underwent open surgery, 58 had VATS, and 53 had RATS. Hospital stay was shorter after RATS than OPEN (median 4.5 versus 5; = 0.047). Comparing matched RATS and VATS groups, the number of hilar lymph nodes and nodal stations removed was significantly higher in the former approach ( = 0.01 vs. < 0.0001); conversely, pain at 2 weeks was slightly lower after VATS ( = 0.004). No significant difference was observed in conversions, complications, duration of surgery, and postoperative hospitalization. The robotic approach was superior to OPEN in terms of QOL, pain, and length of postoperative stay and showed improved lymph node dissection compared to VATS.
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http://dx.doi.org/10.3390/jcm10081687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071041PMC
April 2021

Mastectomy alone for pT1-2 pN0-1 breast cancer patients: when postmastectomy radiotherapy is indicated.

Breast Cancer Res Treat 2021 Apr 27. Epub 2021 Apr 27.

Division of Breast Surgery, IEO European Institute of Oncology, IRCCS, Milan, Italy.

Purpose: To assess outcome of breast cancer (BC) stages pT1-2 N0-1 after mastectomy alone and to identify prognostic factors calling for the need of postmastectomy radiotherapy.

Methods: Patients who were not eligible for breast conserving surgery (BCS) were operated on with mastectomy between 1998 and 2008. Locoregional (LRR), distant (DM) control and breast cancer specific survival (BCSS) were retrospectively evaluated. Cumulative incidence (CI) of events was estimated according to Kalbfleisch and Prentice while Gray's test tested difference. Kaplan-Meier method for survival and Cox proportional hazards model for univariable and multivariable analysis were used. A matched pair analysis between mastectomy alone and BCS plus whole breast irradiation (WBI), using the propensity score method, was performed.

Results: 1281 pT1-2 N0 and 1081 pT1-2 N1 were identified. Median follow-up was 8.2 years (9.2 years for survival). Overall, LRR rate was low for both N0 and N1 subgroups (10-year CI, 8.8% and 10.9%, respectively). Young age, lymphovascular invasion and Ki-67 ≥ 20% were proved to be statistically significant prognostic factors at multivariable analysis. The combination of ≥ 2 risk factors increased LRR rate to ≥ 15%. Risk factors combination weighed on LRR rate more than nodal status itself. DM rate doubled moving from negative to positive nodal status (10-year CI 10.5% versus 20.3%, respectively). BCSS remained high in both N0 and N1 subgroups (10-year CI 92.4% versus 84.5%, respectively). Remarkably, all the molecular subtypes except Luminal A significantly affected DM and BCSS both in the N0 and N1 subgroups. Nodes number significantly impacted on DM and BCSS but not on locoregional control. In the matched pair analysis, WBI decreased nodal recurrence rate and improved distant control, without affecting survival.

Conclusions: Selected patients, namely those with at least two additional risk factors, presented high enough LRR risk to support the use of postmastectomy radiotherapy in both N0 and N1 subgroups. Moreover, the observation that radiotherapy may provide benefits that go beyond local control deserves to be further investigated.
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http://dx.doi.org/10.1007/s10549-021-06227-2DOI Listing
April 2021

Epidemiology of tobacco use in Qatar: Prevalence and its associated factors.

PLoS One 2021 15;16(4):e0250065. Epub 2021 Apr 15.

Department of Medicine, Tobacco Control Center, WHO Collaborative Center, Hamad Medical Corporation, Doha, Qatar.

Tobacco use is a serious public health concern as it causes various deleterious health problems. The aim of this study was to determine the prevalence of tobacco use and various types of tobacco used among a population-based sample of adults 18 years and above in Qatar (residents and expatriates). The study also attempted to assess tobacco use initiation age, tobacco dependency, and to identify factors associated with current tobacco use. This 2019 cross-sectional study was conducted among governmental employees and University students in Qatar using cluster sampling methodology. Study participants completed a self-administered, country-adapted summarized version of the Global Adult Tobacco Survey. 25.2% (n = 1741; N = 6904) of the surveyed sample reported current tobacco use. 21.5% (n = 1481) smoked tobacco (cigarettes, waterpipe, medwakh and cigar) concomitant with other forms of tobacco and only 1.0% (n = 69) were using other forms of tobacco (electronic cigarettes, smokeless tobacco and heat-not-burn tobacco products) and 2.7% (n = 191) did not mention the type of tobacco products used by them. Of the 1550 tobacco users, 42.8% were cigarette smokers, 20.9% waterpipe, 3.2% medwakh (Arabic traditional pipe) and 0.7% cigar. Moreover, 1.9% reported smokeless tobacco use (sweika), 2.0% electronic cigarette use, and 0.3% heat-not-burn tobacco use. The mean age for smoking initiation was 19.7±5.3 (Qataris 18.6±4.8 and non-Qataris 20.3±5.6). Using multivariable logistic regression, significant association was observed between tobacco use and gender, nationality, age, monthly income, living with a smoker, and self-rated health. This large population-based cross-sectional survey provides the first evidence for the prevalence of different types of tobacco use including medwakh smoking among adults (Qataris and non-Qataris) 18 years and above in Qatar. This can serve as a baseline for future research studies on the topic. Based on the review of previous and current tobacco survey findings, it is evident that the prevalence of tobacco use (current) in Qatar has declined suggesting that tobacco control measures implemented by the country have been effective in reducing tobacco consumption.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250065PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049255PMC
April 2021

Intraoperative irradiation for early breast cancer (ELIOT): long-term recurrence and survival outcomes from a single-centre, randomised, phase 3 equivalence trial.

Lancet Oncol 2021 05 9;22(5):597-608. Epub 2021 Apr 9.

Division of Breast Surgery, IEO European Institute of Oncology IRCCS, Milan, Italy.

Background: In the randomised, phase 3 equivalence trial on electron intraoperative radiotherapy (ELIOT), accelerated partial breast irradiation (APBI) with the use of intraoperative radiotherapy was associated with a higher rate of ipsilateral breast tumour recurrence (IBTR) than whole-breast irradiation (WBI) in patients with early-stage breast cancer. Here, we aimed to examine the planned long-term recurrence and survival outcomes from the ELIOT trial.

Methods: This single-centre, randomised, phase 3 equivalence trial was done at the European Institute of Oncology (Milan, Italy). Eligible women, aged 48-75 years with a clinical diagnosis of a unicentric breast carcinoma with an ultrasound diameter not exceeding 25 mm, clinically negative axillary lymph nodes, and who were suitable for breast-conserving surgery, were randomly assigned (1:1) via a web-based system, with a random permuted block design (block size of 16) and stratified by clinical tumour size, to receive post-operative WBI with conventional fractionation (50 Gy given as 25 fractions of 2 Gy, plus a 10 Gy boost), or 21 Gy intraoperative radiotherapy with electrons (ELIOT) in a single dose to the tumour bed during surgery. The trial was open label and no-one was masked to treatment group assignment. The primary endpoint was the occurrence of IBTR. The trial was designed assuming a 5-year IBTR rate of 3% in the WBI group and equivalence of the two groups, if the 5-year IBTR rate in the ELIOT group did not exceed a 2·5 times excess, corresponding to 7·5%. Overall survival was the secondary endpoint. The main analysis was done by intention to treat. The cumulative incidence of IBTR events and overall survival were assessed at 5, 10, and 15 years of follow-up. This trial is registered with ClinicalTrials.gov, NCT01849133.

Findings: Between Nov 20, 2000, and Dec 27, 2007, 1305 women were enrolled and randomly assigned: 654 to the WBI group and 651 to the ELIOT group. After a median follow-up of 12·4 years (IQR 9·7-14·7), 86 (7%) patients developed IBTR, with 70 (11%) cases in the ELIOT group and 16 (2%) in the WBI group, corresponding to an absolute excess of 54 IBTRs in the ELIOT group (HR 4·62, 95% CI 2·68-7·95, p<0·0001). In the ELIOT group, the 5-year IBTR rate was 4·2% (95% CI 2·8-5·9), the 10-year rate was 8·1% (6·1-10·3), and the 15-year rate was 12·6% (9·8-15·9). In the WBI group, the 5-year IBTR rate was 0·5% (95% CI 0·1-1·3), the 10-year rate was 1·1% (0·5-2·2), and the 15-year rate was 2·4% (1·4-4·0). At final follow-up on March 11, 2019, 193 (15%) women had died from any cause, with no difference between the two groups (98 deaths in the ELIOT group vs 95 in the WBI group; HR 1·03, 95% CI 0·77-1·36, p=0·85). In the ELIOT group, the overall survival rate was 96·8% (95% CI 95·1-97·9) at 5 years, 90·7% (88·2-92·7) at 10 years, and 83·4% (79·7-86·4) at 15 years; and in the WBI group, the overall survival rate was 96·8% (95·1-97·9) at 5 years, 92·7% (90·4-94·4) at 10 years, and 82·4% (78·5-85·6) at 15 years. We did not collect long-term data on adverse events.

Interpretation: The long-term results of this trial confirmed the higher rate of IBTR in the ELIOT group than in the WBI group, without any differences in overall survival. ELIOT should be offered to selected patients at low-risk of IBTR.

Funding: Italian Association for Cancer Research, Jacqueline Seroussi Memorial Foundation for Cancer Research, Umberto Veronesi Foundation, American Italian Cancer Foundation, The Lombardy Region, and Italian Ministry of Health.
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http://dx.doi.org/10.1016/S1470-2045(21)00080-2DOI Listing
May 2021

Impact of radiation and hormonal therapy on the locoregional recurrence of elderly breast cancer: Are these necessary after breast-conserving surgery?

Cancer 2021 Apr 1. Epub 2021 Apr 1.

Division of Breast Surgery, European Institute of Oncology, IRCCS, Milan, Italy.

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http://dx.doi.org/10.1002/cncr.33550DOI Listing
April 2021

Long-term outcome and axillary recurrence in elderly women (≥70 years) with breast cancer: 10-years follow-up from a matched cohort study.

Eur J Surg Oncol 2021 Jul 3;47(7):1593-1600. Epub 2021 Mar 3.

Division of Breast Surgery, IEO European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Italy.

Background And Objectives: The oncological benefit of axillary surgery (AS), with sentinel lymph node biopsy (SLNB) or axillary dissection (ALND), in elderly women affected by breast cancer (BC) is controversial. We evaluated AS trends over a 10-year follow-up period as well as locoregional and survival outcomes in this subset of patients.

Methods: Patients aged 70 years or older, treated between 1994 and 2008, were selected and divided in two groups, depending on whether or not AS was performed. A (1:1) matched analysis for all relevant clinicopathological features was performed. Outcomes were analyzed using the Kaplan-Meier method and univariate Cox-proportional hazard ratio analysis.

Results: A total of 1.748 patients were identified and stratified by age (70-74, 75-79, 80-84). A matched analysis was performed for 252 patients: 122 who underwent AS and 122 who did not. At 10-year follow-up, ipsilateral breast tumor recurrence, distant metastasis and contralateral BC were similar, p = 0.83, p = 0.42 and p = 0.28, respectively. In the no-AS group, a significant increased risk of axillary lymph-node recurrence was identified at 5- and confirmed at 10-years (p = 0.038), without impact on overall survival at 5- and 10-years (p = 0.52). In the non-AS group, higher rate of axillary recurrence at 10-years was observed in patients with poorly differentiated (24.1%, 95% CI 7.2-46.2), highly proliferative (Ki67 ≥ 20%: 17.1%, 95% CI 0.6-33.3) and luminal B tumors (16.8%, 95% CI 5.9-35.5).

Conclusions: Axillary staging in elderly women does not impact long-term survival. Tailoring surgery according to tumor biology and age may improve locoregional outcome.
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http://dx.doi.org/10.1016/j.ejso.2021.02.027DOI Listing
July 2021

Factors associated with perceived stress in Middle Eastern university students.

J Am Coll Health 2021 Feb 12:1-8. Epub 2021 Feb 12.

Institute for Population Health, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha, Qatar.

Objective: University students face high levels of stress-related factors, such as an unfamiliar environment, challenging workload, and uncertainty about their ability to succeed. A total of 370 students in Qatar who consented to participate between February 2017 and February 2018. This cross-sectional study assessed perceived stress [using a validated 4-point perceived stress scale (PSS-4)], as well as diet, exercise, body mass index, sleep, and life satisfaction. Among students aged 18-39 (mean = 20.1 ± 3.0 years), PSS-4 scores varied between 0 and 16 (mean = 7.4 ± 3.4). Elevated stress was significantly associated with female sex, country of origin, residing off-campus, eating when bored, lack of self-discipline, disturbed sleep, and low levels of life satisfaction. Furthermore, students with PSS-4 scores above the median level were 2.3 times likelier to report difficulty concentrating on academic work. Elevated stress levels are present in university students in Qatar. Strengthening coping skills may improve health and academic performance.
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http://dx.doi.org/10.1080/07448481.2020.1865979DOI Listing
February 2021

Response to Braillon.

JNCI Cancer Spectr 2021 Feb 23;5(1):pkab005. Epub 2021 Jan 23.

Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA.

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http://dx.doi.org/10.1093/jncics/pkab005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853174PMC
February 2021

Low-Dose Aspirin in High-Risk Individuals With Screen-Detected Subsolid Lung Nodules: A Randomized Phase II Trial.

JNCI Cancer Spectr 2020 Dec 20;4(6):pkaa096. Epub 2020 Oct 20.

Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA.

Lung cancer screening by helical low-dose computed tomography detects nonsolid nodules that may be lung adenocarcinoma precursors. Aspirin's anti-inflammatory properties make it an attractive target for prevention of multiple cancers, including lung cancer. Therefore, we conducted a phase IIb trial (NCT02169271) to study the efficacy of low-dose aspirin to reduce the size of subsolid lung nodules (SSNs). A total of 98 current or former smokers (67.3% current) undergoing annual low-dose computed tomography screening with persistent SSNs were randomly assigned to receive aspirin 100 mg/day or placebo for 1 year. There was no difference in change in the sum of the longest diameters of target nodules in the placebo and aspirin arm after 12 months of treatment (-0.12 mm [SD = 1.55 mm] and +0.30 mm [SD= 2.54 mm], respectively; 2-sided  = .33 primary endpoint). There were no changes observed in subgroup analyses by individual characteristics or nodule type. One year of low-dose aspirin did not show any effect on lung SSNs. SSNs regression may not be the proper target for aspirin, and/or longer duration may be needed to see SSNs modifications.
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http://dx.doi.org/10.1093/jncics/pkaa096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771428PMC
December 2020

The state of population health research performance in the Middle East and North Africa: a meta-research study.

Syst Rev 2021 01 2;10(1). Epub 2021 Jan 2.

Institute for Population Health, Weill Cornell Medicine-Qatar, Doha, Qatar.

Background: Population health (PH) research capacity and performance are essential pillars of evidence-based practice to help address health inequalities. Best evidence is provided by systematic reviews (SRs). None of the published bibliometric analysis specifically assess the production of SRs on PH in the Middle East and North Africa (MENA). The aim of our study is to investigate publication patterns and time trends of SRs reporting PH in the MENA region to evaluate the state of PH research performance in the region.

Method: The study protocol was developed a priori (protocol registration number: CRD42017076736). PubMed was searched. Two independent reviewers screened 5747 identified articles. We investigated author affiliation and collaboration, yearly citations of the SRs and journal information. Joinpoint regression was used to explore these characteristics overtime.

Results: Our meta-research included 387 SRs published between 2008 and 2016 which reported data on PH in 20 MENA countries. Publication of SRs increased over time in journals with impact factor < 4 and in the categories of yearly number of citations < 50 (p values ≤ 0.0024). Authors belonging to the region published increasingly (p value = 0.0001) over time. Thirty percent of the SRs were from authors solely from the region, while an additional 30% were from the region collaborating with Western country authors. Of these collaborative reviews, 79% were led by authors from the region. However, collaboration in the region (with the exclusion of collaboration with Western country authors) was rare (0.8%). These authors from the region published more in open-access journals while authors from Western countries collaborating or not with authors from the region published more in hybrid or non-open-access journals (p value < 0.0001). Collaboration between authors from MENA and Western countries led to published SRs in journals with impact factor ≥ 10. Systematic reviews with global coverage were published more by authors from Western countries, while SRs with country-level coverage were published by authors from the region (p value < 0.0001).

Conclusion: The incremental trend of PH SR publications on MENA likely reflects the ongoing improvement in research performance in the region. Authors from the region appear to be taking a lead role in conducting and disseminating MENA PH research. Open-access journals are a major contributor in facilitating MENA research dissemination.

Systematic Review Registration: PROSPERO registration number CRD42017076736.
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http://dx.doi.org/10.1186/s13643-020-01552-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7777412PMC
January 2021

Surgery for small cell lung cancer: When and how.

Lung Cancer 2021 02 22;152:71-77. Epub 2020 Dec 22.

Division of Thoracic Surgery, IEO, European Institute of Oncology, IRCCS, Milan, Italy; University of Milan, Department of Oncology and Hemato-oncology, Milan, Italy.

Objective: Since data from large retrospective observational studies and cancer registries became available, suggesting a benefit for patients undergoing surgery, the role of surgery in the treatment of small cell lung cancer (SCLC) needs to be reconsidered. The aim of this study was to evaluate outcomes and results of patients with SCLC undergoing intent-to-treat surgery.

Material And Methods: We retrospectively analyzed 324 patients (1998-2018) with a diagnosis of SCLC referred to our Institution. 65 patients underwent surgical resection with curative intent. Kaplan-Meier and Cox regression analyses were used to compare overall survival (OS) for all patients.

Results: Among the patients, 39 (60.0 %) patients had surgery upfront, whereas 24 (36.9 %) had surgery after chemotherapy (CT) alone, and 2 (3.1 %) after CT plus radiotherapy (RT). Twenty-nine (44.6 %) patients were stage I or had a complete response to induction treatment, 21 (32.3 %) had stage II, and 15 (23.1 %) stage III. Forty-four (67.7 %) patients underwent adjuvant treatment: 21 (32.3 %) had CT, 31 (47.7 %) RT, and 7 (10.8 %) both. Prophylactic cranial irradiation was administered in 15 patients (23.1 %). The median OS after initial diagnosis at 1, 5, 10 years was 1, 5, 10 years was 81.4 %, 41.4 % and 25.4 % respectively. Among patients who underwent surgical resection with curative intent, those with clinical stage I had a longer survival (5-year OS 62.9 %) p < 0.0001.

Conclusion: patients with stage I SCLC could be considered the best candidates for surgery, in a multidisciplinary setting. Instead, considering their worse survival, those with stage II and III should be carefully selected for the surgical approach, and alternative therapy should be considered.
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http://dx.doi.org/10.1016/j.lungcan.2020.12.006DOI Listing
February 2021

An innovative approach to identify past exposure to asbestos integrating questionnaire information and administrative data.

Health Policy 2021 Feb 11;125(2):246-253. Epub 2020 Dec 11.

Department of Occupational and Environmental Medicine, Epidemiology and Hygiene, Italian Workers' Compensation Authority (INAIL), Via Fontana Candida 1, 00078, Monte Porzio Catone, Rome, Italy. Electronic address:

Reconstruction of work history of subjects exposed to occupational carcinogens might be extremely challenging and provide unreliable results. This study, carried out in Italy from February to November 2014, aimed to explore the validity of an innovative approach to reconstruct the occupational history of workers who have previously been exposed to asbestos combining the administration of structured questionnaire with the use of administrative data. Subjects recruited in this study were enrolled in the cohorts of COSMOS 1 and 2 studies. Participants indicating an exposure to asbestos were contacted and a structured questionnaire was administered to them to verify the validity of the self-reported asbestos exposure. Subsequently, work histories of respondents were investigated using administrative information. The record linkage with social security archives allowed the reassembling of the complete work history of 487 participants. In detail, administrative files allow the retrieval of 98 % of workers declaring not to be exposed, versus 77 % using the questionnaire. Furthermore, the percentage of retrieved cases is not relevant for high risk sectors but it is almost double for industries with probable presence of asbestos. The combined and integrated use of structured questionnaire with administrative data proved effective in accurately identifying subjects who actually had an asbestos exposure. This innovative strategy, being cost-effective and easily adaptable to other carcinogens, could be particularly useful in selecting subjects to recruit in specific screening and control programs for the early diagnosis of occupational cancers.
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http://dx.doi.org/10.1016/j.healthpol.2020.11.013DOI Listing
February 2021

Risk of Developing Pancreatic Cancer in Patients with Chronic Pancreatitis.

J Clin Med 2020 Nov 19;9(11). Epub 2020 Nov 19.

Department of Upper Abdominal Diseases, Karolinska University Hospital, 14186 Stockholm, Sweden.

: Patients with chronic pancreatitis (CP) have an increased risk of developing pancreatic ductal adenocarcinoma (PDAC). We present data on PDAC in one of the most extensive European single-centre cohort studies of patients with CP. : Retrospective analysis of prospectively collected data of patients with CP was performed. Aetiology of CP was determined according to the M-ANNHEIM classification system and only patients with definite CP > 18 years at data analysis were included. The final dataset included 581 patients with definite CP diagnosed between 2003 and 2018. At CP diagnosis, there were 371 (63.9%) males and 210 (36.1%) females (median age 57 years, range 2-86). During 3423 person-years of observation, six pancreatic cancers were diagnosed (0.2% year). The mean time between diagnosis of CP and the occurrence of PDAC was 5.0 years (range 2.7-8.6). None of the cancer patients had a family history of PDAC. Diabetes mellitus (DM) was present in five of six (83.3%) patients with PDAC: in three patients before and in two after CP diagnosis. Clinical/laboratory signs of pancreatic exocrine insufficiency (PEI) were present in five of six (83.3%) patients with PDAC: in two at diagnosis of CP and in three after diagnosis. The mean survival time was 4 months after the diagnosis of PDAC (range 0.5-13). PDAC occurred significantly more often ( < 0.001) in two groups of patients without previous acute pancreatitis (AP): 2 of 20 patients (10%) with low body mass index (BMI) and PEI and in 3 of 10 (30%) patients with high BMI and DM at diagnosis of CP. Patients with CP have a high risk of developing PDAC, although risk is low in absolute terms. Our data suggest the possibility of defining subgroups of patients with a particularly elevated risk of PDAC. Such a possibility would open a path to personalised decision making on initiation of PDAC surveillance of patients with no previous episode of AP, (i) with low BMI and PEI, or (ii) elevated BMI and DM.
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http://dx.doi.org/10.3390/jcm9113720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699479PMC
November 2020

Results of Surgical Resection of Locally Advanced Pulmonary Neuroendocrine Tumors.

Ann Thorac Surg 2020 Oct 29. Epub 2020 Oct 29.

Division of Thoracic Surgery, European Institute of Oncology (IEO), IRCCS, Milan, Italy; Department of Oncology and Hematology-Oncology, University of Milan, Milan, Italy. Electronic address:

Background: Pulmonary neuroendocrine tumors include well-differentiated and poorly differentiated histology for which cell type has proved to be a determinant of survival in many studies. In patients diagnosed with bronchial carcinoid and large cell neuroendocrine carcinoma (LCNEC), surgery is the treatment of choice even in the case of locally advanced disease with lymph node involvement.

Methods: We retrospectively analyzed patients undergoing anatomic lung resection for bronchial carcinoid or LCNEC with lymph node involvement (N1/N2) at the final pathologic examination (pN+). Characteristics of patients and differences in overall survival and disease-free survival are presented according to tumor type. Overall survival of distinct histologic groups was compared with survival in our institutional experience in stage I patients, without nodal involvement (pN0).

Results: In all, 325 patients underwent surgical resection for neuroendocrine tumors; 89 patients had nodal involvement. Five-year survival was 89% in pN+ bronchial carcinoid both for typical carcinoid and atypical carcinoid but worse for pN+ LCNEC (47%). Cell type did not influence the prognosis in N0 disease, and no differences in survival were evident between N0 and N+ in the bronchial carcinoid group. In the group of LCNEC, 5-year overall survival was much worse for pN+ LCNEC (47%) compared with pN0 LCNEC (91%).

Conclusions: Bronchial carcinoids have the best prognosis, and surgery remains the treatment of choice for both early and locally advanced disease. On the contrary, aggressive forms (LCNEC) with lymph nodal metastasis have a poor prognosis, and they need to be treated with an aggressive multidisciplinary approach.
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http://dx.doi.org/10.1016/j.athoracsur.2020.09.021DOI Listing
October 2020

Pancreatic Cancer Malnutrition and Pancreatic Exocrine Insufficiency in the Course of Chemotherapy in Unresectable Pancreatic Cancer.

Front Med (Lausanne) 2020 3;7:495. Epub 2020 Sep 3.

Gastroenterology and Interventional Endoscopy Department, Clinical Emergency Hospital Bucharest, Bucharest, Romania.

Malnutrition and cachexia are common in patients with advanced pancreatic ductal adenocarcinoma (PDAC) and have a significant influence on the tolerance and response to treatments. If timely identified, malnourished PDAC patients could be treated to increase their capacity to complete the planned treatments and, therefore, possibly, improve their efficacy. The aim of this study is to assess the impact of nutritional status, pancreatic exocrine insufficiency (PEI), and other clinical factors on patient outcomes in patients with advanced PDAC. PAncreatic Cancer MAlnutrition and Pancreatic Exocrine INsufficiency in the Course of Chemotherapy in Unresectable Pancreatic Cancer (PAC-MAIN) is an international multicenter prospective observational cohort study. The nutritional status will be determined by means of Mini-Nutritional Assessment score and laboratory blood tests. PEI will be defined by reduced fecal elastase levels.

Main Outcome: adherence to planned chemotherapy in the first 12 weeks following the diagnosis, according to patients' baseline nutritional status and quantified and reported as "percent of standard chemotherapy dose delivered."

Secondary Outcomes: rate of chemotherapy-related toxicity, progression-free survival, survival at 6 months, overall survival, quality of life, and the number of hospitalizations.

Analysis: chemotherapy dosing over the first 12 weeks of therapy (i.e., percent of chemotherapy received in the first 12 weeks, as defined above) will be compared between well-nourished and malnourished patients.

Sample Size: based on an expected percentage of chemotherapy delivered of 70% in well-nourished patients, with a type I error of 0.05 and a type II error of 0.20, a sample size of 93 patients per group will be required in case of a percentage difference of chemotherapy delivered of 20% between well-nourished and malnourished patients, 163 patients per group in case of a difference of 15% between the groups, and 356 patients per group in case of a 10% difference. Centers from Russia, Romania, Turkey, Spain, Serbia, and Italy will participate in the study upon Local Ethics Committee approval. PAC-MAIN will provide insights into the role of malnutrition and PEI in the outcomes of PDAC. The study protocol was registered at clinicaltrials.gov as NCT04112836.
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http://dx.doi.org/10.3389/fmed.2020.00495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509408PMC
September 2020

Early Weight-Based Aggressive vs. Non-Aggressive Goal-Directed Fluid Resuscitation in the Early Phase of Acute Pancreatitis: An Open-Label Multicenter Randomized Controlled Trial (The WATERFALL Trial), Design, and Rationale.

Front Med (Lausanne) 2020 2;7:440. Epub 2020 Sep 2.

Gastroenterology Department, Alicante University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain.

Treatment options are limited for acute pancreatitis (AP). Early aggressive fluid resuscitation (AFR) has been widely considered beneficial because of theoretical improvement in end-organ perfusion, including the pancreas and gut, with pancreatic necrosis and bacterial translocation as consequences of ischemia. There is scarce direct evidence for its association to improved outcomes. Furthermore, it has been described that AFR may be associated with poor outcomes in severe AP. WATERFALL is an investigator-initiated international multicenter open-label randomized controlled trial comparing AFR vs. moderate fluid resuscitation (MFR) in AP. The main outcome variable will be the incidence of moderate to severe AP (a clinically relevant outcome that has been validated). Aggressive fluid resuscitation will consist in lactated Ringer solution (LR) 20-mL/kg bolus (administered over 2 h) followed by LR 3 mL/kg per hour. Patients randomized to MFR will receive an LR bolus 10 mL/kg in case of hypovolemia or no bolus in patients with normal volemia, followed by LR 1.5 mL/kg per hour. The patients will be assessed at 3 (±1), 12 (±4), 24 (±4), 48 (±4), and 72 (±4) h from recruitment, and fluid resuscitation will be adjusted to the patient's clinical and analytical status according to a protocol. Based on a prospective multicenter study, the incidence of moderate to severe AP is 35%. Sample sizes of 372 patients per group (overall 744) achieve 80% power to detect a difference in the incidence of moderate to severe AP of 10%, at a significance level (α) of 0.05 using a two-sided -test, assuming a 10% dropout rate. These results assume that three sequential tests are made using the O'Brien-Fleming spending function to determine the test boundaries.
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http://dx.doi.org/10.3389/fmed.2020.00440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492535PMC
September 2020

MC1R variants and cutaneous melanoma risk according to histological type, body site, and Breslow thickness: a pooled analysis from the M-SKIP project.

Melanoma Res 2020 10;30(5):500-510

Departments of Dermatology.

Little is known on whether melanocortin 1 receptor (MC1R) associated cutaneous melanoma (CM) risk varies depending on histological subtype and body site, and whether tumour thickness at diagnosis (the most important prognostic factor for CM patients) differs between MC1R variant carriers and wild-type individuals. We studied the association between MC1R variants and CM risk by histological subtype, body site, and Breslow thickness, using the database of the M-SKIP project. We pooled individual data from 15 case-control studies conducted during 2005-2015 in Europe and the USA. Study-specific, multi-adjusted odds ratios were pooled into summary odds ratios (SOR) and 95% confidence intervals (CI) using random-effects models. Six thousand eight hundred ninety-one CM cases and 5555 controls were included. CM risk was increased among MC1R variant carriers vs. wild-type individuals. The increase in risk was comparable across histological subtypes (SOR for any variant vs. wild-type ranged between 1.57 and 1.70, always statistical significant) except acral lentiginous melanoma (ALM), for which no association emerged; and slightly greater on chronically (1.74, 95% CI 1.47-2.07) than intermittently (1.55, 95% CI 1.34-1.78) sun-exposed skin. CM risk was greater for those carrying 'R' vs. 'r' variants; correlated with the number of variants; and was more evident among individuals not showing the red hair colour phenotype. Breslow thickness was not associated with MC1R status. MC1R variants were associated with an increased risk of CM of any histological subtype (except ALM) and occurring on both chronically and intermittently sun-exposed skin.
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http://dx.doi.org/10.1097/CMR.0000000000000668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479262PMC
October 2020

Clinical performance of contrast-enhanced spectral mammography in pre-surgical evaluation of breast malignant lesions in dense breasts: a single center study.

Breast Cancer Res Treat 2020 Dec 28;184(3):723-731. Epub 2020 Aug 28.

School of Medicine, University of Bari, Bari, Italy.

Purpose: To compare the efficacy of contrast-enhanced spectral mammography, with ultrasound, full field digital mammography and magnetic resonance imaging in detection and size estimation of histologically proven breast tumors.

Methods: This open-label, single center, prospective study, included 160 dense breast women with at least one suspicious mammary lesion evaluated by ultrasound, full field digital mammography and magnetic resonance imaging in whom a mammary tumor was histologically proven after surgery performed at the European Institute of Oncology between January 2013 and December 2015. Following the complete diagnostic procedure, the patients were further investigated by contrast-enhanced spectral mammography prior to surgery.

Results: Overall, the detection rate of malignant breast lesions (in situ and invasive) was 93.8% (165/176) for contrast-enhanced spectral mammography, 94.4% (168/178) for ultrasound, 85.5 (147/172) for full field digital mammography and 97.7% (173/177) for magnetic resonance imaging. Radiological measurements were concordant with the post-surgical pathological measurements of the invasive tumor (i.e., within 5 mm) in: 64.6% for contrast-enhanced spectral mammography, 62.0% for ultrasound, 45.2% for full field digital mammography (p < 0.0001) and 69.9% for magnetic resonance imaging (p = 0.28); underestimated in: 17.4% for contrast-enhanced spectral mammography, 19.6% for ultrasound, 24.2% for full field digital mammography (p = 0.03) and 6.7% for magnetic resonance imaging (p = 0.0005); and overestimated in: 16.2% for contrast-enhanced spectral mammography, 16.6% for ultrasound, 16.6% for full field digital mammography and 22.7% for magnetic resonance imaging (p = 0.02).

Conclusions: Our data suggest that contrast-enhanced spectral mammography improves on full field digital mammography and is comparable to ultrasound and magnetic resonance imaging in terms of detection sensitivity and size estimation of malignant lesions in dense breasts.
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http://dx.doi.org/10.1007/s10549-020-05881-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655556PMC
December 2020

Gallbladder disease, cholecystectomy, and pancreatic cancer risk in the International Pancreatic Cancer Case-Control Consortium (PanC4).

Eur J Cancer Prev 2020 09;29(5):408-415

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.

Background: The association among gallbladder disease, cholecystectomy, and pancreatic cancer is unclear. Moreover, time interval between gallbladder disease or cholecystectomy and pancreatic cancer diagnosis is not considered in most previous studies.

Aim: To quantify the association among gallbladder disease, cholecystectomy, and pancreatic cancer, considering time since first diagnosis of gallbladder disease or cholecystectomy.

Methods: We used data from nine case-control studies within the Pancreatic Cancer Case-Control Consortium, including 5760 cases of adenocarcinoma of the exocrine pancreas and 8437 controls. We estimated pooled odds ratios and the corresponding 95% confidence intervals by estimating study-specific odds ratios through multivariable unconditional logistic regression models, and then pooling the obtained estimates using fixed-effects models.

Results: Compared with patients with no history of gallbladder disease, the pooled odds ratio of pancreatic cancer was 1.69 (95% confidence interval, 1.51-1.88) for patients reporting a history of gallbladder disease. The odds ratio was 4.90 (95% confidence interval, 3.45-6.97) for gallbladder disease diagnosed <2 years before pancreatic cancer diagnosis and 1.11 (95% confidence interval, 0.96-1.29) when ≥2 years elapsed. The pooled odds ratio was 1.64 (95% confidence interval, 1.43-1.89) for patients who underwent cholecystectomy, as compared to those without cholecystectomy. The odds ratio was 7.00 (95% confidence interval, 4.13-11.86) for a surgery <2 years before pancreatic cancer diagnosis and 1.28 (95% confidence interval, 1.08-1.53) for a surgery ≥2 years before.

Conclusions: There appears to be no long-term effect of gallbladder disease on pancreatic cancer risk, and at most a modest one for cholecystectomy. The strong short-term association can be explained by diagnostic bias and reverse causation.
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http://dx.doi.org/10.1097/CEJ.0000000000000572DOI Listing
September 2020

Chronic use of statins and acetylsalicylic acid and incidence of post-endoscopic retrograde cholangiopancreatography acute pancreatitis: A multicenter, prospective, cohort study.

Dig Endosc 2021 May 28;33(4):639-647. Epub 2020 Sep 28.

Gastroenterology Department, Alicante University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain.

Objectives: Post-endoscopic retrograde cholangiopancreatography (ERCP) acute pancreatitis (PEP) is a frequent complication of this endoscopic procedure. Chronic statin intake has been linked to lower incidence and severity of acute pancreatitis (AP). Periprocedural rectal administration of non-steroidal anti-inflammatory drugs is protective against PEP, but the role of chronic acetylsalicylic acid (ASA) treatment is unclear. We aimed to investigate whether statins and chronic ASA intake are associated with lower risk of PEP.

Methods: An international, multicenter, prospective cohort study. Consecutive patients undergoing ERCP in seven European centers were included. Patients were followed-up to detect those with PEP. Multivariate analysis by means of binary logistic regression was performed, and adjusted odds ratios (aORs) were calculated.

Results: A total of 1150 patients were included, and 70 (6.1%) patients developed PEP. Among statins users, 8.1% developed PEP vs. 5.4% among non-users (P = 0.09). Multivariate analysis showed no association between statin use and PEP incidence (aOR 1.68 (95% CI 0.94-2.99, P = 0.08)). Statin use had no effect on severity of PEP, being mild in 92.0% of statin users vs. 82.2% in non-statin users (P = 0.31). Chronic ASA use was not associated with PEP either (aOR 1.02 (95% CI 0.49-2.13), P = 0.96). Abuse of alcohol and previous endoscopic biliary sphincterotomy were protective factors against PEP, while >1 pancreatic guidewire passage, normal bilirubin values, and duration of the procedure >20 minutes, were risk factors.

Conclusions: The use of statins or ASA is not associated with a lower risk or a milder course of PEP.
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http://dx.doi.org/10.1111/den.13801DOI Listing
May 2021

Temozolomide alone or in combination with capecitabine in patients with advanced neuroendocrine neoplasms: an Italian multicenter real-world analysis.

Endocrine 2021 Apr 22;72(1):268-278. Epub 2020 Jul 22.

Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, Italy.

Purpose: Temozolomide (TEM) has been reported to be active alone or in combination with capecitabine (CAP) in patients with neuroendocrine neoplasms (NENs). We retrospectively evaluated activity and toxicity of TEM-based chemotherapy in patients with advanced NENs and explored the potential correlation with clinical/biological factors.

Methods: Patients received oral TEM alone or in combination with CAP. Objective response rate (ORR) [complete response + partial response (PR)], median progression-free survival (mPFS), and toxicity were calculated. The O-methylguanine-DNA-methyltransferase (MGMT) gene inactivation status in tumor tissue was evaluated by pyrosequencing.

Results: From September 2008 to April 2020, 170 patients (84% progressive on different therapies) were consecutively treated, 114 (67%) patients received TEM-CAP and 56 (33%) TEM alone. Primary tumor sites were: pancreas 98 (58%), gastrointestinal tract 21 (12%), lung 35 (21%), and unknown 16 (9%). The ORR was 28% for the whole population (33% for TEM-CAP and 18% for TEM as single agent). The median OS (mOS) and mPFS of the whole population were 35.6 months (32.6-48.7) and 14.7 months (10.1-18.3), respectively. There were 48% PR in the MGMT hypermethylated, mainly in pancreatic NENs. Vomiting and leukopenia were the most frequent grade 3/4 toxicity.

Conclusions: This large retrospective analysis suggested that a TEM-based chemotherapy is active in advanced, pretreated NEN patients. It generated solid hypotheses that warrant a future prospective study in a biological homogeneous NEN population and clinical setting.
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http://dx.doi.org/10.1007/s12020-020-02421-2DOI Listing
April 2021

International consensus guidelines on surveillance for pancreatic cancer in chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club.

Pancreatology 2020 Jul 31;20(5):910-918. Epub 2020 May 31.

Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. Electronic address:

Background: Patients with chronic pancreatitis (CP) have an increased risk of pancreatic cancer. We present the international consensus guidelines for surveillance of pancreatic cancer in CP.

Methods: The international group evaluated 10 statements generated from evidence on 5 questions relating to pancreatic cancer in CP. The GRADE approach was used to evaluate the level of evidence available per statement. The working group voted on each statement for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach's alpha reliability coefficient.

Results: In the following domains there was strong consensus: (1) the risk of pancreatic cancer in affected individuals with hereditary pancreatitis due to inherited PRSS1 mutations is high enough to justify surveillance; (2) the risk of pancreatic cancer in patients with CP associated with SPINK1 p. N34S is not high enough to justify surveillance; (3) surveillance should be undertaken in pancreatic specialist centers; (4) surveillance should only be introduced after the age of 40 years and stopped when the patient would no longer be suitable for surgical intervention. All patients with CP should be advised to lead a healthy lifestyle aimed at avoiding risk factors for progression of CP and pancreatic cancer. There was only moderate or weak agreement on the best methods of screening and surveillance in other types of environmental, familial and genetic forms of CP.

Conclusions: Patients with inherited PRSS1 mutations should undergo surveillance for pancreatic cancer, but the best methods for cancer detection need further investigation.
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http://dx.doi.org/10.1016/j.pan.2020.05.011DOI Listing
July 2020

Recommendations for Implementing Lung Cancer Screening with Low-Dose Computed Tomography in Europe.

Cancers (Basel) 2020 Jun 24;12(6). Epub 2020 Jun 24.

Department of Bioimaging and Radiological Sciences, Catholic University, 00168 Rome, Italy.

Lung cancer screening (LCS) with low-dose computed tomography (LDCT) was demonstrated in the National Lung Screening Trial (NLST) to reduce mortality from the disease. European mortality data has recently become available from the Nelson randomised controlled trial, which confirmed lung cancer mortality reductions by 26% in men and 39-61% in women. Recent studies in Europe and the USA also showed positive results in screening workers exposed to asbestos. All European experts attending the "Initiative for European Lung Screening (IELS)"-a large international group of physicians and other experts concerned with lung cancer-agreed that LDCT-LCS should be implemented in Europe. However, the economic impact of LDCT-LCS and guidelines for its effective and safe implementation still need to be formulated. To this purpose, the IELS was asked to prepare recommendations to implement LCS and examine outstanding issues. A subgroup carried out a comprehensive literature review on LDCT-LCS and presented findings at a meeting held in Milan in November 2018. The present recommendations reflect that consensus was reached.
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http://dx.doi.org/10.3390/cancers12061672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352874PMC
June 2020

Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis.

Neuroendocrinology 2021 4;111(5):475-489. Epub 2020 May 4.

Unit of Pathology, Department of Medicine and Surgery and Research Center for the Study of Hereditary and Familial tumors, University of Insubria, Varese, Italy.

Background: Little information is available concerning prognostic factors for bronchopulmonary large cell neuroendocrine carcinomas (BP-LCNECs) and even less is known about combined LCNECs (Co-LCNECs). We investigated whether an integrated morphological, immunohistochemical, and molecular approach could be used for their prognostic evaluation.

Methods: Morphological (including combined features), proliferative (mitotic count/Ki-67 index), immunohistochemical (napsin A, p40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, RB1, and MDM2), and genomic (TP53, RB1, ATM, JAK2, KRAS, and STK11) findings were analyzed in BP-LCNECs from 5 Italian centers, and correlated with overall survival (OS). The Ki-67 index was expressed as the percentage of positive cells in hot spots as indicated in the WHO 2019 Digestive System Tumors and, for Co-LCNECs, the Ki-67 index was evaluated only in the LCNEC component.

Results: A total of 111 LCNECs were distinguished into 70 pure LCNECs, 35 Co-LCNECs (27 with adenocarcinoma [ADC] and 8 with squamous cell carcinoma [SqCC]), and 6 LCNECs with only napsin A immunoreactivity. The Ki-67 index cutoff at 55% evaluated in the neuroendocrine component was the most powerful predictor of OS (log-rank p = 0.0001) in all LCNECs; 34 cases had a Ki-67 index <55% (LCNEC-A) and 77 had a Ki-67 index ≥55% (LCNEC-B). Statistically significant differences in OS (log-rank p = 0.0001) were also observed between pure and Co-LCNECs. A significant difference in OS was found between pure LCNECs-A and Co-LCNECs-A (p < 0.05) but not between pure LCNECs-B and Co-LCNECs-B. Co-LCNEC-ADC and LCNEC napsin A+ cases had longer OS than pure LCNEC and Co-LCNEC-SqCC cases (log-rank p = 0.0001). On multivariable analysis, tumor location, pure versus combined features, and napsin A, but no single gene mutation, were significantly associated with OS after adjustment for Ki-67 index and study center (p < 0.05).

Conclusions: The Ki-67 proliferation index and the morphological characterization of combined features in LCNECs seem to be important tools for predicting clinical outcome in BP-LCNECs.
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http://dx.doi.org/10.1159/000508376DOI Listing
May 2020

Immunoglobulin G subtypes-1 and 2 differentiate immunoglobulin G4-associated sclerosing cholangitis from primary sclerosing cholangitis.

United European Gastroenterol J 2020 06 29;8(5):584-593. Epub 2020 Apr 29.

Department for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.

Background: Autoimmune pancreatitis is a special form of chronic pancreatitis with strong lymphocytic infiltration and two histopathological distinct subtypes, a lymphoplasmacytic sclerosing pancreatitis and idiopathic duct centric pancreatitis. Immunoglobulin G4-associated cholangitis may be present at the time of autoimmune pancreatitis type 1 diagnosis or occur later over the course of the disease. Immunoglobulin G4 is considered reliable but not an ideal marker for diagnosis of autoimmune pancreatitis type 1 with reported sensitivity between 71-81%. It is essential to differentiate sclerosing cholangitis with autoimmune pancreatitis from primary sclerosing cholangitis as the treatment and prognosis of the two diseases are totally different. It was the aim of the study to find a marker for immunoglobulin G4-associated cholangitis that would distinguish it from primary sclerosing cholangitis.

Patients And Methods: We performed a retrospective analysis of patients with autoimmune pancreatitis at our outpatient clinic. Patients from the primary sclerosing cholangitis registry were taken as a control group. Blood samples for the measurement of immunoglobulin subclasses were analysed at the time of diagnosis.

Results: Patients with autoimmune pancreatitis and immunoglobulin G4-associated cholangitis had higher values of immunoglobulin G2 when compared to autoimmune pancreatitis alone or primary sclerosing cholangitis with a high specificity (97%) and high positive predictive value (91%). In patients with normal or low immunoglobulin G2 or immunoglobulin G4, a high level of immunoglobulin G1 indicated primary sclerosing cholangitis.

Conclusion: Immunoglobulin G1 and immunoglobulin G2 can distinguish patients with immunoglobulin G4-associated cholangitis from those with primary sclerosing cholangitis.
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http://dx.doi.org/10.1177/2050640620916027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268946PMC
June 2020

Improvement of survival after surgical resection of pancreatic cancer independent of adjuvant chemotherapy in the past two decades - A meta-regression.

Eur J Surg Oncol 2020 08 19;46(8):1516-1523. Epub 2020 Feb 19.

Department of General, Visceral and Transplantation Surgery, Ludwig-Maximilians-University, Munich, Germany.

Introduction: Surgical resection improves survival in pancreatic ductal adenocarcinoma (PDAC) and adjuvant chemotherapy adds an additional survival-benefit. While surgical technique has improved in recent years, it remains unclear whether these improvements translate into a survival benefit independent of adjuvant chemotherapy. Thus, we aimed to clarify whether survival of patients who were treated with either Gemcitabine (GEM) or who were observed only in randomized controlled trials on adjuvant chemotherapy of PDAC improved over time.

Methods: A systematic search of MEDLINE/PubMed was performed to identify randomized controlled trials on adjuvant chemotherapy of PDAC. The search was limited to studies with arms on GEM monotherapy or postoperative observation and studies were grouped by the median year of enrolment and the use of GEM. Subsequently, a meta-regression on the effect of the median year of enrolment on patient survival was performed.

Results: A total of 13 studies with 2469 patients was included, with median years of enrollment ranging from 1996 to 2015. While disease-free survival decreased in patients with postoperative observation (18.0 vs. 5.0 months, p = 0.001), median survival improved over time in patients with postoperative observation (15.8 vs. 18.4 months, p = 0.01) and in patients treated with adjuvant GEM (22.8 vs. 35.0 months, p < 0.001). One- (p ≤ 0.01) and two-year survival (p = 0.056) improved in both patients treated with adjuvant GEM and those observed only.

Conclusion: Survival after surgical resection of PDAC has improved since 1996, even in patients who did not receive adjuvant chemotherapy. Improved surgical technique and postoperative management are likely to be causative factors.
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http://dx.doi.org/10.1016/j.ejso.2020.02.016DOI Listing
August 2020

Lung cancer surgery in oligometastatic patients: outcome and survival.

Eur J Cardiothorac Surg 2020 06;57(6):1173-1180

Division of Thoracic Surgery, IEO, European Institute of Oncology IRCCS, Milan, Italy.

Objectives: A few studies have already demonstrated survival benefits for local treatment in solitary metastatic non-small-cell lung cancer (NSCLC). The aim of this study is to retrospectively investigate the role of surgery in patients with oligometastatic (OM) NSCLC.

Methods: Between January 1998 and December 2018, 57 patients with OM stage IV NSCLC (1 or 2) underwent a multidisciplinary approach including lung cancer surgery, local treatment of the distant metastasis (DM) and systemic medical treatments.

Results: All patients had DM synchronous to lung cancer. Fifty-one (90%) patients had a single DM whereas 6 (11%) patients had 2 DMs. Forty-eight (84%) patients underwent induction chemotherapy. We performed 47 (82%) lobectomies, 4 (7%) segmentectomies and 6 (11%) pneumonectomies. Pathological lymph node involvement was evident in 28 (49%) patients. Adjuvant chemotherapy was administered in 20 (35%) patients. Forty-six (81%) patients had local treatment of the DM before lung resection, and 11 (19%) patients had after lung resection; 6 (11%) patients had both treatments. The median overall survival (OS) was 30 months, with the 2-, 3- and 5-year OS of 57%, 50% and 30%, respectively. OS was significantly related to lymph node involvement (P = 0.04), size of the primary tumour (P < 0.001), neoadjuvant chemotherapy (P = 0.02) and the time period between metastasis diagnosis and primary tumour removal (P = 0.04).

Conclusions: Multidisciplinary approach is the gold standard in OM patients. Patients with no lymph node involvement are the best candidates, with an acceptable OS. Thus, patients with OM-NSCLC should not be excluded from surgery as a matter of principle.
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http://dx.doi.org/10.1093/ejcts/ezaa005DOI Listing
June 2020