Publications by authors named "Francesco Leone"

94 Publications

A Novel Multidrug-Resistant Cell Line from an Italian Intrahepatic Cholangiocarcinoma Patient.

Cancers (Basel) 2021 Apr 23;13(9). Epub 2021 Apr 23.

Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (Torino), Italy.

Chemotherapy resistance is a relevant clinical issue in tumor treatment, in particular in biliary tract carcinoma (BTC), for which there are no effective therapies, neither in the first nor in the second line. The development of chemoresistant cell lines as experimental models to investigate the mechanisms of resistance and identify alternative druggable pathways is mandatory. In BTC, in which genetics and biological behavior depend on the etiology, ethnicity, and anatomical site of origin, the creation of models that better recapitulate these characteristics is even more crucial. Here we have established and characterized an intrahepatic cholangiocarcinoma (iCCA) cell line derived from an Italian patient, called 82.3. Cells were isolated from a patient-derived xenograft (PDX) and, after establishment, immunophenotypic, biological, genetic, molecular characteristics, and tumorigenicity in vivo in NOD/SCID mice were investigated. 82.3 cells exhibited epithelial morphology and cell markers (EPCAM, CK7, and CK19); they also expressed different cancer stem markers (CD44, CD133, CD49b, CD24, Stro1, PAX6, FOXA2, OCT3/4), α-fetoprotein and under anchorage-independent and serum-free conditions were capable of originating cholangiospheres. The population doubling time was approximately 53 h. In vitro, they demonstrated a poor ability to migrate; in vivo, 82.3 cells retained their tumorigenicity, with a long latency period (16 weeks). Genetic identity using DNA fingerprinting analysis revealed 16 different loci, and the cell line was characterized by a complex hyperdiploid karyotype. Furthermore, 82.3 cells showed cross-resistance to gemcitabine, 5-fluorouracil, carboplatin, and oxaliplatin; in fact, their genetic profile showed that 60% of genes ( = 168), specific for drug resistance and related to the epithelial-mesenchymal transition, were deregulated in 82.3 cells compared to a control iCCA cell line sensitive to chemotherapeutics. RNA sequencing analysis revealed the enrichment for genes associated with epithelial to mesenchymal transition (EMT), vasculature development, and extracellular matrix (ECM) remodeling, underlining an aggressive phenotype. In conclusion, we have created a new iCCA cell line of Caucasian origin: this could be exploited as a preclinical model to study drug resistance mechanisms and to identify alternative therapies to improve the prognosis of this tumor type.
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http://dx.doi.org/10.3390/cancers13092051DOI Listing
April 2021

Cone-Beam Computed Tomography: A User-Friendly, Practical Roadmap to the Planning and Execution of Every Rhinoplasty-A 5-Year Review.

Plast Reconstr Surg 2021 May;147(5):749e-762e

From private practice.

Background: Cone-beam computed tomography has recently rapidly developed worldwide as a versatile and convenient alternative to traditional computed tomography for imaging of the maxillofacial region. However, most surgeons performing rhinoplasty are surprisingly unfamiliar with it, in both the plastic surgery and ear, nose, and throat communities.

Methods: The broad clinical experience of a single center over the past 5 years is reviewed. The many applications of cone-beam computed tomography to primary and secondary rhinoplasty are analyzed regarding septum, turbinates, nasal bones, skin thickness, and other issues. The importance of a paradigm shift from a two-dimensional to a three-dimensional approach in image reconstruction is demonstrated, together with the value of surface contour enhancement.

Results: Cone-beam computed tomography has a multitude of practical applications highly relevant to rhinoplasty. The surface image will strengthen aesthetic analysis, and the detailed preview of bony and functional anatomy will facilitate surgical planning. Cone-beam computed tomography serves as a roadmap to plan and execute rhinoplasties more predictably and efficiently. The availability of spatial views and accurate detail, together with the possibility of easy, accurate measuring, offers a plenitude of potential applications.

Conclusions: Cone-beam computed tomography is a user-friendly, quick technique with abundant advantages in planning any rhinoplasty. It causes the patient no inconvenience and has very few, if any, drawbacks, with these being limited to radiation exposure and limited cost.
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http://dx.doi.org/10.1097/PRS.0000000000007900DOI Listing
May 2021

A Rare Case of Pulmonary Restrictive Syndrome after Liquid Silicone Injection: The Role of the Plastic Surgeon.

Indian J Plast Surg 2021 Jan 22;54(1):90-93. Epub 2021 Feb 22.

Department of Plastic and Reconstructive Surgery, ASST Papa Giovanni XXIII, Bergamo, Italy.

Despite being especially used in its solid form, silicone is still injected as a liquid filler for breast contouring in many countries. Here, we present a rare case of a woman with silicone pneumonitis and extended breast scarring after breast silicone injection. Because of evidence of a restrictive syndrome due to the thoracic extensive scarring tissue and the high demand of oxygen therapy, as jointly agreed with the pulmonologists, we decided to perform a surgical asportation of the scarring tissue and covering with microsurgical flap. We chose the deep inferior epigastric perforator flap mainly because of the large amount of skin that is possible to use, the good skin texture matching, and the possibility of double team working without changing patient's position.
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http://dx.doi.org/10.1055/s-0040-1721862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012792PMC
January 2021

Effects of Metformin and Vitamin D on Clinical Outcome in Cholangiocarcinoma Patients.

Oncology 2021 24;99(5):292-299. Epub 2021 Feb 24.

IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy.

Background And Aims: In the last few years, there has been increasing interest in non-cancer medications and their potential anti-cancer activity. Data are not available in cholangiocarcinoma (CCA) patients. The aim of this study is to fill this gap by investigating the potential impact in terms of clinical outcome of the common non-cancer medications.

Methods: All consecutive patients with CCAs were retrospectively identified from 7 Italian medical institutions. We investigated the role of intake of vitamin D, aspirin, metformin, statins, and diuretics.

Results: A total of 537 patients with CCAs were identified; 197 patients undergoing surgery were evaluated for disease-free survival (DFS), and 509 patients with an advanced stage were evaluated for overall survival (OS). A longer DFS was found in patients with intake of vitamin D versus never users (HR 0.55, 95% CI 0.32-0.92, p = 0.02). In an advanced stage an association with OS was found in patients with intake of metformin versus never users (HR 0.70, 95% CI 0.52-0.93, p = 0.0162), and in patients who have started taking metformin after chemotherapy versus before chemotherapy and never users (HR 0.44, 95% CI 0.26-0.73, p = 0.0016).

Conclusions: Our results highlighted that vitamin D intake improves DFS in patients undergoing surgery. Metformin intake after starting chemotherapy can improve the clinical outcome in advanced disease. These results could open up new therapeutic strategies in cholangiocarcinoma patients. We are planning to undertake a prospective study to validate these data.
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http://dx.doi.org/10.1159/000512796DOI Listing
May 2021

Prognostic Role of a New Index Tested in European and Korean Advanced Biliary Tract Cancer Patients: the PECS Index.

J Gastrointest Cancer 2021 Feb 5. Epub 2021 Feb 5.

Department of Medical Oncology, Università Vita-Salute, San Raffaele Hospital IRCCS, Milan, Italy.

Background And Aim: The aim of the present study is to evaluate a new index (PECS (PsECogSii)index) influenced by PS ECOG and systemic immune-inflammation index (SII) in unresectable locally advanced or metastatic BTC patients treated with first-line chemotherapy.

Methods: This multicenter, international, study was conducted on a training cohort of 130 patients and in three European and Korean validation cohorts The PECS index was calculated as ECOG × SII index (neutrophil count × platelet count/lymphocyte count). Event-time distributions were estimated using the Kaplan-Meier method and survival curves were compared using the log-rank test.

Results: In the training cohort, the median overall survival (mOS) was 13.2 months, 8.7 months, and 3.8 months for patients with PECS-0, PECS-1, and PECS-2, respectively (PECS-0: HR = 1; PECS-1: HR 1.41; PECS-2: HR 3.23) (p < 0.0001). In the first validation cohort, the mOS was 12.8 months, 10.1 months, and 5.3 months for patients with PECS-0, PECS-1, and PECS-2, respectively (PECS-0: HR = 1; PECS-1: HR 1.29; PECS-2: HR 2.40) (p < 0.0001). In the second validation cohort, the mOS was 21.2 months, 10.2 months, and 3.0 months for patients with PECS-0, PECS-1, and PECS-2, respectively (PECS-0: HR = 1; PECS-1: HR 2.25; PECS-2: HR 9.00) (p < 0.0001). In the third validation cohort, the median OS was 15.5 months, 7.5 months, and 3.7 months for patients with PECS-0, PECS-1, and PECS-2, respectively (PECS-0: ref HR = 1; PECS-1: HR 2.14; PECS-2: HR 5.00) (p < 0.0001). Multivariate analysis in all cohorts confirmed the PECS index as an independent prognostic factor for OS.

Conclusions: The easy assessment, low cost, and reproducibility make PECS index a promising tool to assess the prognosis of BTC patients in future clinical practice.
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http://dx.doi.org/10.1007/s12029-021-00596-zDOI Listing
February 2021

Association between cardiac troponin I and mortality in patients with COVID-19.

Biomarkers 2020 Dec 24;25(8):634-640. Epub 2020 Nov 24.

Laboratory Medicine, Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy.

Background: Severe pneumonia is pathological manifestation of Coronavirus Disease 2019 (COVID-19), however complications have been reported in COVID-19 patients with a worst prognosis. Aim of this study was to evaluate the role of high sensitivity cardiac troponin I (hs-TnI) in patients with SARS-CoV-2 infection.

Methods: we retrospectively analysed hs-TnI values measured in 523 patients (median age 64 years, 68% men) admitted to a university hospital in Milan, Italy, and diagnosed COVID-19.

Results: A significant difference in hs-TnI concentrations was found between deceased patients (98 patients) vs discharged (425 patients) [36.05 ng/L IQR 16.5-94.9 vs 6.3 ng/L IQR 2.6-13.9,  < 0.001 respectively]. Hs-TnI measurements were independent predictors of mortality at multivariate analysis adjusted for confounding parameters such as age (HR 1.004 for each 10 point of troponin, 95% CI 1.002-1.006,  < 0.001). The survival rate, after one week, in patients with hs-TnI values under 6 ng/L was 97.94%, between 6 ng/L and the normal value was 90.87%, between the normal value and 40 ng/L was 86.98, and 59.27% over 40 ng/L.

Conclusion: Increase of hs-TnI associated with elevated mortality in patients with COVID-19. Troponin shows to be a useful biomarker of disease progression and worse prognosis in COVID-19 patients.
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http://dx.doi.org/10.1080/1354750X.2020.1831609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711728PMC
December 2020

Pertuzumab and trastuzumab emtansine in patients with HER2-amplified metastatic colorectal cancer: the phase II HERACLES-B trial.

ESMO Open 2020 09;5(5):e000911

Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy; Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano (La Statale), Milano, Italy. Electronic address:

Background: HER2 is a therapeutic target for metastatic colorectal cancer (mCRC), as demonstrated in the pivotal HERACLES-A (HER2 Amplification for Colo-rectaL cancer Enhanced Stratification) trial with trastuzumab and lapatinib. The aim of HERACLES-B trial is to assess the efficacy of the combination of pertuzumab and trastuzumab-emtansine (T-DM1) in this setting.

Methods: HERACLES-B was a single-arm, phase II trial, in patients with histologically confirmed wild-type and HER2+ mCRC refractory to standard treatments. HER2 positivity was assessed by immunohistochemistry and in situ hybridisation according to HERACLES criteria. Patients were treated with pertuzumab (840 mg intravenous load followed by 420 mg intravenous every 3 weeks) and T-DM1 (3.6 mg/kg every 3 weeks) until disease progression or toxicity. Primary and secondary end points were objective response rate (ORR) and progression-free survival (PFS). With a Fleming/Hern design (H0=ORR 10%; α=0.05; power=0.85), 7/30 responses were required to demonstrate an ORR ≥30% (H1).

Results: Thirty-one patients, 48% with ≥4 lines of previous therapies, were treated and evaluable. ORR was 9.7% (95% CI: 0 to 28) and stable disease (SD) 67.7% (95% CI: 50 to 85). OR/SD ≥4 months was associated with higher HER2 immunohistochemistry score (3+ vs 2+) (p = 0.03). Median PFS was 4.1 months (95% CI: 3.6 to 5.9). Drug-related grade (G) 3 adverse events were observed in two patients (thrombocytopaenia); G≤2 AE in 84% of cycles (n = 296), mainly nausea and fatigue.

Conclusions: HERACLES-B trial did not reach its primary end point of ORR; however, based on high disease control, PFS similar to other anti-HER2 regimens, and low toxicity, pertuzumab in combination with T-DM1 can be considered for HER2+mCRC as a potential therapeutic resource.

Trial Registration Number: 2012-002128-33 and NCT03225937.
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http://dx.doi.org/10.1136/esmoopen-2020-000911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523198PMC
September 2020

Long-term Clinical Outcome of Trastuzumab and Lapatinib for HER2-positive Metastatic Colorectal Cancer.

Clin Colorectal Cancer 2020 12 27;19(4):256-262.e2. Epub 2020 Jun 27.

Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, Milan, Italy. Electronic address:

Background: ERBB2 amplification occurs in 5% of RAS wild-type metastatic colorectal cancer (mCRC) and it has been shown to be a target for treatment with 2 HER2-directed combinations of trastuzumab and lapatinib or trastuzumab and pertuzumab. We present long-term clinical results of trastuzumab and lapatinib (HERACLES-A trial) at 6.7 years (82 months) follow-up and focus on central nervous system (CNS) recurrences.

Patients And Methods: Patients had histologically confirmed KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive mCRC. HER2 positivity was assessed by immunohistochemistry and in situ hybridization HERACLES diagnostic criteria. Patients were treated with intravenous trastuzumab 4 mg/kg loading dose, then 2 mg/kg once per week, and oral lapatinib 1000 mg per day until disease progression or toxicity. Patients who presented with symptoms or signs of CNS disease received brain computed tomography scan or magnetic resonance imaging.

Results: A total of 35 patients received trastuzumab and lapatinib and 32 were evaluable for response. One patient (3%) achieved complete response (CR), 8 (25%) partial response, and 13 (41%) stable disease. Therefore, response rate was 28%. Median progression-free survival was 4.7 months (95% confidence interval [CI] 3.7-6.1). Median overall survival was 10.0 months (95% CI 7.9-15.8). One patient achieved sustained CR still maintained at 7 years of follow-up. Progression in the central nervous system (CNS) occurred in 6 (19%) of 32 patients.

Conclusions: Long-term (6.7 years) follow-up analysis of HERACLES-A supports using of trastuzumab and lapatinib as treatment reference for KRAS wild-type, chemorefractory HER2-positive mCRC. In this subset of patients, prolongation of survival is accompanied by CNS recurrences that will require diagnostic and therapeutic attention in future studies. Clinicaltrials. Gov identifier: NCT 03225937.
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http://dx.doi.org/10.1016/j.clcc.2020.06.009DOI Listing
December 2020

Radiomics predicts response of individual HER2-amplified colorectal cancer liver metastases in patients treated with HER2-targeted therapy.

Int J Cancer 2020 12 14;147(11):3215-3223. Epub 2020 Sep 14.

Radiology Unit, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.

The aim of our study was to develop and validate a machine learning algorithm to predict response of individual HER2-amplified colorectal cancer liver metastases (lmCRC) undergoing dual HER2-targeted therapy. Twenty-four radiomics features were extracted after 3D manual segmentation of 141 lmCRC on pretreatment portal CT scans of a cohort including 38 HER2-amplified patients; feature selection was then performed using genetic algorithms. lmCRC were classified as nonresponders (R-), if their largest diameter increased more than 10% at a CT scan performed after 3 months of treatment, responders (R+) otherwise. Sensitivity, specificity, negative (NPV) and positive (PPV) predictive values in correctly classifying individual lesion and overall patient response were assessed on a training dataset and then validated on a second dataset using a Gaussian naïve Bayesian classifier. Per-lesion sensitivity, specificity, NPV and PPV were 89%, 85%, 93%, 78% and 90%, 42%, 73%, 71% respectively in the testing and validation datasets. Per-patient sensitivity and specificity were 92% and 86%. Heterogeneous response was observed in 9 of 38 patients (24%). Five of nine patients were carriers of nonresponder lesions correctly classified as such by our radiomics signature, including four of seven harboring only one nonresponder lesion. The developed method has been proven effective in predicting behavior of individual metastases to targeted treatment in a cohort of HER2 amplified patients. The model accurately detects responder lesions and identifies nonresponder lesions in patients with heterogeneous response, potentially paving the way to multimodal treatment in selected patients. Further validation will be needed to confirm our findings.
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http://dx.doi.org/10.1002/ijc.33271DOI Listing
December 2020

Validation of models to diagnose ovarian cancer in patients managed surgically or conservatively: multicentre cohort study.

BMJ 2020 07 30;370:m2614. Epub 2020 Jul 30.

Department of Development and Regeneration, KU Leuven, Herestraat 49 Box 805, 3000 Leuven, Belgium.

Objective: To evaluate the performance of diagnostic prediction models for ovarian malignancy in all patients with an ovarian mass managed surgically or conservatively.

Design: Multicentre cohort study.

Setting: 36 oncology referral centres (tertiary centres with a specific gynaecological oncology unit) or other types of centre.

Participants: Consecutive adult patients presenting with an adnexal mass between January 2012 and March 2015 and managed by surgery or follow-up.

Main Outcome Measures: Overall and centre specific discrimination, calibration, and clinical utility of six prediction models for ovarian malignancy (risk of malignancy index (RMI), logistic regression model 2 (LR2), simple rules, simple rules risk model (SRRisk), assessment of different neoplasias in the adnexa (ADNEX) with or without CA125). ADNEX allows the risk of malignancy to be subdivided into risks of a borderline, stage I primary, stage II-IV primary, or secondary metastatic malignancy. The outcome was based on histology if patients underwent surgery, or on results of clinical and ultrasound follow-up at 12 (±2) months. Multiple imputation was used when outcome based on follow-up was uncertain.

Results: The primary analysis included 17 centres that met strict quality criteria for surgical and follow-up data (5717 of all 8519 patients). 812 patients (14%) had a mass that was already in follow-up at study recruitment, therefore 4905 patients were included in the statistical analysis. The outcome was benign in 3441 (70%) patients and malignant in 978 (20%). Uncertain outcomes (486, 10%) were most often explained by limited follow-up information. The overall area under the receiver operating characteristic curve was highest for ADNEX with CA125 (0.94, 95% confidence interval 0.92 to 0.96), ADNEX without CA125 (0.94, 0.91 to 0.95) and SRRisk (0.94, 0.91 to 0.95), and lowest for RMI (0.89, 0.85 to 0.92). Calibration varied among centres for all models, however the ADNEX models and SRRisk were the best calibrated. Calibration of the estimated risks for the tumour subtypes was good for ADNEX irrespective of whether or not CA125 was included as a predictor. Overall clinical utility (net benefit) was highest for the ADNEX models and SRRisk, and lowest for RMI. For patients who received at least one follow-up scan (n=1958), overall area under the receiver operating characteristic curve ranged from 0.76 (95% confidence interval 0.66 to 0.84) for RMI to 0.89 (0.81 to 0.94) for ADNEX with CA125.

Conclusions: Our study found the ADNEX models and SRRisk are the best models to distinguish between benign and malignant masses in all patients presenting with an adnexal mass, including those managed conservatively.

Trial Registration: ClinicalTrials.gov NCT01698632.
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http://dx.doi.org/10.1136/bmj.m2614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391073PMC
July 2020

"Radix Pillow" Constructs with Fascial Extension for Radix Augmentation in Primary Rhinoplasty.

Aesthetic Plast Surg 2020 12 6;44(6):2232-2243. Epub 2020 Jul 6.

, Montebello Ionico, Italy.

Temporalis fascia and diced cartilage, in varying combinations, are currently commonly employed for augmentation of the radix in rhinoplasty. Although existing literature is replete with papers and suggested variations, there is some lack of practical detail on how to use such techniques. The authors present a reproducible, multilayered, "pillow" construct of temporalis fascia for selective radix augmentation in primary rhinoplasty, with or without the addition of diced cartilage. Precise measurements for accurate multiple folding, exact tailoring of the construct to recipient size dimensions, and fixation by a "litter" concept with proximal and distal fixation point are key to this technique. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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http://dx.doi.org/10.1007/s00266-020-01850-8DOI Listing
December 2020

The SPF-SPLF Graft: Building the Ideal Dorsum in Revision Rhinoplasty.

Plast Reconstr Surg 2020 06;145(6):1420-1424

From private practice.

Achieving a natural appearing dorsum in secondary rhinoplasty remains an elusive goal. An inherent contradiction exists between the two most usually used techniques: solid rib segment and diced cartilage fascia constructs. The former will often cause edge visibility, in addition to potential warping and distortion; the latter prevents from both but may generate obtuse, ill-defined borders with poor shape control, possible contour asymmetries, and often a tubular appearance. A solution to the equation can be found in an innovative technique that combines three elements: perichondrium, rectus fascia, and a rib lamination. The combination is called the sandwich of perichondrium and fascia (SPF) or the sandwich of perichondrium, rib lamination, and fascia (SPLF). As a single unit over the entire dorsum, the issues of junction irregularity inherent in the use of separate graft segments, and of asymmetries in the dorsal contour because of inadequate distribution of diced cartilage, are avoided. In a greater than 18-month experience on 23 cases at the time of writing, the SPF-SPLF graft has proved to be an ideal solution. Adequate edge definition and elegant related shadowing are provided, precise tailoring is attained, and proper height of the dorsum contour is reestablished, following adequate reconstruction of the underlying dorsal plateau. The gradual flow from SPF to SPLF is logical and progressive according to need, and proper fixation ensures long-term stability of the hybrid construct. All three elements required are harvested from the same donor site with a resulting minimal scar.
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http://dx.doi.org/10.1097/PRS.0000000000006865DOI Listing
June 2020

Quality of life assessment and reporting in colorectal cancer: A systematic review of phase III trials published between 2012 and 2018.

Crit Rev Oncol Hematol 2020 Feb 18;146:102877. Epub 2020 Jan 18.

Department of Oncology, University of Turin, Ordine Mauriziano Hospital, Torino, Italy. Electronic address:

Background: In this study, our aim was to describe quality of life (QoL) prevalence and heterogeneity in QoL reporting in colorectal cancer phase III trials.

Methods: We included all phase III trials evaluating anticancer drugs in colorectal cancer patients published between 2012 and 2018 by 11 major journals.

Results: Out of the 67 publications identified, in 41 (61.2 %) QoL was not listed among endpoints. Out of 26 primary publications of trials including QoL among endpoints, QoL results were not reported in 10 (38.5 %). Overall, no QoL data were available in 51/67 (76.1 %) primary publications. In particular, in the metastatic setting, QoL data were not available in 12/18 (66.7 %) trials with primary endpoint overall survival, and in 20/29 (69.0 %) trials with other primary endpoints.

Conclusions: QoL was absent in a high proportion of recently published phase III trials in colorectal cancer, even in trials of second or further lines, where attention to QoL should be particularly high.
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http://dx.doi.org/10.1016/j.critrevonc.2020.102877DOI Listing
February 2020

Prediction of Benefit from Checkpoint Inhibitors in Mismatch Repair Deficient Metastatic Colorectal Cancer: Role of Tumor Infiltrating Lymphocytes.

Oncologist 2020 06 22;25(6):481-487. Epub 2020 Jan 22.

Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Padua University Hospital, Padua, Italy.

Background: Immunotherapy with immune checkpoint inhibitors (ICIs) is highly effective in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC); however, specific predictive biomarkers are lacking.

Patients And Methods: Data and samples from 85 patients with MSI-H mCRC treated with ICIs were gathered. Tumor infiltrating lymphocytes (TILs) and tumor mutational burden (TMB) were analyzed in an exploratory cohort of "super" responders and "clearly" refractory patients; TILs were then evaluated in the whole cohort of patients. Primary objectives were the correlation between the number of TILs and TMB and their role as biomarkers of ICI efficacy. Main endpoints included response rate (RR), progression-free survival (PFS), and overall survival (OS).

Results: In the exploratory cohort, an increasing number of TILs correlated to higher TMB (Pearson's test, p = .0429). In the whole cohort, median number of TILs was 3.6 in responders compared with 1.8 in nonresponders (Mann-Whitney test, p = .0448). RR was 70.6% in patients with high number of TILs (TILs-H) compared with 42.9% in patients with low number of TILs (odds ratio = 3.20, p = .0291). Survival outcomes differed significantly in favor of TILs-H (PFS: hazard ratio [HR] = 0.42, p = .0278; OS: HR = 0.41, p = .0463).

Conclusion: A significant correlation between higher TMB and increased number of TILs was shown. A significantly higher activity and better PFS and OS with ICI in MSI-H mCRC were reported in cases with high number of TILs, thus supporting further studies of TIL count as predictive biomarker of ICI efficacy.

Implications For Practice: Microsatellite instability is the result of mismatch repair protein deficiency, caused by germline mutations or somatic modifications in mismatch repair genes. In metastatic colorectal cancer (mCRC), immunotherapy (with immune checkpoint inhibitors [ICIs]) demonstrated remarkable clinical benefit in microsatellite instability-high (MSI-H) patients. ICI primary resistance has been observed in approximately 25% of patients with MSI-H mCRC, underlining the need for predictive biomarkers. In this study, tumor mutational burden (TMB) and tumor infiltrating lymphocyte (TIL) analyses were performed in an exploratory cohort of patients with MSI-H mCRC treated with ICIs, demonstrating a significant correlation between higher TMB and increased number of TILs. Results also demonstrated a significant correlation between high number of TILs and clinical responses and survival benefit in a large data set of patients with MSI-H mCRC treated with ICI. TMB and TILs could represent predictive biomarkers of ICI efficacy in MSI-H mCRC and should be incorporated in future trials testing checkpoint inhibitors in colorectal cancer.
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http://dx.doi.org/10.1634/theoncologist.2019-0611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288636PMC
June 2020

Piezo-Assisted Turbinoplasty: A Novel Rapid and Safe Technique.

Facial Plast Surg 2020 Jun 31;36(3):235-241. Epub 2019 Dec 31.

Private Practice-Plastic Surgery, Bergamo, Italy.

Consensus is still lacking on the ideal treatment of turbinate hypertrophy concurrent with rhinoseptoplasty. A novel technique of turbinoplasty consisting of incision-bone fracturing by the use of piezoelectric technique-intramucosal microcauterization-lateralization is described in detail. A series of 157 consecutive patients is reviewed with a maximum follow-up of one year. The technique is fast and easy and allows predictability in avoiding postoperative bleeding and preventing remedialization of the lateralized turbinates. Due to the technology required, its use is suggested especially when piezo is employed during other steps of rhinoseptoplasty.
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http://dx.doi.org/10.1055/s-0039-3401803DOI Listing
June 2020

The prognostic nutritional index predicts survival and response to first-line chemotherapy in advanced biliary cancer.

Liver Int 2020 03 11;40(3):704-711. Epub 2019 Dec 11.

Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy.

Background: An accurate risk-stratification is key to optimize the benefit-to-risk ratio of palliative treatment in advanced biliary cancer. We aimed at assessing the impact of the prognostic nutritional index (PNI) on survival and treatment response in advanced biliary cancer (ABC) receiving first-line chemotherapy.

Methods: Medical records of ABC treated with standard chemotherapy at the Modena Cancer Centre were retrospectively reviewed for variables deemed of potential interest, including the PNI. Univariate and multivariate analyses were performed to investigate the association between the covariates and overall survival (OS).

Results: 114 ABC fulfilled the inclusion criteria and made up the training cohort. A PNI cut-off value of 36.7 was established using the receiver operating characteristic (ROC) analysis. At both the univariate and the multivariate analysis, low PNI value (<36.7) was associated with shorter OS (P = .0011), together with increased NLR (P = .0046) and ECOG >1 (P < .0001). The median OS was 5.4 vs 12.1 months in the low- vs high PNI-group. Moreover, a PNI value >36.7 resulted in a higher disease control in patients treated with gemcitabine/platinum combination (61.4% vs 34.3%). These results were validated in an independent cohort of 253 ABC.

Conclusions: We demonstrated and externally validated a prognostic role for the PNI in ABC treated with first-line chemotherapy. Although the PNI turned out to be predictive in the subset of patients receiving platinum/gemcitabine combination, future prospective confirmation is needed.
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http://dx.doi.org/10.1111/liv.14314DOI Listing
March 2020

Is There a Standard Adjuvant Therapy for Resected Pancreatic Cancer?

Cancers (Basel) 2019 Oct 12;11(10). Epub 2019 Oct 12.

Department of Oncology, University of Turin Medical School, Strada Provinciale 142, km 3.95, 10060 Candiolo (TO), Italy.

Surgical resection remains the only treatment that offers a potential chance of long-term survival. Unfortunately, about 80% of patients treated with curative intent will develop recurrence. Since 2001, adjuvant therapy with gemcitabine or 5-fluorouracyle was recommended. This approach allows a median overall survival (OS) of around 23 months, and 5-year survival of 22%. In recent years, two phase-3 trials investigating new chemotherapy regimens resulted in considerably improved survival times. The doublet gemcitabine-capecitabine has shown improvement in OS from 25.5 to 28 months ( = 0.032) compared to gemcitabine, in the ESPAC-4 trial. Later, preliminary results of PRODIGE 24 trial presented at the 2018 ASCO meeting showed a superiority of a combination chemotherapy regimen with fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) when compared to gemcitabine alone, both in terms of median disease-free survival (21.6 vs. 12.8 months, < 0.0001) and OS (54.4 vs. 35 months, = 0.003). Contrary to chemotherapy, the role of adjuvant radiotherapy is still controversial, even in the case of R1 surgery. A randomized trial exploring the role of chemoradiotherapy in this setting is now ongoing in the US (RTOG-0848). Overall, the management of localized pancreatic adenocarcinoma is evolving. In this review, we summarize the current status and the most up-to-date developments in adjuvant treatment.
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http://dx.doi.org/10.3390/cancers11101547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826876PMC
October 2019

Validated Nomogram Predicting 6-Month Survival in Pancreatic Cancer Patients Receiving First-Line 5-Fluorouracil, Oxaliplatin, and Irinotecan.

Clin Colorectal Cancer 2019 12 4;18(4):e394-e401. Epub 2019 Sep 4.

S.C. Oncologia, Department of Oncology, ASL BI, Biella, Italy.

Background: FOLFIRINOX (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) is an option for fit patients with metastatic (MPC) and locally advanced unresectable (LAPC) pancreatic cancer. However, no criteria reliably identify patients with better outcomes.

Patients And Methods: We investigated putative prognostic factors among 137 MPC/LAPC patients treated with triplet chemotherapy. Association with 6-month survival status (primary endpoint) was assessed by multivariate logistic regression models. A nomogram predicting the risk of death at 6 months was built by assigning a numeric score to each identified variable, weighted on its level of association with survival. External validation was performed in an independent data set of 206 patients. The study was registered at ClinicalTrials.gov (NCT03590275).

Results: Four variables (performance status, liver metastases, baseline carbohydrate antigen 19-9 level, and neutrophil-to-lymphocyte ratio) were found to be associated with 6-month survival by multivariate analysis or had sufficient clinical plausibility to be included in the nomogram. Accuracy was confirmed in the validation cohort (C index = 0.762; 95% confidence interval, 0.713-0.825). After grouping all cases, 4 subsets with different outcomes were identified by 0, 1, 2, or > 2 poor prognostic features (P < .0001).

Conclusion: The nomogram we constructed accurately predicts the risk of death in the first 6 months after initiation of FOLFIRINOX in MPC/LAPC patients. This tool could be useful to guide communication about prognosis, and to inform the design and interpretation of clinical trials.
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http://dx.doi.org/10.1016/j.clcc.2019.08.004DOI Listing
December 2019

Pharmacotherapeutic options for biliary tract cancer: current standard of care and new perspectives.

Expert Opin Pharmacother 2019 Dec 24;20(17):2121-2137. Epub 2019 Sep 24.

Department of Oncology, University of Turin, Candiolo, Italy.

: Biliary tract cancer (BTC), which comprises gallbladder cancer, ampullary cancer, and cholangiocarcinoma, is a rare and heterogeneous entity, with limited approved therapeutic options. However, interest in this disease has grown exponentially in recent years, as a mounting body of evidence has shed light on the complex molecular and microenvironmental background of BTC, and clinical investigations have explored a variety of new agents and combinations, with promising results.: This review describes the standard of care in advanced BTC and summarizes the most recent evidence available on the pharmacological treatment of resected and advanced disease, focusing on chemotherapy, targeted therapy, and immunotherapy.: The therapeutic armamentarium of BTC has made radical progress after almost a decade of very few positive results. Phase-III evidence now supports the use of adjuvant capecitabine after resection of localized disease, while investigations into improved regimens in the advanced setting are underway, exploring alternative options to the standard gemcitabine-cisplatin doublet. The first positive phase-III trial supports the use of the mFOLFOX6 regimen as a second-line chemotherapy. Targeted therapy against specific genomic alterations can combine with chemotherapy in specific subsets of patients. Despite recent advancements, conducting clinical trials for BTC is still a real challenge.
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http://dx.doi.org/10.1080/14656566.2019.1667335DOI Listing
December 2019

Grain free diets for utility dogs during training work: Evaluation of the nutrient digestibility and faecal characteristics.

Anim Nutr 2019 Sep 20;5(3):297-306. Epub 2019 May 20.

Department of Veterinary Sciences, University of Messina, Polo Universitario Annunziata, Messina, 98168, Italy.

Two different diets characterized by the absence of cereals or by the presence of conventional cereals were evaluated on the nutrient digestibility and faecal characteristics and faecal fermentative end-product concentrations of 8 neutered adult Labrador retrievers housed at the Regional Centre Helen Keller (Messina, Italy) during the training work for the service guide for the blind. Dogs (age = 17 ± 1 months, initial body weight [BW] = 26.3 ± 1 kg, and body condition score [BCS] = 4.5 ± 0.11) were divided into 2 homogeneous groups for sex (half males and half females). Dogs in the grain free (GF) group were fed a commercial diet characterized by the absence of grain cereals, and dogs in the control (CTR) group were fed a super-premium pet food characterized by conventional grains as the carbohydrate source. The trial lasted 84 d, preceded by a 7-d of adaption period. Physical examination, digestibility, and faecal characteristics were studied. The statistical model included the effects of diet (GF vs. CTR), time (from d 0 to 84, end of the trial) and the interaction (diet × time). The high-protein, low-carbohydrate dry diet (GF) offered higher apparent nutrient digestibility of protein (+10%;  = 0.002) and fat (+7%;  < 0.001) and more stable large intestinal fermentation of carbohydrate compared to the commercial high-carbohydrate dry diet, enabling dogs to use nutrients from the diet more efficiently and thus requiring less food (-13%) to satisfy their nutrient requirements, producing less excrement (-33%;  = 0.033), and reaching a higher final BW (+8%;  < 0.0001) and a higher final BCS (+15%;  = 0.003). Therefore, the GF diet appears the nutritional plan most suitable for these animals taking due account not only of the training work done by animals with their increased nutrient and energy needs, but also of the gastrointestinal disorders consequent to stress coming from work and life in kennels, which cause in the Labrador retrievers an unusual weight loss.
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http://dx.doi.org/10.1016/j.aninu.2019.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737487PMC
September 2019

A validated prognostic classifier for BRAF-mutated metastatic colorectal cancer: the 'BRAF BeCool' study.

Eur J Cancer 2019 09 19;118:121-130. Epub 2019 Jul 19.

Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-oncology, Università Degli Studi di Milano, Milan, Italy.

Background: Despite the well-known negative prognostic value of the BRAF mutation in patients with metastatic colorectal cancer (mCRC), its outcome is quite heterogeneous, and the basis for this prognostic heterogeneity should be better defined.

Methods: Two large retrospective series of BRAF-mutated mCRC from 22 institutions served as an exploratory and validation set to develop a prognostic score. The model was internally and externally validated.

Results: A total of 395 BRAF-mutated mCRCs were included in the exploratory set. Performance status, CA19.9, lactate dehydrogenase, neutrophil/lymphocyte ratio, grading and liver, lung and nodal involvement emerged as independent prognostic factors for overall survival (OS). Two different scoring systems were built: a 'complete' score (0-16) including all significant covariates and a 'simplified' score (0-9), based only on clinicopathological covariates, and excluding laboratory values. Adopting the complete score, proportions of patients with a low (0-4), intermediate (5-8) and high (9-16) score were 44.7%, 42.6% and 12.6%, respectively. The median OS was 29.6, 15.5 (hazard ratio [HR] for intermediate vs low risk: 2.16, 95% confidence interval [CI]: 1.44-3.22, p < .001) and 6.6 months (HR for high vs low risk: 4.72, 95% CI: 2.72-8.20, p < .001). Similar results were observed also after adjusting for the type of first-line treatment and adopting the simplified score. The simplified prognostic score derived from the exploratory set was then applied to the validation set for external confirmation.

Conclusions: These scoring systems are based on easy-to-collect data and defined specific subgroups with relevant differences in their life expectancy. These tools could be useful in clinical practice, would allow better stratification of patients in clinical trials and may be adopted for proper adjustments in exploratory translational analyses.
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http://dx.doi.org/10.1016/j.ejca.2019.06.008DOI Listing
September 2019

A Modified Dorsal Split Preservation Technique for Nasal Humps with Minor Bony Component: A Preliminary Report.

Aesthetic Plast Surg 2019 10 25;43(5):1257-1268. Epub 2019 Jun 25.

, Bergamo, Italy.

Background: In scenarios of a dorsal hump with minor bony cap, ideal esthetic dorsal lines can be preserved and refined by component separation of the upper lateral cartilages from the septal T, resection of a septal strip and ethmoid bone wedge, adjustment of width and symmetry and final re-suture of the cartilaginous dorsum after pushdown, improving width and symmetry. The associated bony cap is managed by osteoplasty only with or without narrowing osteotomies, and septal deviations can be concomitantly corrected.

Objectives: A novel technique of modified dorsal cartilaginous pushdown after component separation is described in detail. This method illustrates the importance of preserving the integrity of the septal T anatomy and the elastic keystone junction.

Methods: A preliminary series of 41 consecutive patients with follow-up up to 1 year, with a mean of 6 months, is reviewed.

Results: All patients presented favorable outcomes with a natural looking dorsum. A learning curve led to progressive improvements by suture fixation of the septal T, finesse adjustment of dorsal width and symmetry, fine-tuning of deviation and gradual extension of the technique to include cases that required osteotomies without transverse element and those with any degree of septal manipulation.

Conclusion: Disrupting the keystone area is fraught with potential complications which often lead to secondary revision. A modified dorsal preservation technique with pushdown limited to the septal T component of the cartilaginous dorsum combines the popular component separation concept with the preservation of the delicate anatomy of the mid-vault.

Level Of Evidence V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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http://dx.doi.org/10.1007/s00266-019-01425-2DOI Listing
October 2019

Establishment and Characterization of a New Intrahepatic Cholangiocarcinoma Cell Line Resistant to Gemcitabine.

Cancers (Basel) 2019 Apr 11;11(4). Epub 2019 Apr 11.

Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Torino, Italy.

Intrahepatic cholangiocarcinoma (ICC) is one of the most lethal liver cancers. Late diagnosis and chemotherapy resistance contribute to the scarce outfit and poor survival. Resistance mechanisms are still poorly understood. Here, we established a Gemcitabine (GEM) resistant model, the MT-CHC01R1.5 cell line, obtained by a GEM gradual exposure (up to 1.5 µM) of the sensitive counterpart, MT-CHC01. GEM resistance was irreversible, even at high doses. The in vitro and in vivo growth was slower than MT-CHC01, and no differences were highlighted in terms of migration and invasion. Drug prediction analysis suggested that Paclitaxel and Doxycycline might overcome GEM resistance. Indeed, in vitro MT-CHC01R1.5 growth was reduced by Paclitaxel and Doxycycline. Importantly, Doxycycline pretreatment at very low doses restored GEM sensitivity. To assess molecular mechanisms underlying the acquisition of GEM resistance, a detailed analysis of the transcriptome in MT-CHC01R1.5 cells versus the corresponding parental counterpart was performed. Transcriptomic analysis showed that most up-regulated genes were involved in cell cycle regulation and in the DNA related process, while most down-regulated genes were involved in the response to stimuli, xenobiotic metabolism, and angiogenesis. Furthermore, additional panels of drug resistance and epithelial to mesenchymal transition genes ( = 168) were tested by qRT-PCR and the expression of 20 genes was affected. Next, based on a comparison between qRT-PCR and microarray data, a list of up-regulated genes in MT-CHC01R1.5 was selected and further confirmed in a primary cell culture obtained from an ICC patient resistant to GEM. In conclusion, we characterized a new GEM resistance ICC model that could be exploited either to study alternative mechanisms of resistance or to explore new therapies.
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http://dx.doi.org/10.3390/cancers11040519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520787PMC
April 2019

HER2 Positivity Predicts Unresponsiveness to EGFR-Targeted Treatment in Metastatic Colorectal Cancer.

Oncologist 2019 10 5;24(10):1395-1402. Epub 2019 Apr 5.

Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy

Background: HER2 amplification is detected in 3% of patients with colorectal cancer (CRC), making tumors in the metastatic setting vulnerable to double pharmacological HER2 blockade. Preclinical findings show that it also might impair response to anti-epidermal growth factor receptor (EGFR) treatment.

Subjects And Methods: Patients with exon 2 wild-type metastatic CRC underwent molecular screening of HER2 positivity by HERACLES criteria (immunohistochemistry 3+ or 2+ in ≥50% of cells, confirmed by fluorescence in situ hybridization). A sample of consecutive HER2-negative patients was selected as control. A regression modeling strategy was applied to identify predictors explaining the bulk of HER2 positivity and the association with response to previous anti-EGFR treatment.

Results: From August 2012 to April 2018, a total of 100 HER2-positive metastatic CRC tumors were detected out of 1,485 exon 2 wild-type screened patients (6.7%). HER2-positive patients show more frequently lung metastases (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.15-3.61; = .014) and higher tumor burden (OR, 1.48; 95% CI, 1.10-2.01; = .011), and tumors were more likely to be left sided (OR, 0.50; 95% CI, 0.22-1.11; = .088). HER2-positive patients who received treatment with anti-EGFR agents ( = 79) showed poorer outcome (objective response rate, 31.2% vs. 46.9%, = .031; progression-free survival, 5.7 months vs. 7 months, = .087).

Conclusion: Testing for HER2 should be offered to all patients with metastatic CRC because the occurrence of this biomarker is unlikely to be predicted based on main clinicopathological features. Patients with HER2-amplified metastatic CRC are less likely to respond to anti-EGFR therapy.

Implications For Practice: Patients with -amplified/overexpressed metastatic colorectal cancer (mCRC) harbor a driver actionable molecular alteration that has been shown in preclinical models to hamper efficacy of the anti-epidermal growth factor receptor (EGFR) targeted therapies. The present study confirmed that this molecular feature was associated with worse objective tumor response and shorter progression-free survival in response to previous anti-EGFR therapies. Moreover, it was found that the occurrence of this biomarker is unlikely to be predicted based on main clinicopathological features. Therefore, HER2 status assessment should be included in the molecular diagnostic workup of all mCRC for speedy referral to clinical trials encompassing HER2-targeted double blockade independently of previous anti-EGFR treatment.
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http://dx.doi.org/10.1634/theoncologist.2018-0785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795149PMC
October 2019

Assessment of a High Sensitivity Method for Identification of R132x Mutations in Tumors and Plasma of Intrahepatic Cholangiocarcinoma Patients.

Cancers (Basel) 2019 Mar 30;11(4). Epub 2019 Mar 30.

Department of Oncology, University of Turin, 10100 Torino, Italy.

Hotspot codon 132 mutations (R132xm) are frequent in intrahepatic cholangiocarcinoma (ICC), are druggable by anti-m agents, and could represent a marker of disease progression. Developing an assay to identify R132xm would provide a useful tool to select patients benefitting from targeted treatments. We tested a quantitative real-time allele-specific polymerase chain reaction (qPCR)-based method to detect the main R132xm in an Italian ICC series ( = 61) of formalin-fixed paraffin-embedded (FFPE) samples, and on circulating-free DNA samples. The outcomes were compared with nested PCR/Sanger sequencing. Reconstitution experiments of plasmids harboring the different R132xm mixed with wild-type (WT) DNA demonstrated that qPCR is able to detect at least 2% of all mutated allele. High efficiency was also observed on patient-derived mutated DNA mixed with WT DNA (up to 10% and 0.3 ng of mutated template); qPCR detected 16.4% of mutated samples (one R132G, three R132C and six R132L) while nested PCR/Sanger sequencing only 8.2% (four R132L and one R132G). In a single patient with an R132C-mutated tumor, qPCR was also performed on plasma samples collected at four time-points, observing an increase correlating with disease progression. In conclusion, we developed a qPCR assay which could represent a fast, inexpensive and sensitive tool both for detection of R132xm in ICC samples and monitoring disease progression from liquid biopsy.
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http://dx.doi.org/10.3390/cancers11040454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521091PMC
March 2019

Improvement of Metastatic Colorectal Cancer Patient Survival: Single Institution Experience.

Cancers (Basel) 2019 Mar 15;11(3). Epub 2019 Mar 15.

Department of Oncology, University of Turin Medical School, Corso Dogliotti, 38, Turin 10126, Italy.

The survival rates of patients with metastatic colorectal cancer (mCRC) have improved in recent years. We analysed the survival of mCRC patients followed at a single institution over the last 17 years. We retrospectively collected data from 899 mCRC patients treated from 2001 to 2016. Patients were divided into two groups based on the year of diagnosis: Cohort A (2001⁻2006) and Cohort B (2007⁻2014). A total of 788 patients were analysed. The median survival of the whole population was 32.0 months with a significant difference between Cohort A and B (29.2 vs. 33.5 months; = 0.041). Surgical procedures significantly increased in Cohort B, however, no significant changes in survival were observed in patients undergoing surgery (58.9 months Cohort A vs. 58.2 months Cohort B, = 0.822). Similarly, we did not demonstrate survival improvement in patients treated with systemic therapy alone (18.9 months Cohort A vs. 20.7 months Cohort B; = 0.948). At the multivariate analysis, right-sided primary and synchronous metastatic tumour were found to be independent unfavorable prognostic factors. Improvements of mCRC patient survival might relate to integrated approach, with more patients undergoing extra-hepatic surgery. The medical approach seems to have had a more favourable impact on subgroups characterized by a worse prognosis.
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http://dx.doi.org/10.3390/cancers11030369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468423PMC
March 2019

Intra- and Inter-Rater Agreement Describing Myometrial Lesions Using Morphologic Uterus Sonographic Assessment: A Pilot Study.

J Ultrasound Med 2019 Oct 23;38(10):2673-2683. Epub 2019 Feb 23.

Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark.

Objectives: To evaluate the intra- and inter-rater agreement for myometrial lesions using Morphologic Uterus Sonographic Assessment terminology.

Methods: Thirteen raters with high (n = 6) or medium experience (n = 7) assessed 30 3-dimensional ultrasound clips with (n = 20) and without (n = 10) benign myometrial lesions. Myometrial lesions were reported as poorly or well defined and then systematically evaluated for the presence of individual features. The clips were blindly assessed twice (at a 2-month interval). Intra- and inter-rater agreements were calculated with κ statistics.

Results: The reporting of poorly defined lesions reached moderate intra-rater agreement (κ = 0.49 [high experience] and 0.47 [medium experience]) and poor inter-rater agreement (κ = 0.39 [high experience] and 0.25 [medium experience]). The reporting of well-defined lesions reached good to very good intra-rater agreement (κ = 0.73 [high experience] and 0.82 [medium experience]) and good inter-rater agreement (κ = 0.75 [high experience] and 0.63 [medium experience]). Most individual features associated with ill-defined lesions reached moderate intra- and inter-rater agreement among highly experienced raters (κ = 0.41-0.60). The least reproducible features were myometrial cysts, hyperechoic islands, subendometrial lines and buds, and translesional flow (κ = 0.11-0.34). Most individual features associated with well-defined lesions reached moderate to good intra- and inter-rater agreement among all observers (κ = 0.41-0.80). The least reproducible features were a serosal contour, asymmetry, a hyperechoic rim, and fan-shaped shadows (κ = 0.00-0.35).

Conclusions: The reporting of well-defined lesions showed excellent agreement, whereas the agreement for poorly defined lesions was low, even among highly experienced raters. The agreement on identifying individual features varied, especially for features associated with ill-defined lesions. Guidelines on minimum requirements for features associated with ill-defined lesions to be interpreted as poorly defined lesions may improve agreement.
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http://dx.doi.org/10.1002/jum.14971DOI Listing
October 2019

Risk of complications in patients with conservatively managed ovarian tumours (IOTA5): a 2-year interim analysis of a multicentre, prospective, cohort study.

Lancet Oncol 2019 03 5;20(3):448-458. Epub 2019 Feb 5.

Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium. Electronic address:

Background: Ovarian tumours are usually surgically removed because of the presumed risk of complications. Few large prospective studies on long-term follow-up of adnexal masses exist. We aimed to estimate the cumulative incidence of cyst complications and malignancy during the first 2 years of follow-up after adnexal masses have been classified as benign by use of ultrasonography.

Methods: In the international, prospective, cohort International Ovarian Tumor Analysis Phase 5 (IOTA5) study, patients aged 18 years or older with at least one adnexal mass who had been selected for surgery or conservative management after ultrasound assessment were recruited consecutively from 36 cancer and non-cancer centres in 14 countries. Follow-up of patients managed conservatively is ongoing at present. In this 2-year interim analysis, we analysed patients who were selected for conservative management of an adnexal mass judged to be benign on ultrasound on the basis of subjective assessment of ultrasound images. Conservative management included ultrasound and clinical follow-up at intervals of 3 months and 6 months, and then every 12 months thereafter. The main outcomes of this 2-year interim analysis were cumulative incidence of spontaneous resolution of the mass, torsion or cyst rupture, or borderline or invasive malignancy confirmed surgically in patients with a newly diagnosed adnexal mass. IOTA5 is registered with ClinicalTrials.gov, number NCT01698632, and the central Ethics Committee and the Belgian Federal Agency for Medicines and Health Products, number S51375/B32220095331, and is ongoing.

Findings: Between Jan 1, 2012, and March 1, 2015, 8519 patients were recruited to IOTA5. 3144 (37%) patients selected for conservative management were eligible for inclusion in our analysis, of whom 221 (7%) had no follow-up data and 336 (11%) were operated on before a planned follow-up scan was done. Of 2587 (82%) patients with follow-up data, 668 (26%) had a mass that was already in follow-up at recruitment, and 1919 (74%) presented with a new mass at recruitment (ie, not already in follow-up in the centre before recruitment). Median follow-up of patients with new masses was 27 months (IQR 14-38). The cumulative incidence of spontaneous resolution within 2 years of follow-up among those with a new mass at recruitment (n=1919) was 20·2% (95% CI 18·4-22·1), and of finding invasive malignancy at surgery was 0·4% (95% CI 0·1-0·6), 0·3% (<0·1-0·5) for a borderline tumour, 0·4% (0·1-0·7) for torsion, and 0·2% (<0·1-0·4) for cyst rupture.

Interpretation: Our results suggest that the risk of malignancy and acute complications is low if adnexal masses with benign ultrasound morphology are managed conservatively, which could be of value when counselling patients, and supports conservative management of adnexal masses classified as benign by use of ultrasound.

Funding: Research Foundation Flanders, KU Leuven, Swedish Research Council.
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http://dx.doi.org/10.1016/S1470-2045(18)30837-4DOI Listing
March 2019

Immediate Implant-based Breast Reconstruction with Acellular Dermal Matrix Compared with Tissue-expander Breast Reconstruction: Rate of Infection.

Plast Reconstr Surg Glob Open 2018 Dec 14;6(12):e1949. Epub 2018 Dec 14.

Plastic and Reconstructive Surgery Unit, ASST Papa Giovanni XXIII, Bergamo, Italy.

Background: The risk of infection continues to be a subject of discussion within the field of implant-based breast reconstruction. Studies have shown the feasibility of immediate single-stage procedures with acellular dermal matrix (ADM), yet 2-stage tissue expander techniques continue to be the procedure most often performed. The purpose of this study was to evaluate postoperative infections and to identify associated predictors.

Methods: A retrospective study at Papa Giovanni XXIII Hospital was conducted between 2013 and 2017. Patients' demographic data were compared between single-stage and 2-stage procedures. Rate of infection and predictors were examined. Minor infections could be treated by oral antibiotics only, major infections required inpatient treatment. Healing was considered a successful treatment with antibiotics only, whereas any supplementary surgical intervention resulting in the preservation of an implant device was considered salvage. Breast reconstruction was defined a failure in case of implant loss or need for autologous reconstruction.

Results: Three hundred ninety-three patients underwent 336 monolateral and 57 bilateral implant-based breast reconstruction. Ninety-two patients had a submuscular direct-to-implant reconstruction with ADM with an infection rate of 11.4% compared with an infection rate of 7.8% among the 268 patients with a 2-stage tissue expander procedure. Beta-binomial regression showed obesity and preoperative radiotherapy as significant predictors for infection (OR, 4.65, = 0.038, and OR, 7.13, = 0.015, respectively). Average time of onset of infection among the submuscular direct-to-implant with ADM group was 67.1 days compared with 80.1 days among tissue-expander group with postoperative chemotherapy and preoperative radiotherapy having a significant effect on time of infection onset ( = 0.014, = 0.034, respectively).

Conclusions: Direct-to-implant breast reconstruction with ADM is a procedure with acceptable risks of infection in comparison to tissue expander procedures. A profound patient selection pre- and intraoperatively is the basis of successful breast reconstruction.
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http://dx.doi.org/10.1097/GOX.0000000000001949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326629PMC
December 2018

Second-line treatment efficacy and toxicity in older vs. non-older patients with advanced gastric cancer: A multicentre real-world study.

J Geriatr Oncol 2019 07 11;10(4):591-597. Epub 2018 Dec 11.

Department of Oncology, University and General Hospital, Udine, Italy; Department of Oncology, San Bortolo General Hospital, ULSS8 Berica - East District, Vicenza, Italy. Electronic address:

Objectives: Although gastric cancer (GC) incidence rises with age, older patients are poorly represented in clinical trials, whose results are therefore difficult to translate into standard management of older patients. Purpose of this study was to compare clinico-pathological features and survival outcomes between older and non-older patients with advanced GC treated with at least two chemotherapy lines.

Materials And Methods: Clinico-pathological characteristics, basal values, and treatment data of older (≥70 years at second-line start) and non-older patients were compared using chi-square test or 2-tailed Fisher exact test. The Kaplan-Meier estimation was used to calculate progression-free survival (PFS) and overall survival (OS), which were examined by log-rank test.

Results: Older patients represented 31.8% of the population (N = 868). Intestinal type was more frequent in older patients (P = .02). Poorly differentiated tumours were more often observed in non-older patients (P = .009). At stage IV diagnosis, the rate of liver metastases was higher in older patients (P = .02), while peritoneal spread was more represented in non-older patients (P = .002). Although older patients were more often treated with monotherapy (P = .001), they had similar PFS (HR 0.86, 95%CI 0.71-1.03, P = .102) and OS (HR 0.82, 95%CI 0.65-1.02, P = .08) compared to the non-older counterpart. No statistical differences were observed in treatment-related adverse events, hospital admissions, or further treatment lines between age groups.

Conclusion: In our large cohort study, despite some differences in tumour characteristics and treatment intensity, no survival difference was found between older and non-older patients with advanced GC treated with at least two chemotherapy lines. Incidence of adverse events was similar between age groups.
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http://dx.doi.org/10.1016/j.jgo.2018.11.009DOI Listing
July 2019