Istituto Scientifico Research Articles

Proportion of Thick versus Thin Melanomas as a Benchmarking Tool.

Background: The ratio of benign moles excised for each malignant melanoma diagnosed (number-needed-to-excise (NNE)) is a metric used to express the efficiency of diagnostic accuracy of melanoma. The literature suggests a progressive effort to reduce the NNE, thus raising concerns about missing early melanoma because the NNE does not capture the most significant outcome for melanoma prognosis, which is linked to the Breslow thickness. A lower NNE could reduce health costs related to melanoma diagnosis only if doing so does not increase the proportion of thicker melanomas. Objectives: The diagnostic performance by two tertiary referral centres using the NNE and proportion of thick (Breslow thickness > 1 mm) versus thin (Breslow thickness ≤ 1 mm) excised melanoma (thick/thin ratio: TTR) was compared to determine if a lower NNE is associated with a greater proportion of thicker melanoma. Combining TTR with NNE allows a better estimate of the effectiveness in melanoma diagnosis, assessing both the overall cost for a given pool of excised melanomas and costs due to unnecessary nevi excision at a particular dermatology centre. Methods: Demographic data and Breslow thickness of excised melanoma were extracted from patient histologic records at two referral centres for melanoma (Parma Dermatology Unit and Ravenna and Meldola Skin Cancer Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori. IRCCS (IRST)) on all skin tumours excised between 2002 and 2011 and diagnosed as melanoma or melanocytic nevus. NNE and TTR were calculated and compared among the considered variables. Logistic regression was used to assess the contribution of each variable in predicting a higher TTR. Results: Data from 16,738 excised lesions were analysed. The IRST Unit reported a mean NNE of 4.6, whereas the Parma Unit excised 10.6 nevi for each melanoma. No statistically significant differences existed in the mean (IRST Unit, 0.56 ± 0.89 mm; Parma Unit, 1.07 ± 2.2 mm) and median (range) Breslow thickness (IRST Unit, 0.4 (9) mm; Parma Unit 0.4 (30) mm). The TTR between centres was significantly different (Parma Unit, 24%; IRST Unit, 12%; p < 0.001). Based on logistic regression, the diagnosing centre was the most powerful factor in determining a thickness of >1 mm among diagnosed melanomas (OR = 1.8; 95% CI, 1.2–2.7; p < 0.01), with all other factors being equal. The NNE decreased at both centres from younger-to-older patients, whereas the TTR increased simultaneously; however, the increase in TTR was non-significantly related to NNE reduction after adjusting for confounders (age, gender, and localization). Conclusions: A better diagnostic performance is capable of reducing the NNE and TTR, i.e., unnecessary excisions of melanocytic nevi can be reduced without increasing the risk of overlooking melanomas. The TTR, in addition to the NNE, allows stakeholders to better estimate the effectiveness in melanoma diagnosis because both overall costs for a given pool of excised melanomas and costs due for unnecessary nevi excision at a particular dermatology centre can be compared.

Erratum: Evaluation of Colorectal Cancer Risk and Prevalence by Stool DNA Integrity Detection.

An erratum was issued for:Evaluation of Colorectal Cancer Risk and Prevalence by Stool DNA Integrity Detection. Anaffiliationwasupdated. The firstaffiliation was updated from: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) to: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

How Many Cancer Clinical Trials Can a Clinical Research Coordinator Manage? The Clinical Research Coordinator Workload Assessment Tool.

Cancer clinical trials (CTs) are now more complex than ever before and require dedicated personnel (clinical research coordinators [CRCs]) to perform regulatory and administrative activities and protocol- and patient-related procedures. We developed a simple tool to measure the workload (WL) of CRCs involved in cancer research and to estimate personnel requirements within a Clinical Trial Center. A literature review and 2-month period in which CRCs recorded their activities in a diary provided valuable information that led to the Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori Workload Assessment Tool (IWAT) being divided into three sections: Protocol, On-Treatment Patients, and Follow-Up Patients. Twelve full-time senior CRCs from three sites of the Network measured their monthly WL for 30 months to evaluate IWAT reproducibility and accuracy. The IWAT proved to be a user-friendly tool (3-6 minutes required for each CT), with high reproducibility (interobserver reproducibility ranged from 82% to 100% for each IWAT item). In December 2017, the Network had 185 ongoing CTs, with a median of 2.5 active centers for each CT. On the basis of 448 total IWAT measures by CRCs, the majority of trials were academic (57%) or dealt with advanced disease (77%). The median IWAT WL score for each study was 20.98 ± 22.90 (range, 2-188) and 475 ± 229 (range, 150 [junior staff] - 930 [extreme heavy WL]) for each CRC. On the basis of our experience, a monthly WL score of 500-600 was considered an appropriate value for a full-time CRC. The IWAT could prove useful in evaluating CT complexity, estimating appropriate CRC WLs, and defining personnel requirements. Independent validation by other CRCs working in different organizational contexts and in different countries is needed.

PROTECT Trial: A cluster-randomized study with hydroxychloroquine versus observational support for prevention or early-phase treatment of Coronavirus disease (COVID-19): A structured summary of a study protocol for a randomized controlled trial

PROTECT Trial: A cluster-randomized study with hydroxychloroquine versus observational support for prevention or early-phase treatment of Coronavirus disease (COVID-19): A structured summary of a study protocol for a randomized controlled trial

Randomised phase II trial of CAPTEM or FOLFIRI as SEcond-line therapy in NEuroendocrine CArcinomas and exploratory analysis of predictive role of PET/CT imaging and biological markers (SENECA trial): a study protocol

IntroductionPatients with metastatic or locally advanced, non-resectable, grade 3 poorly differentiated gastroenteropancreatic (GEP) and lung neuroendocrine carcinomas (NECs) are usually treated with in first-line platinum compounds. There is no standard...

Retrospective analysis of gastric cancer management in a real-world setting: a single-institution experience.

In a gastric cancer (GC) setting, phase II and III studies refer to an ideal patient population and only describe a specific category of patients. Older patients or those in poorer clinical condition are generally excluded from clinical trials. We aimed to evaluate therapeutic approaches to GC in a real-world setting at our institute (Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori [IRST] IRCCS) over a 10-year period. A total of 621 consecutive patients with GC diagnosed between January 2000 and December 2009 were considered retrospectively. Among these, 573 with available information on stage of disease were included in the analysis. Demographic and clinical data were collected from paper or electronic medical records. During the study period, 343 (59.8%) patients were diagnosed with GC stage 0 to IIIC (M0): of these, 118 patients had a relapse of disease. A total of 230 patients (40.2%) presented with metastatic disease at diagnosis. Older age was associated with less frequent administration of adjuvant chemotherapy (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.83-0.91); interaction between age and period (OR, 1.02; 95% CI, 1.01-1.03) and stage of disease at diagnosis (OR, 7.95; 95% CI, 3.71-17.1) were positively associated with administration of adjuvant chemotherapy. Older age (OR, 0.87; 95% CI, 0.84-0.90) and presence of comorbidity (OR, 0.46; 95% CI, 0.26-0.83) were associated with less frequent administration of palliative chemotherapy, whereas from 2000-2004 to 2005-2009, patients were more frequently treated with palliative chemotherapy overall (OR, 3.70; 95% CI, 2.01-6.81). Our results confirm that resection is the standard surgical approach to GC, and that chemotherapy is not widely used in adjuvant and metastatic settings. Older age and comorbidities are associated with nontreatment.

Pan-genome cfDNA methylation analysis of metastatic prostate cancer

Abstract Background Tumour DNA circulates in the plasma of cancer patients admixed with DNA from non-cancerous cells. The genomic landscape of plasma tumour DNA has been characterised in metastatic castration-resistant prostate cancer (mCRPC) but the plasma methylome in mCRPC has not been extensively explored. Methods mCRPC plasma samples collected from three different centres were concurrently subject to targeted genomic and pan-genome methylation profiling. The treatment courses and outcomes were also obtained. Tumour fraction of each plasma sample was estimated based on heterogyzous SNPs located in two truncal genomic deletions (8q21 and 21q22). Targeted methylome was performed using pre-designed capture panel followed by deep sequencing. We integrated genomic information with methylation data to extract methylation signatures associated with genomically-determined tumour fraction or private to individual's tumour. Results Principal component analysis on the mCRPC plasma methylome indicated that the main contributor to methylation variance (principal component one, or PC1) was strongly correlated with genomically-determined tumour fraction (r=-0.96; P Conclusions Plasma methylome analysis can accurately quantitate tumour fraction and identify distinct biologically-relevant mCRPC phenotypes associated with worse clinical outcome. Clinical trial identification Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy (REC 2192/2013) Royal Marsden, London, UK (REC 04/Q0801/6) PREMIERE trial (EudraCT: 2014-003192-28, NCT02288936). Legal entity responsible for the study The authors. Funding Cancer Research UK (CRUK), Prostate Cancer Foundation (PCF). Disclosure V. Conteduca: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Janssen-Cilag; Honoraria (self), Advisory / Consultancy: Sanofi-Aventis. E. Gonzalez-Billalebeita: Honoraria (self): Astellas; Honoraria (self): Janssen-Cilag; Honoraria (self): Sanofi-Aventis. U.D. Giorgi: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Janssen-Cilag,; Honoraria (self), Advisory / Consultancy: Sanofi-Aventis. G. Attard: Honoraria (self): Institute of Cancer Research; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Medivation; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Arno. All other authors have declared no conflicts of interest.

The Malignant Hemopoietic Clone of Triple Negative Patients with Myelofibrosis Shows in Vitro Functional Defects but Is Highly Responsive to the Pro-Survival Signals of Circulating Autologous Microvesicles

BackgroundMyelofibrosis (MF) is a clonal hemopoietic stem/progenitor cells (HSPCs) disorder with mutations in 3 driver genes (JAK2, MPL, or CALR) and inflammatory microenvironment. Triple negative (TN) patients (pts) do not carry the 3 driver mutations and display a significantly worse survival-rate which can be partially due to a greater mutation complexity. Circulating microvesicles (MVs; 0.1-1 μm), most of megakaryocytes (MKMVs) and platelets (PMVs) origin, play a role in intercellular signalling and are increased in inflammation and cancer including MF. We hypothesized that in TN pts the HSPCs and/or the inflammatory microenvironment show a more aggressive and malignant phenotype.AimsTo identify a biomolecular signature of TN pts by comparatively evaluating the circulating HSPCs behaviour and their functional interplay with the inflammatory microenvironment.MethodsEDTA-anticoagulated peripheral blood (PB) was collected from 16 MF pts (WHO-2016 criteria-JAK2(V617F) mutated (n=10) and TN (n=6)) and 20 age/sex-matched healthy donors (HD). Driver mutation status was obtained by PCR/NGS. Plasma MVs were isolated by ultracentrifugation (45.000 rpm for 2 hours), counted by Nanosight technology and phenotypically characterized for PMVs (CD61+CD62P+) and MKMVs (CD61+CD62P-) by flow cytometry (size 0.5-0.9 µm). in vitro survival (24 hours), CXCL12-driven migration (12 hours) and clonogenic ability of immunomagnetically isolated CD34+ cells from pts PB or cord blood (CB; n=10) was performed in the presence/absence of the isolated MVs or IL-1β, TNF-α and IL-6 (alone/ in combination). Incorporation of CFSE-labelled MVs into CD34+ cells was analyzed by confocal microscopy. MicroRNA (miRs) profile analysis of the isolated MVs and Gene expression profile (GEP) analysis of CD34+ cells from 3 JAK2(V617F) mutated, 3 TN pts and 3 HD/CB was performed. Plasma inflammatory cytokines levels were evaluated by ELISA.ResultsWe firstly compared the TN and JAK2(V617F) CD34+ cells. TN CD34+ cells showed decreased in vitro survival and clonogenic ability but comparable migration capacity (Fig. 1 A, B, C). Consistently, comparing the GEP, the expression of selected anti-apoptotic (TSPYL5, GFI-1 and FCMR) and pro-apototic (TNFSF10, TP53INP1) genes was significantly down- and up-regulated, respectively, in TN CD34+ cells. We then investigated whether signals from the microenvironment may affect the in vitro behaviour of the TN CD34+ cells. IL-1β, IL-6 and TNF-α plasma levels were significantly increased (p<0.05) in MF pts. However, at variance with the JAK2(V617F) mutated counterparts, survival and clonogenic ability of TN CD34+ cells were not significantly promoted by IL-1β, IL-6 and TNF-α, alone or in combination. This was due, at least in part, to the reduced expression of IL-6 and TNF-α (type I) receptors on TN CD34+ cells. We then analyzed the phenotype of the isolated circulating MVs showing that the PMVs were significantly increased (p<0.05) in the JAK2(V617F) mutated pts only. Conversely, the MKMVs were significantly decreased in both pts groups (p<0.01) as compared to the HD counterparts (Fig. 1 D, E). When we co-cultured CD34+ cells with the isolated MVs we found that TN MVs significantly increased the survival of TN CD34+ cells but inhibited CB CD34+ cells survival (p<0.05, respectively). Conversely, JAK2(V617F) MVs did not significantly affected the survival of CB/pts CD34+ cells. HD MVs significantly increased the survival of CB CD34+ cells (p<0.05) only (Fig. 1 F, G, H). Of note, MVs from pts were transferred into cytosol after co-cultured with CB CD34+ cells (Fig. 1 I). Consistently, comparing the miRs profile of pts and HD MVs, various pro-apoptotic (+) and anti-apoptotic (-) miRs were upregulated. Specifically, miR-155(-), 24(-) and 222(-) were upregulated in TN MVs only; miR-21(-), 19a(-), 34a-5p(+), 423-5p(+) were upregulated in both JAK2(V617F) and TN MVs. Further, miRs regulating inflammation (miR-146a) and proliferation (miR-1274A, downregulated in TN vs JAK2(V617F) MVs), were overexpressed in pts MVs.ConclusionsOur results demonstrate that TN CD34+ cells show in vitro defective function and are unresponsive to the inflammatory microenvironment. Interestingly, only the autologous circulating MVs promoted the malignant clone, suggesting that MVs, as signals from microenvironment, may have a pathogenetic role in TN MF and may be the target of novel therapeutic approaches. [Display omitted] DisclosuresFabbri:Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS: Employment. Cavo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Palandri:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Unravel Inter-Tumor and Intra-Tumor Heterogeneity of Digitally Sorted Single Hodgkin and Reed Sternberg Cells Using Genome-Wide Copy Number Profiling

IntroductionImmune-checkpoint blockade has emerged as an effective therapeutic strategy in solid tumor and in hematologic malignancies, including classical Hodgkin Lymphoma (cHL).cHL represents about 11% of all malignant lymphoma and it is generally highly curable with standard frontline therapies, although about 20% of the patients will relapse or become refractory after initial treatment.The hallmark of cHL is the presence of malignant Hodgkin and Reed-Sternberg Cells (HRS) that represent only a small fraction (about 1%) of the surrounding heterogeneous immune infiltrate. Despite this extensive inflammatory microenvironment, HRS are able to escape immune surveillance using several mechanisms, including the overexpression of PD-1 ligands (PD-Ls) that bind PD-1 on reactive T-cells, inhibiting their activity and proliferation and causing ultimately T-cell exhaustion. The PD-Ls expression is upregulated in a dose-dependent manner by copy number alterations of chromosome 9p24.1, a locus encoding for PD-L1/PD-L2 as well as JAK2, which further enhances PD-Ls expression through JAK2/STAT pathway.Here we present a method for the isolation and the genetic characterization of single purified HRS, which overcomes the limitations posed by the low tumor cellularity of cHL biopsies and gives an estimation of inter-tumor and intra-tumor heterogeneity which may be useful to guide immune treatment selection.MethodsFFPE tissue sections from 4 cHL patients were dissociated down to single-cell suspension and stained using anti-CD30 and anti-PD-L1 antibodies. Since CD30 is not expressed exclusively by malignant cells, beyond the positivity to CD30 and PD-L1 HRS were selected according to morphological criteria, such as cell size and the presence of nuclei with ploidy higher than the surrounding lymphocytes.DEPArray™ NxT system (Menarini Silicon Biosystems) was used to isolate single target cells. After recovery, single cells were whole genome amplified (Ampli1™ WGA, Menarini Silicon Biosystems), and genome-wide copy-number alterations (CNAs) profiles were obtained using Ampli1™ LowPass kits (Menarini Silicon Biosystems) on Illumina® and Ion Torrent™ platforms.ResultsFor each patient, at least 8 HRS cells and infiltrating lymphocytes were identified and isolated from lymphoid tissue using DEPArray™ NxT system.Copy-number analyses of recovered cells allowed us to precisely discriminate HRS, characterized by extensive gains and losses, from non-tumor cells, showing flat profiles as expected (Fig.1). Ploidy of HRS was automatically determined, based on best-fitting of profiles with underlying copy number levels.Hierarchical clustering showed that some alterations are highly conserved among patients, e.g. the region containing PD-L1/PD-L2/JAK2 has several copy gains in the majority of malignant cells. Interestingly, these alterations show high variable copy-number levels between different HRS even in the same patient, ranging from few copy-gains to amplifications, suggesting some level of heterogeneity.Different CNAs are also detected in regions containing genes belonging to pathways already known to be altered in cHL, like REL/NFKB and JAK/STAT pathways, which may be involved in the constitutive activation of proliferative and antiapoptotic phenotype of HRS.ConclusionSingle HRS sorting combined with low-pass whole genome sequencing offer a valuable tool to uncover genetic alterations hidden by the massive cHL immune infiltrate and to estimate inter-tumor and intra-tumor heterogeneity in cHL patients. Considering that PD-Ls locus amplifications are associated with advanced stages of the disease and with a shorter progression free survival, the analysis of purified HRS could be helpful for patient stratification for the adoption of immune therapy. [Display omitted] DisclosuresMangano:Menarini Silicon Biosystems: Employment. Edoardo:Menarini Silicon Biosystems: Employment. Garonzi:Menarini Silicon Biosystems: Employment. Lanzellotto:Menarini Silicon Biosystems: Employment. Papadopulos:Menarini Silicon Biosystems: Employment. Bolognesi:Menarini Silicon Biosystems: Employment. Buson:Menarini Silicon Biosystems: Employment. Ferrarini:Menarini Silicon Biosystems: Employment. Forcato:Menarini Silicon Biosystems: Employment. Fontana:Menarini Silicon Biosystems: Employment. Ceccolini:Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS: Employment. Fabbri:Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS: Employment. Fici:Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS: Employment. Gallerani:Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS: Employment. Simonelli:Menarini Silicon Biosystems: Employment. Medoro:Menarini Silicon Biosystems: Employment. Manaresi:Menarini Silicon Biosystems: Employment.

Correction: MYC-containing amplicons in acute myeloid leukemia: genomic structures, evolution, and transcriptional consequences

In the original version of this Article, the affiliation details for Giovanni Martinelli were incorrectly given as 'Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138, Bologna, Italy' and it should have been given as 'Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy and not Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138, Bologna, Italy.'Furthermore, the original version of this Article contained an error in the spelling of the authors Alberto L'Abbate and Pietro D'Addabbo, an acute accent was used instead of an apostrophe for these authors names.These errors have now been corrected in both the PDF and HTML versions of the Article.

Are There Differences in Androgen Receptor Expression in Invasive Breast Cancer in African (Tanzanian) Population in Comparison With the Caucasian (Italian) Population?

Androgen receptor (AR) has been shown to have prognostic implication on breast cancer (BC). Data on the biological features of African BCs are poor. We decided for the first time to compare AR expression of Tanzanian and Italian BC patients. Of the 69 consecutive patients seen at the Bugando Medical Center (Mwanza, Tanzania) from 2003 to 2010, who underwent resection of primary BC evaluable for estrogen receptor, progesterone receptor (PgR), and HER2 only 65 were evaluable for AR by immunohistochemistry. Histopathological assessment and biomolecular determinations were performed at the Cancer Institute of Romagna [Istituto Scientifico Romagnolo per lo studio e la cura dei tumori (IRST)-IRCCS, Meldola, Italy]. Caucasian BC patients were selected from an electronic database and matched (1:2 ratio) for year of diagnosis and age at diagnosis. The median age of patients at diagnosis was 51 (range 29-83) years for Tanzanian and 53 (range 26-86) years for Italian patients. Tanzanian patients harbored tumors with lower AR expression than Italian patients according to the median percentage of immunopositive tumor cells (30% versus 80%, p < 0.0001) and staining intensity (p = 0.0003). The proportion of AR negative patients was likewise higher among Tanzanian patients as regards both ≥1% and ≥10% cutoffs. AR-positive BCs were higher in luminal A and B tumors and decreased in triple-negative (TN) and HER2-enriched tumors in Tanzanian population. AR loss could represent an unfavorable prognostic marker in the African population. The high frequency of TN tumors with high AR expression could open new perspectives of therapy for population in this low income country.

Stemness Underpinning All Steps of Human Colorectal Cancer Defines the Core of Effective Therapeutic Strategies

Despite their lethality and ensuing clinical and therapeutic relevance, circulating tumor cells (CTCs) from colorectal carcinoma (CRC) remain elusive, poorly characterized biological entities. Here we show how tumor-initiating, human CRC stem-like cells (CCSCs) can establish faithful orthotopic phenocopies of the original disease, which contain cells that spread into the circulatory system. While in the vascular bed, these cells retain stemness, thus qualifying as circulating CCSCs (cCCSCs). This is followed by the establishment of lesions in distant organs, which also contain resident metastatic CCSCs (mCCSCs). Our results support the concept that throughout all the stages of CRC, stemness is retained as a continuous property by some of their tumor cells. Importantly, we describe a useful standardized model that can enable isolation and stable perpetuation of human CRC's CCSCs, circulating and metastatic CCSCs, providing a useful platform for studies of CRC initiation and progression that is suitable for the discovery of reliable stage-specific biomarkers and the refinement of new patient-tailored therapies. Funding Statement: This work was supported by grants from AIRC (IG-14368) and MIUR (GR-2011-02351534, RC1703IC36). Declaration of Interests: The authors declare no competing interests. A.L. Vescovi has ownership interest in Hyperstem SA. Ethics Approval Statement: Fresh human colorectal cancer and blood specimens were collected from consenting patients at IRCCS “Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori” (IRST) and IRCCS “Casa Sollievo della Sofferenza”. All samples were obtained under protocols approved by the Research Ethics Boards (B063 and 94/CE). All animal procedures were carried out in strict accordance with the Guidelines for the Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committees (IACUCs) at the University of Milan-Bicocca.

Update on the role of trabectedin in the treatment of intractable soft tissue sarcomas.

Soft tissue sarcomas (STS) represent a variety of tumors of mesenchymal origin, accounting for about 1% of all adult cancers. This group of tumors comprises over 60 different histotypes with different biology showing different sensitivity to therapeutic agents. For decades, the standard first-line systemic treatment of metastatic STS has comprised anthracycline based-chemotherapy. Second-line therapy options include agents such as ifosfamide, gemcitabine, and pazopanib, but the optimal sequential therapy for the management of metastatic disease has yet to be defined. Trabectedin is one of the new molecules approved for patients in progression after first-line chemotherapy with anthracyclines or for those unfit for these agents. The compound is characterized by multiple potential mechanisms of action combining cytotoxic, targeted, and immunological effects. This article takes an in-depth look at the role of trabectedin in the management of metastatic STS, including L-sarcoma and non-L-sarcoma.

Implementing an evidence-based computerized decision support system linked to electronic health records to improve care for cancer patients: the ONCO-CODES study protocol for a randomized controlled trial

BackgroundComputerized decision support systems (CDSSs) are computer programs that provide doctors with person-specific, actionable recommendations, or management options that are intelligently filtered or presented at appropriate times to enhance health care. CDSSs might be integrated with patient electronic health records (EHRs) and evidence-based knowledge.Methods/DesignThe Computerized DEcision Support in ONCOlogy (ONCO-CODES) trial is a pragmatic, parallel group, randomized controlled study with 1:1 allocation ratio. The trial is designed to evaluate the effectiveness on clinical practice and quality of care of a multi-specialty collection of patient-specific reminders generated by a CDSS in the IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) hospital. We hypothesize that the intervention can increase clinician adherence to guidelines and, eventually, improve the quality of care offered to cancer patients. The primary outcome is the rate at which the issues reported by the reminders are resolved, aggregating specialty and primary care reminders. We will include all the patients admitted to hospital services. All analyses will follow the intention-to-treat principle.DiscussionThe results of our study will contribute to the current understanding of the effectiveness of CDSSs in cancer hospitals, thereby informing healthcare policy about the potential role of CDSS use. Furthermore, the study will inform whether CDSS may facilitate the integration of primary care in cancer settings, known to be usually limited. The increasing use of and familiarity with advanced technology among new generations of physicians may support integrated approaches to be tested in pragmatic studies determining the optimal interface between primary and oncology care.Trial registrationClinicalTrials.gov, NCT02645357

S32 - English Language in Oncology: a Targeted Training Programme for the Researchers and Healthcare Professionals of IRST IRCCS (Romagna Oncology Network, Italy)

Background: Management of oncologic diseases relies on the synergy between practice and research. Since English is the language of research, we believe it is crucial to investigate targeted teaching approaches to encourage interaction with the scientific community and foreign patients. Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS is home to an English Training Programme (ETP) that promotes continuing education and fosters excellence, innovation, and progress in oncology. Materials and methods: In accordance with the action research model, our project includes 3 steps: English language needs analysis (placement tests, motivational letters and questionnaires for researchers and healthcare professionals) and SWOT analysis (interviews to key informants) to identify critical factors for ETP design; identification of SMART ETP goals, settings and indicators; ETP implementation with short- and long-term outcome assessment to improve training methods. Results: Seven key informants were interviewed on the internal and external strengths/weaknesses and opportunities/threats related to an ETP. Among IRST IRCCS professionals, 163 (F:M = 125:38, median age 39 years) completed the questionnaire: 76% have learned English in group classes (46% with English native speaker); 4% as self-taught learners. Most people (59%) have a medical and health sciences educational background, 64% of whom are engaged in research activity. Professional English is more frequently used for online searches (67%), scientific paper reading (64%), and writing (34%); less frequently for working abroad (3%). Spoken language, especially pronunciation (46%) and fluency (63%), accounts for the weakest perceived skill. Preliminary data show that the best-suited training programme would be a long-term course for interprofessional groups of 5-8, with a focus on sociolinguistic and phonological skills. Additional spotlights on specific language issues and individual tutoring for scientific writing or oral presentation will be included. As this project is currently ongoing, updated results will be presented at the congress. Conclusions: To our knowledge no similar project has ever been carried out in any other Italian biomedical research centre. The preliminary results strongly suggest that our ETP could improve language knowledge and communication skills in oncology, promoting collaboration networks and enhancing the performance of the researchers and healthcare professionals of IRST IRCCS.

The Comprehensive Cancer Care Network of Romagna: the opportunities generated by the OECI accreditation program.

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS is a public-private partnership among 3 public sector bodies and 6 private nonprofit organizations and represents the hub of the Oncology Network of Romagna, which provides a wide range of services for the population ranging from primary prevention to palliative care. In 2012, IRST took part in the ministerial research project of the Organisation of European Cancer Institutes (OECI) accreditation program for Comprehensive Cancer Centers. The self-assessment period lasted 6months and was coordinated by a multidisciplinary project team headed by a project leader. Each project team member coordinated a subgroup whose task was to analyze specific standards from qualitative and quantitative questionnaires. During the self-assessment period for the areas in which IRST did not meet OECI requirements, the project team outlined several improvement plans. At the end of the self-assessment period, the OECI Accreditation & Designation Board approved the documentation presented by IRST and a peer review visit was scheduled. The OECI report suggested establishing a more specific and stronger centralized management and leadership of all the oncologic activities carried out in other centers. In accordance with these suggestions, IRST and the Local Health Authority of Romagna laid the foundations for a new management model for the Oncology Network of Romagna: the Comprehensive Cancer Care Network (CCCN). The CCCN is a territory-oriented model (population approach) based on a principle of cooperation and collaboration among the network nodes.

Autonomic modulation for the management of patients with chronic heart failure.

Dysregulation of the autonomic nervous system in heart failure (HF) has received considerable attention during the past 3 decades, largely because of the well-recognized association between increased sympathetic activity and the elaboration of biologically active molecules, collectively referred to as neurohormones, that help to maintain cardiovascular homeostasis through increased volume expansion, peripheral arterial vasoconstriction, and increased myocardial contractility. However, high and sustained levels of these biologically active molecules (eg, norepinephrine, angiotensin II, aldosterone) are overtly toxic to the heart and circulation.1 These and other insights have led to the clinical use of neurohormonal antagonists, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone antagonists, and β-blockers to treat patients with HF with a reduced left ventricular ejection fraction (LVEF).1 The effectiveness of these pharmacological agents is predominantly because of their ability to directly antagonize the deleterious effects of excessive sympathetic and renin–angiotensin activation. However, the current guideline-directed medical therapy (GDMT) in patients with HF fails to completely restore normal autonomic balance disrupted as a part of HF pathophysiology. During the last decade, a novel approach has generated widespread interest: modulation of the autonomic nervous system as a result of either a one-time intervention (eg, denervation) or of ongoing active therapy (eg, electric stimulation) as a means of further diminishing the sympathovagal imbalance that develops in HF.2,3 Of note, therapeutic neuromodulation with device-based therapies, either with spinal cord stimulation (SCS) or vagal stimulation (VS), has been used safely in patients with chronic pain, epilepsy, and depression, since the 1980s. As noted above, HF with a reduced LVEF is associated with sustained activation of the sympathetic nervous system that is accompanied by a withdrawal of parasympathetic tone. Impaired arterial baroreflexes have been proposed as an important mechanism that contributes to the sympathovagal imbalance present in HF4 …

Rapid Treatment Response of Suicidal Symptoms to Lithium, Sleep Deprivation, and Light Therapy (Chronotherapeutics) in Drug-Resistant Bipolar Depression

One third of patients with bipolar disorder attempt suicide. Depression in bipolar disorder is associated with drug resistance. The efficacy of antidepressants on suicidality has been questioned. Total sleep deprivation and light therapy prompt a rapid and stable antidepressant response in bipolar disorder. We studied 143 consecutively admitted inpatients (December 2006-August 2012) with a major depressive episode in the course of bipolar disorder (DSM-IV criteria). Among the 141 study completers, 23% had a positive history of attempted suicide and 83% had a positive history of drug resistance. During 1 week, patients were administered 3 consecutive total sleep deprivation cycles (each composed of a period of 36 hours awake followed by recovery sleep) combined with bright light therapy in the morning for 2 weeks. At admission, patients who had been taking lithium continued it, and those who had not been taking lithium started it. Severity of depression was rated according to the Hamilton Depression Rating Scale (HDRS) (primary outcome measure) and Beck Depression Inventory (BDI). Two patients switched polarity. Among the 141 who completed the treatment, 70% achieved a 50% reduction in HDRS score in 1 week, which persisted 1 month after in 55%. The amelioration involved an immediate and persistent decrease in suicide scores soon after the first total sleep deprivation cycle (F3,411 = 42.78, P < .00001). A positive history of suicide attempts was associated with worse early life stress and with worse suicide scores at baseline, but it did not influence response. Patients with current suicidal thinking or planning responded equally well (F3,42 = 20.70, P < .000001). Remarkably, however, nonresponders achieved a benefit, with significantly decreased final scores also including suicidality ratings (F3,120 = 6.55, P = .0004). Self-ratings showed the same pattern of change. Previous history of drug resistance did not hamper response. During the following month, 78 of 99 responders continued to stay well and were discharged from the hospital on lithium therapy alone. The combination of total sleep deprivation, light therapy, and lithium is able to rapidly decrease depressive suicidality and prompt antidepressant response in drug-resistant major depression in the course of bipolar disorder.

Dysregulated ratio between MARK4 L and S isoforms during glioma progression

1. Medical Genetics, Department of Medicine, Surgery and Dentistry, Universita degli Studi di Milano, Milan, Italy 2. Clinical Epileptology and Experimental Neurophysiology Unit, Istituto Neurologico Carlo Besta, Milan, Italy 3. Neural Stem Cell Biology Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, Istituto Scientifico San Raffaele, Milan, Italy 4. Department of Neurological Sciences, Universita degli Studi di Milano, Milan, Italy 5. Anatomical Pathology, Department of Medicine, Surgery and Dentistry, Universita degli Studi di Milano, Milan, Italy 6. Department of Experimental and Clinical Biomedical Sciences, Universita dell’Insubria, Varese, Italy

Interference by cryoglobulins in a light-scatter instrument

Clinical & Laboratory HaematologyVolume 12, Issue 1 p. 112-114 Interference by cryoglobulins in a light-scatter instrument G. Banfi MD, G. Banfi MD Istituto Scientifico S. Raffaele Via Olgettina 60 20132 Milano ItalySearch for more papers by this authorP.A. Bonini MD, PhD, P.A. Bonini MD, PhD Istituto Scientifico S. Raffaele Via Olgettina 60 20132 Milano ItalySearch for more papers by this author G. Banfi MD, G. Banfi MD Istituto Scientifico S. Raffaele Via Olgettina 60 20132 Milano ItalySearch for more papers by this authorP.A. Bonini MD, PhD, P.A. Bonini MD, PhD Istituto Scientifico S. Raffaele Via Olgettina 60 20132 Milano ItalySearch for more papers by this author First published: March 1990 https://doi.org/10.1111/j.1365-2257.1990.tb01121.xCitations: 3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume12, Issue1March 1990Pages 112-114 RelatedInformation