Kooperativer Bibliotheksverbund

In: British Journal of Surgery, Oxford University Press (OUP), ( 2023-11-14)

Abstract: The association between volume, complications and pathological outcomes is still under debate regarding colorectal cancer surgery. The aim of the study was to assess the association between centre volume and severe complications, mortality, less-than-radical oncologic surgery, and indications for neoadjuvant therapy. Methods Retrospective analysis of 16,883 colorectal cancer cases from 80 centres (2018–2021). Outcomes: 30-day mortality; Clavien-Dindo grade & gt;2 complications; removal of ≥ 12 lymph nodes; non-radical resection; neoadjuvant therapy. Quartiles of hospital volumes were classified as LOW, MEDIUM, HIGH, and VERY HIGH. Independent predictors, both overall and for rectal cancer, were evaluated using logistic regression including age, gender, AJCC stage and cancer site. Results LOW-volume centres reported a higher rate of severe postoperative complications (OR 1.50, 95% c.i. 1.15–1.096, P = 0.003). The rate of ≥ 12 lymph nodes removed in LOW-volume (OR 0.68, 95% c.i. 0.56–0.85, P & lt; 0.001) and MEDIUM-volume (OR 0.72, 95% c.i. 0.62–0.83, P & lt; 0.001) centres was lower than in VERY HIGH-volume centres. Of the 4676 rectal cancer patients, the rate of ≥ 12 lymph nodes removed was lower in LOW-volume than in VERY HIGH-volume centres (OR 0.57, 95% c.i. 0.41–0.80, P = 0.001). A lower rate of neoadjuvant chemoradiation was associated with HIGH (OR 0.66, 95% c.i. 0.56–0.77, P & lt; 0.001), MEDIUM (OR 0.75, 95% c.i. 0.60–0.92, P = 0.006), and LOW (OR 0.70, 95% c.i. 0.52–0.94, P = 0.019) volume centres (vs. VERY HIGH). Conclusion Colorectal cancer surgery in low-volume centres is at higher risk of suboptimal management, poor postoperative outcomes, and less-than-adequate oncologic resections. Centralisation of rectal cancer cases should be taken into consideration to optimise the outcomes.

Type of Medium: Online Resource

ISSN: 0007-1323 , 1365-2168

URL: Article

DOI: 10.1093/bjs/znad373

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2023

detail.hit.zdb_id: 2006309-X

In: JAMA Network Open, American Medical Association (AMA), Vol. 5, No. 11 ( 2022-11-21), p. e2243119-

Abstract: Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. Objective To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. Design, Setting, and Participants This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. Exposures Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. Main Outcomes and Measures The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. Results A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR] , 1.07; 95% CI, 1.01-1.13; P  = .03), aggressive biology (OR, 1.32; 95% CI, 1.15-1.53; P   & amp;lt; .001), and stenotic lesions (OR, 1.15; 95% CI, 1.01-1.31; P  = .03). Conclusions and Relevance This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients.

Type of Medium: Online Resource

ISSN: 2574-3805

URL: Article

DOI: 10.1001/jamanetworkopen.2022.43119

Language: English

Publisher: American Medical Association (AMA)

Publication Date: 2022

detail.hit.zdb_id: 2931249-8

In: Cancers, MDPI AG, Vol. 15, No. 9 ( 2023-04-24), p. 2441-

Abstract: This phase-3 randomized multicenter trial evaluated the efficacy of subcutaneous azacitidine (AZA) post-remission therapy vs. best supportive care (BSC) in elderly acute myeloid leukemia (AML) patients. The primary endpoint was the difference in disease-free survival (DFS) from complete remission (CR) to relapse/death. Patients with newly diagnosed AML aged ≥61 years received two courses of induction chemotherapy (“3+7” daunorubicin and cytarabine) followed by consolidation (cytarabine). At CR, 54 patients were randomized (1:1) to receive BSC (N = 27) or AZA (N = 27) at a dose of 50 mg/m2 for 7 days every 28 days and the dose increased after the 1st cycle to 75 mg/m2 for a further 5 cycles, followed by cycles every 56 days for 4.5 years. At 2 years, median DFS was 6.0 (95% CI: 0.2–11.7) months for patients receiving BSC vs. 10.8 months (95% CI: 1.9–19.6, p = 0.20) months for AZA. At 5 years, DFS was 6.0 (95% CI: 0.2–11.7) months in the BSC arm vs. 10.8 (95% CI: 1.9–19.6, p = 0.23) months in the AZA arm. Significant benefit was afforded by AZA on DFS at 2 and 5 years in patients aged 〉 68 years (HR = 0.34, 95% CI: 0.13–0.90, p = 0.030 and HR = 0.37, 95% CI: 0.15–0.93, p = 0.034, respectively). No deaths occurred prior to leukemic relapse. Neutropenia was the most frequent adverse event. There were no differences in patient-reported outcome measures between study arms. In conclusion, AZA post-remission therapy was found to provide benefit in AML patients aged 〉 68 years.

Type of Medium: Online Resource

ISSN: 2072-6694

URL: Article

DOI: 10.3390/cancers15092441

Language: English

Publisher: MDPI AG

Publication Date: 2023

detail.hit.zdb_id: 2527080-1

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 53-53

Abstract: The genetic basis of myelodysplastic syndromes (MDS) is heterogeneous, and various somatic mutations are associated with different phenotypes and clinical outcomes. The only curative treatment for MDS patients is allogeneic hematopoietic stem cell transplantation (HSCT) which is considered as a therapeutic option until the age of 65-70 in eligible patients. Whether the genetic basis influences the outcome of HSCT is currently unclear. Recently, we observed that mutations on ASXL1, RUNX1 and TP53 genes are independent predictors of relapse and overall survival in MDS patients after HSCT, and that the integration of these mutations into currently available predictive models increases the capability to capture prognostic information at individual patient level (Della Porta MG et al. J Clin Oncol, 2016 in press). In this study, we explored the possibility of developing a clinical/molecular predictive model to specifically estimate the outcome after HSCT in patients with MDS or acute myeloid leukemia evolving from MDS (MDS/AML). We studied 401 patients undergoing allogeneic HSCT for primary MDS or MDS/AML between 1997 and 2013 and reported to the GITMO registry. We used massively parallel sequencing to examine tumor samples collected before HSCT for somatic mutations in 34 recurrently mutated genes in myeloid neoplasms. In multivariable analysis with probability of relapse as endpoint the following factors showed independent prognostic value: percentage of marrow blasts ( 〉 10% vs. ≤10%, HR 1.43, P=0.04), cytogenetic risk according to IPSSR (poor/very poor vs. very low/low/intermediate risk, HR 1.85, P=.002), disease status at transplant (refractoriness to induction chemotherapy vs. complete remission, HR 2.4, P 〈 .001), type of conditioning (reduced intensity vs. standard conditioning, HR 1.35, P=.034) and mutational status of ASLX1/RUNX1/TP53 genes (present vs absent, HR 1.49, P=.021). Recipient age ( 〉 40 vs. ≤40 years, HR 1.68, P=.001), comorbidity risk according to HCT-CI (high vs. low/intermediate risk 2.10, P 〈 .001) type of conditioning (reduced intensity vs. standard conditioning, HR 0.53, P=.033) and HLA matching (≤7/8 vs. 8/8 match, HR 1.97, P=.001) were significant risk factors for transplant-related mortality (TRM). Based on regression coefficients, we developed a clinical/molecular model predictive for the risk of relapse after transplantation in MDS and MDS/AML. Accordingly, a score value of 1 was assigned for each of the following risk factors: marrow blasts 〉 10%, poor/very poor cytogenetic risk according to IPSSR, refractoriness to induction chemotherapy, and driver mutations in ASLX1/RUNX1/TP53 genes. A relapse risk index was calculated as the sum of these weighted scores, and was then categorized into 4 risk groups: low (score=0), intermediate (score=1-2), high (score=3), and very high (score=4). The cumulative incidence of relapse was estimated by a competing risks approach with TRM. In patients receiving standard conditioning, 5-year probability of survival after allogeneic HSCT was 61%, 43%, 39% and 19% for low, intermediate, high and very high risk (P 〈 .001), while cumulative incidence of relapse were 9%, 19%, 24% and 35%, respectively (P=.001). In patients receiving reduced intensity conditioning, 5-year probability of survival was 55%, 42%, 33% and 15% for low, intermediate, high and very high risk (P=.003), while cumulative incidence of relapse were 12%, 25%, 39% and 58%, respectively (P 〈 .001). This model serves as a proof of concept that the integration of somatic mutations significantly increase the capability to capture prognostic information in MDS and MDS/AML patients receiving allogeneic HSCT, and may provide a basis for improving clinical decision-making. Possible interventions in patients with high risk of disease relapse after HSCT according to genotype may include the anticipation of the transplant procedure in early disease phase, the use of innovative conditioning regimens to increase the probability to eradicate MDS clone, and prophylaxis of disease recurrence after transplantation by donor leukocyte infusions and targeted/novel therapies Disclosures Ciceri: MolMed SpA: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.53.53

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: European Journal of Haematology, Wiley, Vol. 85, No. 3 ( 2010-09), p. 231-235

Type of Medium: Online Resource

ISSN: 0902-4441

URL: Article

DOI: 10.1111/j.1600-0609.2010.01473.x

Language: English

Publisher: Wiley

Publication Date: 2010

detail.hit.zdb_id: 2027114-1

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1516-1516

Abstract: Background: In myelodysplastic syndromes (MDS), thrombocytopenia is an adverse risk factor. Treatments in this setting are scarce. In a randomized international phase 2 trial (EQoL-MDS, EudraCT number 2010-022890-33), we reported effecacy and safety of eltrombopag for the treatment of thrombocytopenia in the first 90 patients with lower-risk MDS with a platelet (PLT) count & lt; 30 Gi/L (Oliva et al. Lancet Hem 2017). However, there are concerns of regulatory agencies regarding the use of thrombopoetin rececptor agonists in MDS due to previous reports signalling disease progression in clinical trials with the use of romiplostim and of eltrombopag, the latter in high risk MDS. Objective: We are further evaluating safety by conducting a comprehensive analysis of mutations in a panel of major driver or candidate driver genes in cases enrolled in the EQoL-MDS trial using targeted-capture sequencing. Methods: Serial (every 3 months) sequencing was performed using the SureSelect custom kit (Agilent Technologies), for which 350 genes were selected from known oncogenes or tumour suppressor genes in haematological malignancies. Relevant somatic mutation data with (i) VAF & gt; 0.05; (ii) depth & gt; 100; (iii) P value for EBCall & lt; 0.0001, were filtered by exclusion based on (i) synonymous SNVs; (ii) variants present only in unidirectional reads; (iii) variants occurring in repetitive genomic regions; (iv) missense SNVs with VAF of 0.4-0.6 or & lt;0.04; and (v) known variants listed in SNP databases. The present analysis has been conducted at baseline, at 12 and 24 weeks. Results: We present preliminary results of the first 21 cases (13 eltrombopag, 9 placebo) enrolled in the trial and with biological samples. Mean age was 62 (± 15) and 13 patients were male. According to the WHO 2016 classification, 11 patients had MDS with single lineage dysplasia (SLD), 7 had multi lineage dysplasia (MLD), 1 placebo case had excess blasts-1, and 1 placebo case had unclassifiable. IPSS-R risk was very low, low and intermediate in 4, 8 and 1 eltrombopag cases, respectively, and 5, 2 and 1 placebo cases, respectively. Karyotype was normal in 16 cases, del(20q) was detected in 4 cases and +14 in 1 case. At study entry, in total 49 genes were mutated (Figure), where one or more of the 49 driver genes were mutated in all but 1 placebo patient (Table). The table shows characteristics and events of patients according to treatment arm. Noteworthy, in the eltrombopag arm, two cases experienced a loss of gene mutations, one obtaining International Working Group defined complete remission of MDS, while 1 MDS EB-1 case had a gain in ZRSR2. Two placebo cases experienced a gain in mutations Conclusions: Treatment with eltrombopag in lower risk MDS is effective and safe. Preliminary analyses do not suggest that eltombopag induces disease progression neither at a clinical, nor a molecular level. Loss of mutations may occur during eltrombopag treatment with complete remission. Figure 1 Figure 1. Disclosures Oliva: Novartis: Other: Advisory Board; Celgene BMS: Consultancy, Other: Advisory Board, Patents & Royalties; Alexion: Other: Advisory Board; Argenx: Other: Advisory Board; Daiichi: Other: Advisory Board; Amgen: Other: Advisory Board. Nannya: Otsuka Pharmaceutical Co., Ltd.: Consultancy, Speakers Bureau; Astellas: Speakers Bureau. Kulasekararaj: Alexion, AstraZeneca Rare Disease Inc.: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Ra Pharma: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Achilleon: Consultancy, Honoraria, Speakers Bureau; Biocryst: Consultancy, Honoraria, Speakers Bureau; Akari: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Speakers Bureau. Latagliata: Novartis: Honoraria; Pfizer: Honoraria; BMS Cellgene: Honoraria. Santini: Astex: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Ogawa: Eisai Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Kan Research Laboratory, Inc.: Consultancy, Research Funding; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; ChordiaTherapeutics, Inc.: Consultancy, Research Funding; Ashahi Genomics: Current holder of individual stocks in a privately-held company. OffLabel Disclosure: Eltrombopag (Revolade) is indicated for chronic immune (idiopathic) thrombocytopenic purpura (ITP) patients aged 1 year and above who are refractory to other treatments (e.g. corticosteroids, immunoglobulins).Revolade is indicated in adult patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy.Revolade is indicated in adult patients with acquired severe aplastic anaemia (SAA) who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for haematopoietic stem cell transplantation.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-150619

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 92, No. 1 ( 2013-1), p. 25-32

Type of Medium: Online Resource

ISSN: 0939-5555 , 1432-0584

URL: Article

DOI: 10.1007/s00277-012-1569-0

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2013

detail.hit.zdb_id: 1458429-3

In: The Journal of Infectious Diseases, Oxford University Press (OUP), Vol. 176, No. 1 ( 1997-07), p. 168-76

Type of Medium: Online Resource

ISSN: 0022-1899 , 1537-6613

URL: Issue

URL: Article

DOI: 10.1086/jid.1997.176.issue-1

DOI: 10.1086/514019

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 1997

detail.hit.zdb_id: 1473843-0

In: Drugs in Context, BioExcel, Vol. 11 ( 2022-03-16), p. 1-10

Type of Medium: Online Resource

ISSN: 1740-4398

URL: Journal

URL: Article

DOI: 10.7573/17404398

DOI: 10.7573/dic.2021-9-8

Language: Unknown

Publisher: BioExcel

Publication Date: 2022

detail.hit.zdb_id: 2719560-0

SSG: 15,3

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2622-2622

Abstract: Abstract 2622 Poster Board II-598 Introduction: Genetic alterations reported in myelodysplastic syndromes (MDS) are not disease-specific and the underlying molecular causes of the disease remain poorly understood. It has been suggested that one or more of the genes mapping within the commonly deleted region of the 5q syndrome, together with other distant genes, may be critical to the development of the 5q syndrome. Potential candidate genes have been identified including the tumor suppressor gene SPARC, and the ribosomial protein gene, RPS14. Haploinsufficiency of RPS14 has been demonstrated and recent evidence indicates RPS14 as a causal gene for the 5q syndrome. Lenalidomide has proven efficacy in MDS patients with del(5q). Rapid and durable responses include transfusion-independence, with a rise in Hb, suppression of the 5q-deletion clone and improvement in bone marrow morphologic features. Methods: In a multicenter Italian phase II trial to evaluate safety, changes in quality of life and efficacy of lenalidomide in primary MDS patients with del(5q) and low or Int-1 risk IPSS, we investigate changes in bone marrow cytogenetics and gene expression patterns during treatment. The starting dose of lenalidomide is 10 mg p.o once daily on a continuous daily schedule for a maximum of 12 months. Dosing is based upon clinical and laboratory findings. Bone marrow cytogenetics and gene expression profiling are performed on study entry and every 12 weeks up to end of study (week 52). Gene expression assays of 51 candidate genes from the published literature and genomic databases have been selected and are carried out with TaqMan® Low Density Array Fluidic card (TaqMan® Human Array, Applied Biosystems, Foster City, CA, USA) based on Applied Biosystems PRISM® 7900HT comparative dd CT method, according to manufacturer's instructions. Using an 18S mRNA gene pre-designed assay from Applied Biosystems to detect the expression of the housekeeping gene 18S in each sample, target gene expression is normalized with 18S gene expression derived from a bone marrow pool of normal healthy subjects and for each sample the ratio between the target and 18S are expressed. Results: Baseline values for 23 patients (mean age 73 ± 10 years) are available and 16 have been re-evaluated after 12 weeks. Mean Hb was 8.6 ± 0.9 g/dL and 20 patients were transfusion-dependent. Seven patients had additional cytogenetic abnormalities. At baseline, RPS14 was under-expressed in 19 out of 21 patients evaluated. After 12 weeks RPS14 was re-evaluated in 13 patients: all had erythroid responses and RPS14 increased significantly from 0.07 (IQ Range 0.03–0.13) to 76.1 (0.73– 304.0, p=0.002). SPARC expression was under-expressed in 15/23 patients and variations during treatment were not significant. Baseline FAS gene was under-expressed in all patients and increased above reference values (p=0,006) after 12 weeks in 7/14 cases. IL7R was over-expressed in all patients at baseline (median 3263.3, IQ range 1998.3–5027.1) and was significantly reduced after 12 weeks (median 0.17, IQ range 0.05–2.20, p 〈 0.0001). TINAGL1 gene expression was very high at baseline (mean 5214 ± 3661) and significantly reduced below normal values during treatment (0.63±0.87, p 〈 0.0001). WTI was over-expressed in almost all patients (median 3246, IQ range 1590–7785) and, though reduced during treatment, still remained highly over reference values at 12 weeks (p=0.148). The expression of the other genes did not vary significantly during treatment. Conclusions: A preliminary study evaluating short-term effects of lenalidomide in low and Int-1 IPSS risk MDS and del(5q) demonstrates that gene expression is abnormal and varies during treatment. RPS14 is down-expressed and a significant increase in its expression is observed during treatment with lenalidomide in responsive patients. There is also an increase in FAS expression; the protein encoded by FAS gene is a member of the TNF-receptor superfamily and its interaction with its ligand leads to apoptosis.The IL7R gene on chromosome 5 (5p13) codifies for the IL7 receptor, which blocks apoptosis during differentiation and activation of T lymphocytes. TINAGL1 gene on chromosome 1 codifies for a Cathepsin B-like protein implicated in a number of human diseases such as cancer. During lenalidomide treatment, the expression of IL7R and TINAGL1 are reduced. Further results and repeated testing during this trial may develop new insights in the pathogenesis of MDS with del(5q) and in long-term effects of lenalidomide on bone marrow changes. Disclosures: Oliva: Celgene: Consultancy. Balleari:Celgene: Consultancy. Finelli:Celgene: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.2622.2622

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7