O presente artigo tem como objetivo discutir a aplicabilidade dos royalties de Itaipu, observando seus aspectos quantitativos e qualitativos no campo educacional. A assinatura do Tratado de Itaipu, ...em 1973, ocorreu mediante tensões políticas a partir dos interesses geopolíticos, no contexto da Guerra Fria em face do modelo nacional-desenvolvimentista durante a Ditadura Civil-Militar (1964-1985), no contexto da expansão do capitalismo. Para a formação do reservatório foi preciso inundar uma grande área dos municípios chamados lindeiros ao lago de Itaipu, estando Santa Helena e Itaipulândia entre os maiores atingidos, vindo a perder uma grande parte de suas áreas produtivas, por isso, esses são os maiores recebedores das parcelas dos royalties. Diante disso, procuramos fazer uma análise dos investimentos realizados na educação destes municípios, por parte dos gestores. Os repasses efetuados pela usina criaram possibilidades, expectativas e perspectivas de ampliação e melhorias das escolas. Os repasses financeiros efetuados pela usina de Itaipu permitiram novas possibilidades de ampliação e melhorias para as escolas públicas na região oeste do Paraná.O presente artigo tem como objetivo discutir a aplicabilidade dos royalties de Itaipu, observando seus aspectos quantitativos e qualitativos no campo educacional. A assinatura do Tratado de Itaipu, em 1973, ocorreu mediante tensões políticas a partir dos interesses geopolíticos, no contexto da Guerra Fria em face do modelo nacional-desenvolvimentista durante a Ditadura Civil-Militar (1964-1985), no contexto da expansão do capitalismo. Para a formação do reservatório foi preciso inundar uma grande área dos municípios chamados lindeiros ao lago de Itaipu, estando Santa Helena e Itaipulândia entre os maiores atingidos, vindo a perder uma grande parte de suas áreas produtivas, por isso, esses são os maiores recebedores das parcelas dos royalties. Diante disso, procuramos fazer uma análise dos investimentos realizados na educação destes municípios, por parte dos gestores. Os repasses efetuados pela usina criaram possibilidades, expectativas e perspectivas de ampliação e melhorias das escolas. Os repasses financeiros efetuados pela usina de Itaipu permitiram novas possibilidades de ampliação e melhorias para as escolas públicas na região oeste do Paraná.
For patients with locally advanced rectal cancer (LARC) neoadjuvant chemoradiotherapy is recommended as standard therapy. So far, no predictive or prognostic molecular factors for patients undergoing ...multimodal treatment are established. Increased angiogenesis and altered tumour metabolism as adaption to hypoxic conditions in cancers play an important role in tumour progression and metastasis. Enhanced expression of Vascular-endothelial-growth-factor-receptor (VEGF-R) and Transketolase-like-1 (TKTL1) are related to hypoxic conditions in tumours. In search for potential prognostic molecular markers we investigated the expression of VEGFR-1, VEGFR-2 and TKTL1 in patients with LARC treated with neoadjuvant chemoradiotherapy and cetuximab.
Tumour and corresponding normal tissue from pre-therapeutic biopsies of 33 patients (m: 23, f: 10; median age: 61 years) with LARC treated in phase-I and II trials with neoadjuvant chemoradiotherapy (cetuximab, irinotecan, capecitabine in combination with radiotherapy) were analysed by quantitative PCR.
Significantly higher expression of VEGFR-1/2 was found in tumour tissue in pre-treatment biopsies as well as in resected specimen after neoadjuvant chemoradiotherapy compared to corresponding normal tissue. High TKTL1 expression significantly correlated with disease free survival. None of the markers had influence on early response parameters such as tumour regression grading. There was no correlation of gene expression between the investigated markers.
High TKTL-1 expression correlates with poor prognosis in terms of 3 year disease-free survival in patients with LARC treated with intensified neoadjuvant chemoradiotherapy and may therefore serve as a molecular prognostic marker which should be further evaluated in randomised clinical trials.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background. No predictive or prognostic biomarker is available for patients with locally advanced rectal cancer (LARC) undergoing perioperative chemoradiotherapy (CRT). Members of the human epidermal ...growth factor receptor (HER) family of receptor tyrosine kinases EGFR (HER1, ERBB1), HER2 (ERBB2), HER3 (ERBB3), and HER4 (ERBB4) are therapeutic targets in several cancers. The analysis was performed to assess expression levels and study the potential prognostic impact for disease-free and overall survival in patients with LARC. Patients and Methods. ERBB1–4 mRNA expression and tumor proliferation using Ki-67 (MKI67) mRNA were evaluated using RT-quantitative PCR in paraffin-embedded tumor samples from 86 patients (median age: 63) treated with capecitabine or 5-fluorouracil-based CRT within a phase 3 clinical trial. Results. A positive correlation of HER4 and HER2, HER3 and HER2, and HER4 and HER3 with each other was observed. Patients with high mRNA expression of ERBB1 (EGFR, HER1) had significantly increased risk for recurrence and death. Patients with high mRNA expression of MKI67 had reduced risk for relapse. Conclusion. This analysis suggests a prognostic impact of both ERBB1 and MKi67 mRNA expression in LARC patients treated with capecitabine or fluorouracil-based chemoradiotherapy.
Although acquired mutations in KIT are commonly detected in various categories of mastocytosis, the methodologies applied to detect and quantify the mutant type and allele burden in various cells and ...tissues are poorly defined. We here propose a consensus on methodologies used to detect KIT mutations in patients with mastocytosis at diagnosis and during follow-up with sufficient precision and sensitivity in daily practice. In addition, we provide recommendations for sampling and storage of diagnostic material as well as a robust diagnostic algorithm. Using highly sensitive assays, KIT D816V can be detected in peripheral blood leukocytes from most patients with systemic mastocytosis (SM) that is a major step forward in screening and SM diagnosis. In addition, the KIT D816V allele burden can be followed quantitatively during the natural course or during therapy. Our recommendations should greatly facilitate diagnostic and follow-up investigations in SM in daily practice as well as in clinical trials. In addition, the new tools and algorithms proposed should lead to a more effective screen, early diagnosis of SM and help to avoid unnecessary referrals.
Introduction: Diagnostic criteria of idiopathic hypereosinophilic syndrome (iHES) comprise persisting reactive/non-clonal eosinophilia ≥1.5 G/l and associated organ infiltration/dysfunction. The ...pattern and extent of organ involvement is most relevant for symptoms, quality of life, complications, response to treatment and prognosis. Of note, the potentially life-threatening cardiac involvement (CI) is frequently underrecognized. Patients and Methods: Based on the ´German Registry on Disorders of Eosinophils and Mast Cells (GREM)', we sought to investigate CI in 62 patients (pts) with iHES and predominantly multifocal organ involvement (sinus n=26, lungs n=36, including asthma, n=23, abdominal organs n=15, skin n=15 and lymph nodes n=9) by cardiac magnetic resonance imaging (MRI, 62/62 pts), echocardiography (30/62 pts), myocardial biopsy (10/62 pts) and the cardiac biomarkers troponin I (TNI, 49/62 pts) and N-terminal prohormone B-type natriuretic peptide (NT-proBNP, 38/62 pts). Clonal eosinophilia, e.g. FIP1L1::PDGFRA, alternative tyrosine kinase fusion genes and point mutations, e.g. KIT D816V, was excluded by the combination of cytogenetic/molecular analyses, bone marrow histology and immunohistochemistry. Myeloid peroxidase (MPO)-ANCA antibodies as characteristic marker of eosinophilic granulomatosis with polyangiitis (EGPA) were absent in all 62/62 (100%) pts and no evaluable patient had histologic evidence of vasculitis. Results: Cardiac MRI was pathologic in 34/62 (55%) pts with overlapping presence of late gadolinium enhancement (LGE, 31/34, 91%), pericardial effusion (11/34, 32%), involvement of heart valves/conduction system (9/34, 26%), impaired left-ventricular ejection fraction (LVEF <50%, 9/34, 26%) and presence of intracavitary thrombus (6/34, 18%). Concomitant echocardiography revealed pathological findings only in 10/24 (42%) pts with a pathologic MRI. Myocardial biopsy unveiled fibrosis (4/10, 40%) or eosinophilic infiltration (2/10, 20%) but was also non-informative (4/10, 40%). CI was rather associated with involvement of lungs (24/34, 71%) and sinus (23/34, 68%) than of abdominal organs (8/34, 24%) and skin (5/34, 15%). The combination of CI and asthma, potentially suggestive of ANCA-negative EGPA, was observed in 16/34 (47%) pts, but an indistinguishable pattern of multifocal organ involvement was also present in 18/34 (53%) pts with CI and absence of asthma. All 10/49 (20%) pts with an elevated vs. 0/49 (0%) pts with a normal troponin I (<0.045µg/l) and 20/38 (53%) pts with an elevated vs. 7/38 (18%) pts with a normal NT-proBNP (<125ng/l) revealed a pathologic cardiac MRI (Table). During a median follow-up of 108 months (range 3-470), the occurrence of cardiac events (n=15; death, n=3; cerebral embolism, n=4; worsening of LVEF, n=2; arrhythmias, n=2; valve surgery, n=2; pericardial effusion, n=1; coronary artery aneurysm, n=1) was strongly associated with a pathologic cardiac MRI in 15/15 (100%) pts (prior to MRI, n=6; after MRI, n=9) and an elevated troponin I and/or elevated NT-proBNP in 14/15 (93%) or 12/15 (80%) pts, respectively. During a median follow-up of 7.6 years (range 0.3-29.2), glucocorticoid-based immunosuppressive treatment resulted in improved MRI findings in 9/20 (45%) pts (improved LGE, n=7; regression of thrombus, n=1; improved LVEF, n=1) and a median NT-proBNP decrease of 48%. In pts with a pathologic MRI and elevated biomarkers, 9/13 (69%) and 5/19 (26%) pts, respectively, had a normalization of troponin I or NT-proBNP. Conclusions: In pts with iHES, i) the incidence of CI is high, particularly in pts with multifocal organ involvement, ii) it is questionable whether absence or presence of asthma in pts with multiple organ involvement is qualified for the challenging differentiation between iHES and ANCA-negative EGPA, iii) CI should be assessed by troponin I/NT-proBNP and cardiac MRI as they are superior to echocardiography, iv) the combination of elevated troponin I and to a lesser extent also elevated NT-proBNP with a pathologic cardiac MRI is associated with retrospective and subsequent, potentially life threatening cardiac events, and v) cardiac biomarkers and cardiac MRI are useful for monitoring response to treatment.
Introduction: Advanced systemic mastocytosis (AdvSM) is characterized by presence of the KIT D816V mutation and variably other somatic mutations in the mast cell but also non-mast cell lineages, e.g. ...monocytes or eosinophils, in ≥80-90% of patients. Midostaurin is an approved multikinase/KIT inhibitor for treatment of AdvSM. The intricate landscape in assessment of response, resistance or progression, the occurrence of adverse events with its impact on dose modification and the recent approval of the specific KIT D816V inhibitor avapritinib contribute to complex decision-making. We here sought to characterize the most valuable baseline and on-treatment parameters for prediction of response and survival in midostaurin-treated patients with AdvSM. Methods: On basis of the ´German Registry on Disorders of Eosinophils and Mast Cells' (GREM), this retrospective-prospective analysis included 79 patients with AdvSM. Treatment was initiated between 2009 and 2022 accumulating into a 239 patient-years overall follow-up period. In addition to common serological, morphological, and molecular response parameters, we specifically examined the recurrent observation of an early flare-up in alkaline phosphatase (AP) levels, which was defined as a ≥25% AP increase within three months after treatment initiation, followed by a subsequent decline below baseline within six months. Results: Midostaurin was used in first-line (1L) or second and further lines (2L+; median 1 prior treatment line, range 0-4) in 63 (80%) and 16 (20%) patients, respectively. In 1L/2L+, median overall survival (OS) was 2.6/2.4 years. At baseline, the presence of additional somatic mutations in SRSF2 (n=36, 46%, HR 2.0 1.2-3.6, P=0.014), ASXL1 (n=15, 19%, HR 2.0 1.0-3.9, P=0.043), and EZH2 (n=6, 8%, HR 4.3 1.7-11.3, P=0.003) significantly stratified patients according to their hazard ratio-weighted risk (median OS, 5.8 vs. 2.9 vs. 1.0 years; P<0.001). In 25 evaluable patients, the variant allele frequency in 72 additional somatic mutations remained stable (mean change 8%, absolute change >5% in 16/72 (22%) mutations). New mutations were identified in 9/25 (36%) patients during follow-up (Figure). Durable responses (complete, partial, clinical improvement) according to modified Valent criteria, IWG-MRT-ECNM criteria or Pure Pathological Response (PPR) criteria over a median duration between 12 and 24 months were achieved in 60%, 29% and 13% of patients, respectively. Within the first 12 months, duration of response was associated with an OS benefit ( P<0.001). An AP flare-up was observed in 22/79 (28%) patients, was paralleled by contemporaneous decrease of serum tryptase (median -35%, range -82 - 191%) and resulted into improved OS (median 5.8 vs. 2.2 years, P=0.007). Multivariable analysis identified the AP flare-up ( P=0.029), a ≥25% reduction of bone marrow (BM) mast cell (MC) infiltration ( P=0.046) and a ≥25% reduction of the KIT D816V expressed allele burden (EAB; P=0.034) at any time within the first 6 months as independent markers for improved OS (Table). Dynamic risk assessment of the independent parameters during follow-up allowed to abrogate a negative baseline risk-categorization. The initial dose was 200 mg/d (100 mg BID, including patients with a prespecified rapid dose escalation), 150 mg/d or 100 mg/d in 63/79 (80%), 2/79 (3%) and 14/79 (18%) patients, respectively. In the combined 150 mg and 100 mg cohorts, a dose increase to 200 mg/day was achieved in 9/16 (56%) patients. The 200 mg could be maintained at month 3, 6, 12, 24, and 36 in 50/63 (79%), 30/48 (63%), 23/34 (68%), 15/22 (68%) and 9/9 (100%) patients, respectively. Overall, 96 adverse events (AE) led to dose-adjustment (including temporary or permanent discontinuation). Hematologic and nonhematologic toxicities accounted for 24 (25%) and 36 (38%) of AEs with neutropenia (n=8, 8%) and nausea/emesis (n=22, 22%) being the most common AEs leading to dose-adjustment. Of note, the various dose levels had no impact on response or survival. Conclusions: Baseline mutations in SRSF2, ASXL1 and EZH2 conferred resistance to midostaurin. The various dose levels had no impact on response or survival. The on-treatment parameters AP flare-up, and a ≥25% reduction of BM MC infiltration and of KIT D816V EAB abrogated a negative baseline risk-categorization. No new safety signals occurred.
Zusammenfassung
Hintergrund
Die systemische Mastozytose (SM) ist eine klonale Stammzellerkrankung mit heterogenem klinischem Erscheinungsbild und Prognose.
Ziel
Im vorliegenden Artikel werden ...Diagnostik, Prognosemodelle und Therapieoptionen bei der SM erörtert.
Material und Methoden
Es handelt sich um eine selektive Literaturrecherche und Auswertungen des eigenen Patientenkollektivs.
Ergebnisse
Während Patienten mit einer indolenten Verlaufsform eine normale Lebenserwartung haben, ist das Überleben bei Patienten mit fortgeschrittener Erkrankung (AdvSM) oft eingeschränkt. Blutbild- und Leberwertveränderungen finden sich insbesondere bei der AdvSM, eine Erhöhung der Serumtryptase ist i. d. R. in allen Verlaufsformen zu beobachten, was sich auch in den Diagnosekriterien widerspiegelt. Klinische Symptome treten unabhängig von der Krankheitsschwere in allen Subentitäten auf, sodass eine symptomatische Therapie (u. a. Antihistaminika, Mastzellstabilisatoren, Cortison) je nach der Klinik bei der indolenten SM und bei der AdvSM Anwendung findet. Demgegenüber ist der Einsatz von KIT-Inhibitoren (Nachweis einer
KIT
-Mutation, v. a.
KIT
D816V in > 90 %) i. d. R. Patienten mit AdvSM vorbehalten. Der Multikinaseinhibitor Midostaurin und der spezifische KIT-Inhibitor Avapritinib (ab der Zweitlinie) verbessern hier die mastzellbedingte Organdysfunktion.
Schlussfolgerung
Die variable Klinik macht Diagnostik und Therapie der SM zu einer Herausforderung, eine interdisziplinäre Beurteilung je nach führender Symptomatik ist daher erforderlich. Die KIT-Inhibitortherapie hat zu einer signifikanten Verbesserung der Prognose von AdvSM-Patienten geführt, einzig kurative Therapie bleibt jedoch weiterhin die allogene Stammzelltransplantation in bestmöglicher Remission.
In advanced systemic mastocytosis (advSM), disease evolution is often triggered by KIT mutations (D816V in >80% of cases) and by additional mutations (eg, in SRSF2, ASXL1, and/or RUNX1 S/A/Rpos in ...>60% of cases). In a recently reported phase 2 study, midostaurin, a multikinase/KIT inhibitor, demonstrated an overall response rate (ORR) of 60% in advSM but biomarkers predictive of response are lacking. We evaluated the impact of molecular markers at baseline and during follow-up in 38 midostaurin-treated advSM patients. The median overall survival (OS) was 30 months (95% confidence interval, 6-54) from start of midostaurin. ORR and OS were significantly different between S/A/Rneg (n = 12) and S/A/Rpos (n = 23) patients (ORR: 75% vs 39%, P = .04; OS: P = .01, HR 4.5 1.3-16.2). Depending on the relative reduction of the KIT D816V expressed allele burden (EAB) at month 6, patients were classified as KIT responders (≥25%, n = 17) or KIT nonresponders (<25%, n = 11). In univariate analyses at month 6, reduction of KIT D816V EAB ≥25%, tryptase ≥50%, and alkaline phosphatase ≥50% were significantly associated with improved OS. In multivariate analysis, only KIT D816V EAB reduction ≥25% remained an independent on-treatment marker for improved OS (P = .004, HR 6.8 1.8-25.3). Serial next-generation sequencing analysis of 28 genes in 16 patients revealed acquisition of additional mutations or increasing variant allele frequency in K/NRAS, RUNX1, IDH2, or NPM1 associated with progression in 7 patients. In midostaurin-treated advSM patients, the complexity and dynamics of mutational profiles significantly affect response, progression, and prognosis.
•The complexity and dynamics of mutations significantly impact on response, progression, and prognosis in midostaurin-treated advSM patients.
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