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Most gastrointestinal (GI) cancers have microsatellite-stable (MSS) tumors, which have an immunologically 'cold' phenotype with fewer genetic mutations, reduced immune cell infiltration and downregulated immune checkpoint proteins. These attributes make MSS tumors resistant to conventional immunotherapy including checkpoint blockade therapy. Pelareorep is a naturally occurring, nongenetically modified reovirus. Upon intravenous administration, pelareorep selectively kills tumor cells and promotes several immunologic changes that prime tumors to respond to checkpoint blockade therapy. Given its demonstrated synergy with checkpoint blockade, as well as its encouraging efficacy in prior GI cancer studies, pelareorep plus atezolizumab will be evaluated in the GOBLET study in multiple GI cancer indications.
The GOBLET study is investigating a new drug combination for gastrointestinal tumors, specifically pancreatic, colorectal and anal cancers, which have already spread or might spread to the body. Currently, the standard treatment in most gastrointestinal tumors still consists of chemotherapy. Newer drugs (immune checkpoint inhibitors [ICIs]), which activate the body's natural defenses (immune system) and consequently increase the triggering of the immune system against tumor cells, have been developed and are commonly used as a single agent or in combination with chemotherapy. Yet, these are only effective in a small subset of patients. Certain drugs can also make tumors respond better to ICIs. One such drug being tested is pelareorep. Pelareorep is a safe virus that detects and kills only cancer cells and has shown promising results by increasing the activity of the patient's immune system toward the tumor in combination with ICIs in previous studies. The new drug combination (ICI plus virus) is used together with or without chemotherapy in this study. The aim of the GOBLET study is to investigate the safety of the new drug combination and assess improvements in tumor size related to treatment. Eudra-CT Number: 2020-003996-16.
Asunto(s)
Neoplasias Gastrointestinales , Virus Oncolíticos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/genética , Humanos , Virus Oncolíticos/genéticaRESUMEN
Purpose Adrenal incidentaloma (AI) and adrenal masses in cases of subclinical Cushing's syndrome (SCS) initially require follow-up imaging. In this study we used endoscopic ultrasound (EUS) as a method for high-resolution imaging. The aim was to evaluate the growth rate of AI and SCS by EUS. Materials and Methods This retrospective analysis included 93 out of 229 patients with AI or SCS who were investigated longitudinally by EUS in our university hospital between 1997 and 2013. The longitudinal follow-up required at least two investigations by EUS and evaluation of endocrine function. Plasma renin, serum aldosterone, 24âh urinary catecholamines and 2âmg dexamethasone suppression test were performed. EUS was performed at baseline and during follow-up.âEach time, the maximum diameter was measured. Three groups were defined: non-functioning adenomas (NFA), non-functioning nodular hyperplasias (NFH) and SCS. Results 86 patients had non-functioning masses [NFM] (59 NFA, 48 NFH) and 7 patients had SCS (10 masses). At baseline the mean diameter was 19.4 (±â9.3)âmm (NFM) and 19.6 (±â9.2)âmm (SCS). The mean follow-up period was 31.6â±â28.7 months. The estimated mean growth rates per year were low: They were 0.35âmm/yr [NFA], 0.02âmm/yr [NFH] and 0.53âmm/yr [SCS]. Furthermore, there was no malignant progression of any mass. Conclusion The growth rate as determined by EUS was low for all tumor entities observed in this study. There was no difference in tumor growth between the groups.
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Neoplasias de las Glándulas Suprarrenales , Síndrome de Cushing , Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Síndrome de Cushing/diagnóstico por imagen , Estudios de Seguimiento , Humanos , Estudios RetrospectivosRESUMEN
BACKGROUND: Zotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor thought to inhibit tumor growth via CDK-9-dependent depletion of survival proteins such as c-MYC and MCL-1 which are frequently overexpressed in glioblastoma. METHODS: EORTC 1608 (NCT03224104) (STEAM) had a three parallel group (A,B,C) phase Ib, open-label, non-randomized, multicenter design in IDH wild-type newly diagnosed glioblastoma or anaplastic astrocytoma. Groups A and B explored the maximum tolerated dose (MTD) of TG02 in elderly patients, in combination with hypofractionated radiotherapy alone (group A) or temozolomide alone (group B), according to O6-methylguanine DNA methyltransferase promoter methylation status determined centrally. Group C explored single agent activity of TG02 at first relapse after temozolomide chemoradiotherapy with a primary endpoint of progression-free survival at 6 months (PFS-6). Tumor expression of CDK-9, c-MYC and MCL-1 was determined by immunohistochemistry. RESULTS: The MTD was 150 mg twice weekly in combination with radiotherapy alone (group A) or temozolomide alone (group B). Two dose-limiting toxicities were observed at 150 mg: one in group A (grade 3 seizure), one in group B (multiple grade 1 events). Main toxicities included neutropenia, gastrointestinal disorders and hepatotoxicity. PFS-6 in group C was 6.7%. CDK-9, c-MYC and MCL-1 were confirmed to be expressed and their expression was moderately cross-correlated. High protein levels of MCL-1 were associated with inferior survival. CONCLUSIONS: TG02 exhibits overlapping toxicity with alkylating agents and low single agent clinical activity in recurrent glioblastoma. The role of CDK-9 and its down-stream effectors as prognostic factors and therapeutic targets in glioblastoma warrants further study.
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Neoplasias Encefálicas , Glioblastoma , Compuestos Heterocíclicos de 4 o más Anillos , Humanos , Anciano , Glioblastoma/tratamiento farmacológico , Glioblastoma/radioterapia , Temozolomida/uso terapéutico , Dacarbazina/uso terapéutico , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inhibidores Enzimáticos , Antineoplásicos Alquilantes/uso terapéuticoRESUMEN
AIM: Multidisciplinary management of metastatic colorectal liver metastases (CRLM) is still challenging. To assess postoperative complications in initially unresectable or borderline resectable CRLM, the prospective EORTC-1409 ESSO 01-CLIMB trial capturing 'real-life data' of European centres specialized in liver surgery was initiated. MATERIAL AND METHODS: A total of 219 patients were registered between May 2015 and January 2019 from 15 centres in nine countries. Eligible patients had borderline or initially unresectable CRLM assessed by pre-operative multidisciplinary team discussion (MDT). Primary endpoints were postoperative complications, 30-day and 90-days mortality post-surgery, and quality indicators. We report the final results of the 151 eligible patients that underwent at least one liver surgery. RESULTS: Perioperative chemotherapy with or without targeted treatment were administered in 100 patients (69.4%). One stage resection (OSR) was performed in 119 patients (78.8%). Two stage resections (TSR, incl. Associating Liver Partition and Portal Vein Ligation for Staged hepatectomy (ALPPS)) were completed in 24 out of 32 patients (75%). Postoperative complications were reported in 55.5% (95% CI: 46.1-64.6%), 64.0% (95% CI: 42.5-82%), and 100% (95% CI: 59-100%) of the patients in OSR, TSR and ALPPS, respectively. Post-hepatectomy liver failure occurred in 6.7%, 20.0%, and 28.6% in OSR, TSR, and ALPPS, respectively. In total, four patients (2.6%) died after surgery. CONCLUSION: Across nine countries, OSR was more often performed than TSR and tended to result in less postoperative complications. Despite many efforts to register patients across Europe, it is still challenging to set up a prospective CRLM database.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Resultado del Tratamiento , Estudios Prospectivos , Neoplasias Colorrectales/patología , Neoplasias Hepáticas/secundario , Hepatectomía/métodos , Ligadura , Complicaciones Posoperatorias/etiología , Vena Porta/cirugía , Hígado/patologíaRESUMEN
Adjuvant chemotherapy for colon cancer (UICC stage II and III) has been under investigation over the last 30 years, regarding treatment duration and regimens. In this review, choice of regimen, its duration, possible limitations and future perspectives are discussed. Monotherapy with 5-fluorouracil was followed by addition of oxaliplatin, resulting in improved 3-yr disease free survival (DFS) and overall survival (OS) rates, but also increased peripheral sensory neurotoxicity (PSN). The International Duration Evaluation of Adjuvant therapy (IDEA) collaboration demonstrated less toxicity, especially PSN, when shortening treatment duration to 3 months. However, formally, the anticipated non-inferiority of 3 months with fluoropyrimidine (FP)/oxaliplatin over 6 months (at 3-yr DFS) was not met for all patients groups, although subgroup analyses showed non-inferiority with capecitabine/oxaliplatin (CAPOX) rather than with FOLFOX, and also in relation to the prognostic information (e.g., clinical low-risk group, pT1-3 N0). In addition, first data of newer parameters like Immunoscore® and ctDNA show promising results as stratification parameters. Further investigations to better define clinical risk groups and prognostic factors are mandatory. Besides this, individual decision-making of treatment intensity (FP or FP/oxaliplatin) and duration should always consider patient characteristics and preferences, also given the absolute relatively small differences and their clinical relevance.
RESUMEN
PURPOSE: This study was aimed to investigate the role and relevance of endoscopic ultrasound-guided fine-needle aspiration biopsy in the diagnostic work-up of insulinomas. METHODS: We have analysed the frequency, clinical indications, success rate (obtaining diagnostic tissue), diagnostic accuracy (in comparison to the pathological diagnosis after surgery), complications, and tolerability of endoscopic ultrasound-guided fine-needle aspiration biopsy and the localization and size of the lesions in 47 consecutive patients (29 females, 18 males; 46 ± 15 years) who had surgery for insulinoma following fasting test and were explored by single investigator EUS 1994-2015. RESULTS: Endoscopic ultrasound-guided fine-needle aspiration biopsy was performed in 21 % (10/47) of the patients. The clinical indications for endoscopic ultrasound-guided fine-needle aspiration biopsy were non-conclusive result of fasting test (n = 7), missing toxicology (n = 2), suspected malignancy at EUS (n = 1), suspicious extra-pancreatic localization of the lesion (n = 1). The diagnostic success rate of the procedure was 80 % (8/10 cases), the diagnostic accuracy of the fine-needle aspiration biopsy 70 % (7/10 cases). The lesions undergoing endoscopic ultrasound-guided fine-needle aspiration biopsy were localized in the cauda (n = 5), corpus (n = 2), caput/processus uncinatus (n = 3), the diameter of the tumors was 21 ± 18 (10-70) mm. Only one accidental vascular puncture without any clinical complication occurred and all patients tolerated the procedure well. CONCLUSIONS: In the majority of cases, positive fasting test, negative toxicology, and detection of a typical pancreatic lesion at endoscopic ultrasound is sufficient for the diagnosis of insulinoma and the definition of the appropriate surgical strategy. Based on our data, we suggest including endoscopic ultrasound-guided fine-needle aspiration biopsy in the diagnostic work-up of organic hyperinsulinism in selected patients with inconclusive or uncertain diagnosis before surgery.