Systemic therapy of colorectal cancer - consensus based on the results of clinical trials

Rak okrężnicy i odbytnicy jest istotnym problemem zdrowotnym w Polsce, a liczba nowych rozpoznań rocznie przekracza 13 000. Możliwości leczenia omawianych nowotworów w ostatniej dekadzie rozwinęły się w związku z zatwierdzeniem do stosowania wielu leków cytotoksycznych i ukierunkowanych molekularnie, a wykładnikiem postępu jest poprawa przeżycia chorych. Pomyślnym wynikiem zakończyły się randomizowane badania nowych leków cytotoksycznych (irynotekan, oksaliplatyna i doustne pochodne fluoropirymiynowe) w leczeniu uzupełniającym i paliatywnym. Nadzieję poszerzenia możliwości leczenia w chorobie uogólnionej stwarza wprowadzenie monoklonalnych przeciwciał (bewacyzumab, cetuksymab i panitumumab), jednak ich zastosowanie jest tymczasem ograniczone. Niezależnie od wymienionych osiągnięć środowisko onkologiczne nadal oczekuje odpowiedzi na wiele pytań dotyczących najlepszego wykorzystania nowych metod systemowego leczenia. W obecnym przeglądzie piśmiennictwa przedstawiono wartość dostępnych metod systemowego leczenia, co może ułatwić podejmowanie decyzji w klinicznej praktyce.Colorectal cancer represents a major health problem in Poland, accounting for over 13 000 new cases diagnosed annually. The treatment options in colorectal cancer have evolved significantly over the last decade, with several new cytotoxic and molecularly targeted agents approved for the treatment of this disease. These advances have brought a clear improvement in survival of patients. The efficacy of new cytotoxic drugs (irinotecan, oxaliplatin and oral fluoropyrimidines), both in the adjuvant and palliative settings, have been confirmed in the randomised studies. The advent of monoclonal antibodies (bevacizumab, cetuximab and panitumumab) may further broaden the scope of therapeutic methods in metastatic disease, however the clinical application of these compounds is still limited. Despite these achievements, the oncology community still awaits answers to numerous questions on the optimal use of newly developed systemic treatment options. This article reviews available options of systemic therapy with the aim of assisting clinicians in their daily practice

Blood Pressure and Intracranial Aneurysms in Autosomal Dominant Polycystic Kidney Disease

Background/Aims: Autosomal dominant polycystic kidney disease (ADPKD) is correlated with an increased frequency of both intracranial aneurysms (ICANs), and arterial hypertension (AH). The aim of our study was to search for the association between blood pressure (BP) and ICANs in ADPKD patients. Methods: Sixty-eight adult, pre-dialysis phase ADPKD patients underwent both screening for ICANs with magnetic resonance angiography of the brain, and ambulatory blood pressure monitoring (ABPM). Results: ICANs were diagnosed in 10 patients (ICAN(+) group), while in 58 were not (ICAN(-) group). The nighttime maximum diastolic blood pressure (DBP), maximum increase in DBP from measurement to measurement (positive delta of DBP) at night, and the standard deviation of the daytime mean arterial pressure were significantly higher in ICAN(+) compared to ICAN(-) patients. Additionally, in a subgroup of patients after 45 years-of-age, ICAN(+) patients had significantly higher maximum 24-hour and daytime systolic blood pressure, maximum 24-hour, daytime, nighttime DBP, maximum daytime and nighttime positive delta of DBP compared to ICAN(-) cases. Conclusions: Development of ICANs in hypertensive ADPKD patients is accompanied with higher values of some BP parameters measured by ABPM. Hypertensive ADPKD patients with substantial fluctuations in BP assessed by ABPM, especially those after 45 years-of-age, should become candidates for screening for ICANs

Targeted sequencing of cancer-related genes reveals a recurrent TOP2A variant which affects DNA binding and coincides with global transcriptional changes in glioblastoma

High-grade gliomas are aggressive, deadly primary brain tumors. Median survival of patients with glioblastoma (GBM, WHO grade 4) is 14 months and \u3c10% of patients survive 2 years. Despite improved surgical strategies and forceful radiotherapy and chemotherapy, the prognosis of GBM patients is poor and did not improve over decades. We performed targeted next-generation sequencing with a custom panel of 664 cancer- and epigenetics-related genes, and searched for somatic and germline variants in 180 gliomas of different WHO grades. Herein, we focus on 135 GBM IDH-wild type samples. In parallel, mRNA sequencing was accomplished to detect transcriptomic abnormalities. We present the genomic alterations in high-grade gliomas and the associated transcriptomic patterns. Computational analyses and biochemical assays showed the influence of TOP2A variants on enzyme activities. In 4/135 IDH-wild type GBMs we found a novel, recurrent mutation in the TOP2A gene encoding topoisomerase 2A (allele frequency [AF] = 0.03, 4/135 samples). Biochemical assays with recombinant, wild type (WT) and variant proteins demonstrated stronger DNA binding and relaxation activity of the variant protein. GBM patients carrying the altered TOP2A had shorter overall survival (median OS 150 vs 500 days, P = .0018). In the GBMs with the TOP2A variant we found transcriptomic alterations consistent with splicing dysregulation. luA novel, recurrent TOP2A mutation, which was found exclusively in four GBMs, results in the TOP2A E948Q variant with altered DNA binding and relaxation activities. The deleterious TOP2A mutation resulting in transcription deregulation in GBMs may contribute to disease pathology