Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal.

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention

Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal.

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance

Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal.

Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

A study of patients with acute alcoholic hepatitis

A subset of patients with alcoholic liver disease will develop acute alcoholic hepatitis (AH) which has a substantially worse short term prognosis. In those patients decisions regarding treatment modalities are critically dependent on the ability to estimate a given patient's prognosis. The aim of the current study was to evaluate the prognostic utility of clinical and laboratory variables that could facilitate for the assessment of survival of patients with alcoholic hepatitis. 61 patients were enrolled in the current study, 48 (78.7%) men and 13 (21.3%) women with a median age of 50 years. Patients were followed for a median period of 41.8 months (February 2000-November 2008 range 0.2-91.37+, 95% CI, 25.6-57.9), and a total of 22 (36.1%) deaths were documented. Median survival was estimated to approximately 63.5 months (95% CI 19-108 range 0.2-91.37+). A statistical significant association with overall survival was documented for Maddrey (Hazard ratio (HR) 1.010 p=0.014) and Meld score (HR 1.067 p=0.032), PT (HR 1.129, p=0.000), aPTT (HR 1.036, p=0.000), INR (HR 3, p=0.000) SCOT (HR 1.002, p=0.036), SGPT (HR 1.003, p=0.007) and for C reactive protein (HR 1.015, p=0.043). For each of those variables cut off points were estimated that would designate groups of patients with statistically significant differences in survival rates. Accordingly patients with INR >2.3 had a median survival of 0.52 months against 63.5 months in the group of patients with INR 180 and SGPT >60 defined groups of patients with 2.9 (p=0.023) and 3.4 (p=0.003) hazard ratio, and a median survival of 17.8 months against 63.5 months of the group of patients with aminotransferase level below cut off points. Finally, fibrinogen levels 100 mg/dl defined groups of patients with 12.04 (p=0.000) and 6.29 (p=0.002) hazard ratio, and a median survival of only 1.3 and 0.59 months. When co-evaluated by multivariate logistic regression analysis CRP and fibrinogen were remained in the model. Coexistence of both aggravating factors deteriorated survival in only 0.52 months. In our study a correlation was demonstrated for traditional prognostic models and overall survival and also new prognostic factors were manifested, including aminotransferases, fibrinogen and c reactive protein that could reflect the underlying inflammation either of the hepatic parenchyma or the systemic and its significance the disease's prognosis.Η οξεία αλκοολική ηπατίτιδα αποτελεί μια δυνητικά θανατηφόρο έκφραση του συνδρόμου της αλκοολικής ηπατικής νόσου. Η αναγνώριση εκείνων των ασθενών με ευνοϊκή διαμόρφωση του πηλίκου θεραπευτικό όφελος/κίνδυνος συγκεντρώνουν το σύγχρονο κλινικό ενδιαφέρον. Σκοπός της παρούσας μελέτης ήταν η ανάδειξη ανεξάρτητων προγνωστικών παραγόντων μεταξύ των εργαστηριακών και κλινικών μεταβλητών που να σχετίζονται με την βραχυπρόθεσμη και μακροπρόθεσμη θνητότητα των ασθενών με οξεία αλκοολική ηπατίτιδα. Στην μελέτη εντάχθηκαν 61 ασθενείς με οξεία αλκοολική ηπατίτιδα, 48 (78.7%) άντρες και 13 (21.3%) γυναίκες, μέσης ηλικίας 50 έτη. Οι ασθενείς παρακολουθήθηκαν για διάμεσο χρονικό διάστημα 41.83 μηνών (Φεβρουάριος 2000-Νοεμβριος 2008: διακύμανση 0.2-91.37+, 95% όρια αξιοπιστίας, 25.6-57.9). Μέχρι την ολοκλήρωση της παρακολούθησης των ασθενών καταγράφηκαν 22 (36.1%) θάνατοι. Η επιβίωση υπολογίσθηκε στους 63.5 μήνες (95% όρια αξιοπιστίας 19-108 διακύμανση 0.2- 91.37+). Διαπιστώθηκε συσχέτιση με την συνολική επιβίωση για τους δείκτες Maddrey (Hazard ratio (HR) 1.010, p=0.014) και Meld (HR 1.067, p=0.032), για τους χρόνους πήξης ΡΤ (HR 1.129 p=0.000), aPTT (HR 1.036, p=0.000) και INR (HR 3, p=0. 000), για τις τρανσαμινάσες SGOT (HR 1.002 p=0.036) και SGPT (HR 1.003, p=0.007) και για την C αντιδρώσα πρωτεΐνη (HR 1015 p=0 043). Για καθεμία από τις παραπάνω μεταβλητές προσδιορίσθηκαν οι οριακές τιμές έτσι ώστε όταν ομαδοποιήθηκαν οι ασθενείς με βάση αυτές τις τιμές προέκυψαν ομάδες με στατιστικά σημαντική διάφορα στην επιβίωση. Έτσι οι ασθενείς με τιμή του INR >2.3 εμφάνιζαν μέση επιβίωση 0.52 μήνες έναντι 63.5 μήνες στην ομάδα των ασθενών με τιμή INR 180 και SGPT >60 προσδιόρισαν ομάδες ασθενών με 2.9 (p=0.023) και 3.4 (p=0. 003) φορές μεγαλύτερη πιθανότητα να πεθάνουν, αντιστοίχως, και μέση επιβίωση 17.8 μήνες έναντι 63.5 μήνες της ομάδας των ασθενών με μικρότερες τιμές τρανσαμινασών από τις οριακές. Τέλος, τιμές του ινωδογόνου 100 mg/dl διέκριναν τους ασθενείς εκείνους για τους οποίους η πιθανότητα θανάτου ήταν 12.04 (p=0.000) και 6.29 (p=0.002) φορές μεγαλύτερη και η μέση επιβίωση μόλις 1.3 μήνες και 0.59 μήνες, αντίστοιχα, έναντι της μέσης επιβίωσης των 63.5 μηνών των υπολοίπων ασθενών. Στο πολυπαραγοντικό στατιστικό μοντέλο διατηρήθηκαν τελικά η C αντιδρώσα πρωτεΐνη και το ινωδογόνο. Όταν συναξιολογήθηκε η αθροιστική συνύπαρξη αυτών των δύο παραγόντων η επιβίωση μειώνονταν σε μόλις 0.52 μήνες. Συνολικά, καινούριο εύρημα αποτέλεσε η συσχέτιση των παραδοσιακών δεικτών με την μακροπρόθεσμη επιβίωση, αλλά και η ανάδειξη νέων προγνωστικών παραμέτρων, όπως οι τρανσαμινάσες, το ινωδογόνο και η C αντιδρώσα πρωτεΐνη που εκφράζουν την σημασία της παρουσίας φλεγμονής είτε του ηπατικού παρεγχύματος είτε και την συστηματική, στην πρόγνωση της νόσου

Targeting Brain Metastases in Patients with Melanoma

Patients with brain metastases from malignant melanoma historically have a very poor outcome. Surgery and radiotherapy can be used, but for the majority of patients the disease will progress quickly. In the recent past, patients with brain metastases derived only minimal benefit from cytotoxic chemotherapy. Novel therapies that have been shown to be superior to chemotherapy in metastatic melanoma have made their way in clinic and data regarding their use in patients with treated or untreated brain metastases are encouraging. In this paper we describe the use of vemurafenib, dabrafenib, and ipilimumab in patients with melanoma disseminated to the brain in addition to other treatments currently in development

Novel Approaches for Concurrent Irradiation in Locally Advanced Cervical Cancer: Platinum Combinations, Non-Platinum-Containing Regimens, and Molecular Targeted Agents

Despite the available prevention and early detection strategies, squamous-cell carcinoma of the uterine cervix is still diagnosed as locally advanced disease in a considerable proportion of patients. As a potent sensitizer of cancer cells, cisplatin has been the “traditional partner” of external beam irradiation in this setting for more than two decades. Induction chemotherapy strategies followed by concurrent chemoradiation or surgery and preoperative concurrent chemoradiation have been recently implemented in clinical trials in an effort to optimize local control and to minimize the risk of distant metastases. In this context, cisplatin has been combined with a number of other potential radiosensitizers, including 5-fluorouracil, capecitabine, and gemcitabine. In patients resistant or intolerant to platinum compounds, numerous non-platinum-containing regimens have been developed, implementing various antimetabolites, taxanes, antineoplastic antibiotics, and topoisomerase II inhibitors. More recently, molecular agents targeting critical pathways in cervical malignant transformation are being assessed in early clinical trials in combination with external-beam irradiation. In the current work, we review the evolving role of cisplatin and other platinum compounds, either alone or in combination regimens, in the context of other potent radiosensitizers. The emerging role of molecular targeted agents, as candidate partners of external beam irradiation, is also discussed