Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies

Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies

Analysis of incidence and clinical outcomes in patients with thromboembolic events and invasive exocrine pancreatic cancer

BACKGROUND: Pancreatic adenocarcinoma is among the most common malignancies associated with thromboembolic events (TEs); however, reported incidence figures vary significantly and contain small patient cohorts. Pancreatic cancer-specific thrombosis studies examining the correlation between clinical variables, including thrombosis timing and the impact of thrombosis on survival, have not been reported. METHODS: Survival analyses were performed relating to the development and timing of a TE in 1915 patients administered chemotherapy at Memorial Sloan-Kettering Cancer Center with invasive exocrine pancreatic cancer from January 1, 2000 to December 31, 2009. TE timing, relative to clinical parameters including laboratory data, erythropoietin-stimulating agent use, and body mass index (BMI), were also analyzed. RESULTS: A thrombosis was identified in 690 (36%) patients. After adjusting for patients with pancreatic surgery and thrombosis (n = 127), developing a TE significantly increased the risk of death (hazard ratio [HR], 2.6; 95% confidence interval [CI], 2.3-2.8; P < .01). Patients with an early TE (within 1.5 months from pancreatic cancer diagnosis) had a significantly higher risk of death (HR, 2.1; 95% CI, 1.7-2.5; P < .01) compared with patients with late TE or no TE. Erythropoietin-stimulating agent use and an elevated international normalized ratio were associated with significantly shorter time to thrombosis. Low BMI was associated with significantly longer time to thrombosis. CONCLUSIONS: TEs are common in exocrine pancreatic cancer, with coagulopathy, erythropoietin-stimulating agent use, and underweight BMI influencing thrombosis timing. TEs, particularly early ones, confer a significantly worse prognosis, suggesting a biological significance, underscoring the relevance of ongoing prophylaxis trials, and raising the question of whether early TEs should be considered a stratification factor for clinical trials. Cancer 2012;118: 305361.(C) 2011 American Cancer Society

Potassium loss and cellular dehydration of stored erythrocytes following incubation in autologous plasma: role of the KCl cotransport system

We studied the regulation of cell volume and cation content in erythrocytes stored at 4 degrees C under blood bank conditions for various lengths of time and subsequently incubated in autologous plasma at 37 degrees C for 4 or 24 h. Cell swelled during storage at 4 degrees C whereas marked K+ loss and cell shrinkage were observed when erythrocytes were incubated at 37 degrees C in autologous plasma. The cell shrinkage was inhibited only by the K+ Cl- cotransport-specific inhibitor, [(dihydroindenyl)oxy] alkanoic acid, and not by other specific inhibitors of cation transport systems such as ouabain (Na(+)-K+ ATPase pump), bumetanide (Na(+)-K(+)-Cl- cotransport) or carbocyanine (Ca+(+)-activated K+ channel). Acidification and swelling of the erythrocytes are well known to be able to activate the K+ Cl cotransport; such conditions, which were demonstrated to occur during the storage, could lead to activation of the K+ Cl- cotransport in reinfused cells. These data strongly support the evidence that K+ Cl- cotransport plays a role in K+ loss and dehydration of stored erythrocytes, when incubated in autologous plasma