Targeting p110gamma in gastrointestinal cancers: attack on multiple fronts

Phosphoinositide 3-kinases (PI3Ks) regulate several cellular functions that are critical for cancer progression and development, including cell survival, proliferation and migration. Three classes of PI3Ks exist with the class I PI3K encompassing four isoforms of the catalytic subunit known as p110α, p110β, p110γ, and p110δ. Although for many years attention has been mainly focused on p110α recent evidence supports the conclusion that p110β, p110γ, and p110δ can also have a role in cancer. Amongst these, accumulating evidence now indicates that p110γ is involved in several cellular processes associated with cancer and indeed this specific isoform has emerged as a novel important player in cancer progression. Studies from our laboratory have identified a specific overexpression of p110γ in human pancreatic ductal adenocarcinoma (PDAC) and in hepatocellular carcinoma (HCC) tissues compared to their normal counterparts.Our data have further established that selective inhibition of p110γ is able to block PDAC and HCC cell proliferation, strongly suggesting that pharmacological inhibition of this enzyme can directly affect growth of these tumors. Furthermore, increasing evidence suggests that p110γ plays also a key role in the interactions between cancer cells and tumor microenvironment and in particular in tumor-associated immune response. It has also been reported that p110γ can regulate invasion of myeloid cells into tumors and tumor angiogenesis. Finally p110γ has also been directly involved in regulation of cancer cell migration. Taken together these data indicate that p110γ plays multiple roles in regulation of several processes that are critical for tumor progression and metastasis. This review will discuss the role of p110γ in gastrointestinal tumor development and progression and how targeting this enzyme might represent a way to target very aggressive tumors such as pancreatic and liver cancer on multiple fronts

Factors predicting clinically significant fatigue in women following treatment for primary breast cancer

Cancer-related fatigue is common, complex, and distressing. It affects 70–100% of patients receiving chemotherapy and a significant number who have completed their treatments. We assessed a number of variables in women newly diagnosed with primary breast cancer (BrCa) to determine whether biological and/or functional measures are likely to be associated with the development of clinically significant fatigue (CSF). Two hundred twenty-three women participated in a study designed to document the impact of the diagnosis and treatment of primary breast cancer on function. Forty-four had complete data on all variables of interest at the time of confirmed diagnosis but prior to treatment (baseline) and ≥9 months post-diagnosis. Objective measures and descriptive variables included history, physical examination, limb volume, hemoglobin, white blood cell count, and glucose. Patient-reported outcomes included a verbal numerical rating of fatigue (0–10, a score of ≥4 was CSF), five subscales of the SF-36, Physical Activity Survey, and Sleep Questionnaire. At baseline, the entire cohort (n = 223) and the subset (n = 44) were not significantly different for demographic, biological, and self-reported data, except for younger age (p = 0.03) and ER+ (p = 0.01). Forty-five percent had body mass index (BMI) ≥ 25, 52% were post-menopause, and 52% received modified radical mastectomy, 39% lumpectomy, 52% chemotherapy, 68% radiation, and 86% hormonal therapy. Number of patients with CSF increased from 1 at baseline to 11 at ≥9 months of follow-up. CSF at ≥9 months significantly correlated with BMI ≥ 25, abnormal white blood cell count, and increase in limb volume and inversely correlated with vigorous activity and physical function (p < 0.05). Fatigue increases significantly following the treatment of BrCa. Predictors of CSF include high BMI and WBC count, increase in limb volume, and low level of physical activity. These are remediable

Design of a randomized controlled trial for multiple cancer risk behaviors among Spanish-speaking Mexican-origin smokers

Background: Smoking, poor diet, and physical inactivity account for as much as 60% of cancer risk. Latinos experience profound disparities in health behaviors, as well as the cancers associated with them. Currently, there is a dearth of controlled trials addressing these health behaviors among Latinos. Further, to the best of our knowledge, no studies address all three behaviors simultaneously, are culturally sensitive, and are guided by formative work with the target population. Latinos represent 14% of the U. S. population and are the fastest growing minority group in the country. Efforts to intervene on these important lifestyle factors among Latinos may accelerate the elimination of cancer-related health disparities

Evaluation of Therapeutic Response to Endocrine Therapy for Prostate Cancer by MRI Diffusion-weighted Imaging Based on PI-RADSv2.1

Objective To investigate the value of MRI diffusion-weighted imaging (DWI) technique in endocrine therapy for prostate cancer (PCa) based on PI-RADSv2.1. Methods A retrospective analysis of 57 patients with pathologically confirmed PCa was conducted. All patients underwent multi-parametric MRI (mpMRI) according to PI-RADS v2.1 technical specifications before biopsy and six months after endocrine therapy. The apparent diffusion coefficient (ADC) values were measured in cancer and non-cancer areas before biopsy and six months after endocrine therapy. Patients were grouped based on the mRECIST criteria and PSA level into responders (n=45) and non-responders (n=12). ROC curves were obtained to assess the correlation between changes in ADC values and PSA values before and after endocrine therapy. Results In the responder group, the ADC value of the cancer areas was increased significantly after endocrine therapy (P<0.001). No statistically significant difference of the ADC value of the cancer areas was found in the non-responder group before and six months after endocrine therapy (P=0.714). The ADC change of responders and non-responder groups were (0.411±0.178)×10-3 mm2/s and (-0.014±0.125)×10-3 mm2/s, respectively (P<0.001); the ADC ratio were (60.603±30.201)% and (-1.096±13.175)%, respectively (P<0.001). The cutoff value of the ADC change was 0.165 (AUC=0.974; sensitivity, 88.89%; specificity, 100.00%; PPV, 100.00%; NPV, 70.59%). The cutoff value of ADC ratio was 16.827% (AUC=0.980; sensitivity, 91.11%; specificity, 100.00%; PPV, 100.00%; NPV, 75.00%). The ADC values were negatively correlated with serum PSA before and after endocrine therapy. Conclusion The ADC change and ADC ratio may be facilitated to monitor the efficacy of endocrine therapy for PCa. The ADC values were negatively correlated with serum PSA

Effects of Echo Time on IVIM Quantification of the Normal Prostate

Abstract The two-compartment intravoxel incoherent motion (IVIM) theory assumes that the transverse relaxation time is the same in both compartments. However, blood and tissue have different T2 values, and echo time (TE) may thus have an effect on the quantitative parameters of IVIM. The purpose of this study was to investigate the effects of TE on IVIM-DWI-derived parameters of the prostate. In total, 17 healthy volunteers underwent two repeat examinations. IVIM-DWI data were scanned 6 times with variable TE values of 60, 70, 80, 90, 100, and 120 ms. The ADC of a mono-exponential model and the D, D*, and f parameters of the IVIM model were calculated separately for each TE. Repeat measures were assessed by calculating the coefficient of variation and Bland-Altman limits of agreement for each parameter. Spearman’s rho test was used to analyse relationships between IVIM indices and TE. Our results showed that TE had an effect on IVIM quantification, which should be kept constant in the examination protocol at each individual institution. Alternatively, an extended IVIM could be used to eliminate the effect of the TE value on the quantitative parameters of IVIM. This may be helpful for guiding clinical research, especially for longitudinal studies