Impact of the app-based and nurse-led supportive care program AKO@dom on dose intensity of oral-targeted therapies in patients with metastatic renal cell cancer: a multicentric observational retrospective study.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) remain a cornerstone of metastatic kidney cancer (mRCC). Adverse events (AEs) may lead to dose downregulation, and optimal management of AEs is needed to maintain an efficient dose intensity (DI). The aim of our study was to evaluate the impact of an app-based and nurse-led supportive-care program on DI in mRCC patients. METHOD: This multicenter (n = 3), retrospective study evaluated all consecutive mRCC patients who participated in the AKO@dom program, which consisted of an app-based and nurse-led weekly patient evaluation at home during the first 3 months of TKI intake. Treatment patterns and modifications were described, and the mean DI (mDI) was calculated at the end of AKO@dom. RESULTS: Eighty-nine patients were included: 12 had sunitinib, 18 pazopanib, 12 axitinib, and 47 cabozantinib. Median age was 69 years (60-76). TKIs were mainly initiated at standard doses except for cabozantinib (53% started at 40 mg/day); 71% had prior systemic treatment. Nine patients discontinued permanent treatment during the program. Thirty-two patients required ≥ 1 dose interruption, and 29% experienced ≥ 1 grade 3 AE of any type. The mDI (in mg/day) at 3 months was 34.4 ± 17.7 for sunitinib, 672.8 ± 144 for pazopanib, 8.6 ± 2.6 for axitinib, and 40 (36-48) for cabozantinib. Fifty-five patients [68.75% (95% CI: 57-78%)] had a mDI ≥ than reported in the literature. Overall survival at 12 months was 64.2% (CI 95%: 55-75%). CONCLUSION: The AKO@dom program allowed 68.75% of patients to maintain a high dose intensity after 3 months of TKI treatment. The impact on survival outcomes needs to be evaluated in randomized clinical trials.

Causal Attribution of Breast Cancer by Survivors in French West Indies.

Patients frequently ask about the cause of their breast cancer. To answer, physicians refer to breast cancer risk factors based on medical reports. We aim to assess these risk factors for the point of view of survivors, a point of view which seems to differ from that of medical references. We ran a survey with open- and closed-ended questionnaires on patients' opinions about risks factors both for women in general and for their own case. We also collected data on their sources of information on this subject. Most patients had no opinion. The most frequently cited risk factors were stress, then genetic causes, and poor diet. Internet was the leading source of information for patients, followed by physicians and magazines. Our study highlights the mismatch between breast cancer risk factors as perceived by scientists and by survivors. Survivors tend to focus on non-controllable risk factors. Taking into account attribution theories of life events, an awareness of patient opinion may be valuable for psychological support of survivors, and it may be informative to record the way in which patients attribute causality for life events such as breast cancer and, more generally, all type of cancer.

Combinatorial Effects of the Natural Products Arctigenin, Chlorogenic Acid, and Cinnamaldehyde Commit Oxidation Assassination on Breast Cancer Cells.

Major obstacles in current breast cancer treatment efficacy include the ability of breast cancer cells to develop resistance to chemotherapeutic drugs and the off-target cytotoxicity of these drugs on normal cells, leading to debilitating side effects. One major difference between cancer and normal cells is their metabolism, as cancer cells acquire glycolytic and mitochondrial metabolism alterations throughout tumorigenesis. In this study, we sought to exploit this metabolic difference by investigating alternative breast cancer treatment options based on the application of phytochemicals. Herein, we investigated three phytochemicals, namely cinnamaldehyde (CA), chlorogenic acid (CGA), and arctigenin (Arc), regarding their anti-breast-cancer properties. These phytochemicals were administered alone or in combination to MCF-7, MDA-MB-231, and HCC1419 breast cancer or normal MCF-10A and MCF-12F breast cells. Overall, our results indicated that the combination treatments showed stronger inhibitory effects on breast cancer cells versus single treatments. However, only treatments with CA (35 µM), CGA (250 µg/mL), and the combination of CA + CGA (35 µM + 250 µg/mL) showed no significant cytotoxic effects on normal mammary epithelial cells, suggesting that Arc was the driver of normal cell cytotoxicity in all other treatments. CA + CGA and, to a lesser extent, CGA alone effectively induced breast cancer cell death accompanied by decreases in mitochondrial membrane potential, increased mitochondrial superoxide, reduced mitochondrial and glycolytic ATP production, and led to significant changes in cellular and mitochondrial morphology. Altogether, the combination of CA + CGA was determined as the best anti-breast-cancer treatment strategy due to its strong anti-breast-cancer effects without strong adverse effects on normal mammary epithelial cells. This study provides evidence that targeting the mitochondria may be an effective anticancer treatment, and that using phytochemicals or combinations thereof offers new approaches in treating breast cancer that significantly reduce off-target effects on normal cells.

Sensitive Quantification of Cell-Free Tumor DNA for Early Detection of Recurrence in Colorectal Cancer.

The detection of plasma cell-free tumor DNA (ctDNA) is prognostic in colorectal cancer (CRC) and has potential for early prediction of disease recurrence. In clinical routine, ctDNA-based diagnostics are limited by the low concentration of ctDNA and error rates of standard next-generation sequencing (NGS) approaches. We evaluated the potential to increase the stability and yield of plasma cell-free DNA (cfDNA) for routine diagnostic purposes using different blood collection tubes and various manual or automated cfDNA extraction protocols. Sensitivity for low-level ctDNA was measured in KRAS-mutant cfDNA using an error-reduced NGS procedure. To test the applicability of rapid evaluation of ctDNA persistence in clinical routine, we prospectively analyzed postoperative samples of 67 CRC (stage II) patients. ctDNA detection was linear between 0.0045 and 45%, with high sensitivity (94%) and specificity (100%) for mutations at 0.1% VAF. The stability and yield of cfDNA were superior when using Streck BCT tubes and a protocol by Zymo Research. Sensitivity for ctDNA increased 1.5-fold by the integration of variant reads from triplicate PCRs and with PCR template concentration. In clinical samples, ctDNA persistence was found in ∼9% of samples, drawn 2 weeks after surgery. Moreover, in a retrospective analysis of 14 CRC patients with relapse during adjuvant therapy, we successfully detected ctDNA (median 0.38% VAF; range 0.18-5.04% VAF) in 92.85% of patients significantly prior (median 112 days) to imaging-based surveillance. Using optimized pre-analytical conditions, the detection of postoperative ctDNA is feasible with excellent sensitivity and allows the prediction of CRC recurrence in routine oncology testing.

True and false autobiographical memories in schizophrenia: preliminary results of a diary study.

The frequency of true and false autobiographical memories and associated states of conscious awareness, i.e., conscious recollection and simply knowing, as well as the respective roles of affective and cognitive processes in autobiographical memory construction, were assessed in eight patients with schizophrenia and eight control participants. A diary study methodology was used in combination with the Remember/Know procedure. The results showed a higher frequency of Know responses associated with the retrieval of both true and false memories in patients than in control participants. Whereas control participants rated higher at retrieval than at encoding the distinctiveness and personal importance of events, as well as the extent to which events furthered current personal plans, patients exhibited an opposite pattern of ratings, with ratings being lower at retrieval than at encoding. These preliminary results show a high frequency of simply knowing associated with the retrieval of true and false autobiographical memories in patients with schizophrenia and provide evidence for the interest of the diary study methodology for studying autobiographical memory in schizophrenia.

Trimethoprim-Loaded Microspheres Prepared from Low-Molecular-Weight PLGA as a Potential Drug Delivery System for the Treatment of Urinary Tract Infections.

Commonly, therapy of urinary tract infections suffers from increasing resistance to antibiotics and the ability of uropathogenic Escherichia coli (UPEC) to invade bladder cells and cause recurring infections. As an alternative strategy for instillation into the bladder, trimethoprim-loaded microparticles with poly(d,l-lactic-co-glycolic acid) (PLGA) as a matrix were prepared. To reduce particle loss by washout, their surface was grafted with bioadhesive wheat germ agglutinin, providing biomimicry akin to UPEC. Since PLGA 503H has shown a slow drug release profile, the low-molecular-weight PLGA 2300 was studied. Whereas the drug loading of PLGA 503H particles amounted to 2.8%, the drug content of PLGA 2300 particles was twice as high. Although the drug release pattern started with an initial burst of 30% after 24 h for both PLGA types, half of the trimethoprim content was released after 4 days from PLGA 503H microparticles as opposed to 2 days in the case of PLGA 2300. Higher drug loading and accelerated release render PLGA 2300 a viable alternative to PLGA 503H.

Multi-sample deformability cytometry of cancer cells.

There is growing recognition that cell deformability can play an important role in cancer metastasis and diagnostics. Advancement of methods to characterize cell deformability in a high throughput manner and the capacity to process numerous samples can impact cancer-related applications ranging from analysis of patient samples to discovery of anti-cancer compounds to screening of oncogenes. In this study, we report a microfluidic technique called multi-sample deformability cytometry (MS-DC) that allows simultaneous measurement of flow-induced deformation of cells in multiple samples at single-cell resolution using a combination of on-chip reservoirs, distributed pressure control, and data analysis system. Cells are introduced at rates of O(100) cells per second with a data processing speed of 10 min per sample. To validate MS-DC, we tested more than 50 cell-samples that include cancer cell lines with different metastatic potential and cells treated with several cytoskeletal-intervention drugs. Results from MS-DC show that (i) the cell deformability correlates with metastatic potential for both breast and prostate cancer cells but not with their molecular histotype, (ii) the strongly metastatic breast cancer cells have higher deformability than the weakly metastatic ones; however, the strongly metastatic prostate cancer cells have lower deformability than the weakly metastatic counterparts, and (iii) drug-induced disruption of the actin network, microtubule network, and actomyosin contractility increased cancer cell deformability, but stabilization of the cytoskeletal proteins does not alter deformability significantly. Our study demonstrates the capacity of MS-DC to mechanically phenotype tumor cells simultaneously in many samples for cancer research.

TERT Promoter Mutation Detection in Cell-Free Tumor-Derived DNA in Patients with IDH Wild-Type Glioblastomas: A Pilot Prospective Study.

Purpose: We conducted a pilot study to assess the feasibility and the potential implications of detecting TERT promoter (TERTp)-mutant cell-free tumor-derived DNA (tDNA) in the cerebrospinal fluid (CSF) and plasma of glioblastoma patients.Experimental Design: Matched CSF and plasma samples were collected in 60 patients with glial tumors. The CSF collection was obtained during surgery, before any surgical manipulation of the tumor. The extracted tDNA and corresponding tumor DNA samples were analyzed for TERTp and isocitrate dehydrogenase (IDH) hotspot mutations. In addition, the variant allele frequency (VAF) of TERTp mutation in the CSF-tDNA was correlated with tumor features and patients' outcome.Results: Thirty-eight patients had TERTp-mutant/IDH wild-type glioblastomas. The matched TERTp mutation in the CSF-tDNA was successfully detected with 100% specificity (95% CI, 87.6-100%) and 92.1% sensitivity (95% CI, 78.6-98.3%) (n = 35/38). In contrast, the sensitivity in the plasma-tDNA was far lower [n = 3/38, 7.9% (95% CI, 1.6-21.4%)]. We concordantly observed a longer overall survival of patients with low VAF in the CSF-tDNA when compared with patients with high VAF, irrespective of using the lower quartile VAF [11.45%; 14.0 mo. (95% confidence interval, CI, 10.3-17.6) vs. 8.6 mo. (95% CI, 4.1-13.2), P = 0.035], the lower third VAF [13%; 15.4 mo. (95% CI, 11.6-19.2) vs. 8.3 mo. (95% CI, 2.3-14.4), P = 0.008], or the median VAF [20.3%; 14.0 mo. (95% CI, 9.2-18.7) vs. 8.6 mo. (95% CI, 7.5-9.8), P = 0.062] to dichotomize the patients.Conclusions: This pilot study highlights the value of CSF-tDNA for an accurate and reliable detection of TERTp mutations. Furthermore, our findings suggest that high TERTp mutation VAF levels in the CSF-tDNA may represent a suitable predictor of poor survival in glioblastoma patients. Further studies are needed to complement the findings of our exploratory analysis. Clin Cancer Res; 24(21); 5282-91. ©2018 AACR.

Gray matter volume decreases in elderly patients with schizophrenia: a voxel-based morphometry study.

BACKGROUND: Aged patients (>50 years old) with residual schizophrenic symptoms differ from young patients. They represent a subpopulation with a more unfavorable Kraepelinian course and have an increased risk (up to 30%) for dementia of unknown origin. However, our current understanding of age-related brain changes in schizophrenia is derived from studies that included less than 17% of patients who were older than 50 years of age. This study investigated the anatomical distribution of gray matter (GM) brain deficits in aged patients with ongoing schizophrenia. METHODS: Voxel-based morphometry was applied to 3D-T1 magnetic resonance images obtained from 27 aged patients with schizophrenia (mean age of 60 years) and 40 age-matched normal controls. RESULTS: Older patients with schizophrenia showed a bilateral reduction of GM volume in the thalamus, the prefrontal cortex, and in a large posterior region centered on the occipito-temporo-parietal junction. Only the latter region showed accelerated GM volume loss with increasing age. None of these results could be accounted for by institutionalization, antipsychotic medication, or cognitive scores. CONCLUSIONS: This study replicated most common findings in patients with schizophrenia with regard to thalamic and frontal GM deficits. However, it uncovered an unexpected large region of GM atrophy in the posterior tertiary cortices. The latter observation may be specific to this aged and chronically symptomatic subpopulation, as atrophy in this region is rarely reported in younger patients and is accelerated with age.