Dynamics of circulating tumor DNA represented by the activating and resistant mutations in the EGFR-TKI treatment

Abstract

Circulating tumor DNA (ctDNA) is an emerging field of cancer research. For lung cancer, noninvasive genotyping of epidermal growth factor receptor (EGFR) is the foremost application. The activating mutations represent the ctDNA from all cancer cells, and the T790M-resistant mutation represents that from resistant cells. We examined the ctDNA dynamics of EGFR mutations by using deep sequencing with a massively parallel DNA sequencer. We obtained 190 plasma samples from 57 patients at various timings during the treatment course and classified them according to treatment status. The mutation detection rate of exon 19 deletion/L858R in plasma was high in the initiation of EGFR tyrosine kinase inhibitor (EGFR-TKI; p = 0.001), suppressed during the EGFR-TKI treatment before disease progression, and elevated after the onset of disease progression (p = 0.023). The mutation detection rate of T790M was low until the onset of disease progression and elevated thereafter (p = 0.01). Samples across the development of disease progression were obtained from 10 patients and exhibited a correlation between increased ctDNA level and disease progression. Decreased ctDNA level in response to the initiation of EGFR-TKI was observed in 4 of 6 eligible patients. In 2 patients, the ctDNA dynamics suggested the presence of cancer cell populations only with the T790M mutation. In another patient, the T790M ctDNA represented cell subpopulations that respond to cytotoxic agents differently from the major population. Considering the high incidence, ctDNA could be a clinical parameter to complement information of image analysis.

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Plasmafiltration as a possible contributor to kinetic targeting of pegylated liposomal doxorubicin (PLD) in order to prevent organ toxicity and immunosuppression

Abstract

Purpose

To examine the removal of pegylated liposomal doxorubicin (PLD) during plasmafiltration (PF) and determine whether the drug could be withheld prior to its organ distribution responsible for mucocutaneous toxicity.

Methods

Six patients suffering from platinum-resistant ovarian cancer were treated with a 1-h IV infusion 50 mg/m² of PLD/cycle—for three cycles q4w. Over 44 (46)–47(49) h postinfusion, five patients (14 cycles in total) underwent PF using a cascade PF method consisted of plasma separation by centrifugation and plasma treatment using filtration based one volume of plasma treatment, i.e., 3.18 L (±0.6 L) and plasma flow 1.0 L/h (0.91–1.48 L/h). Doxorubicin concentration in blood was monitored by a high-performance liquid chromatography method for 116 h postinfusion. Pharmacokinetic parameters determined from plasma concentration included volume of distribution, total body clearance, half-life of elimination, and area under the plasma concentration versus time. The amount of doxorubicin in the body eliminated by the patient and via extracorporeal treatment was evaluated. Toxicity was tested using CTCAE v4.0.

Results

The efficacy of PF and early responses to PLD/PF combination strategy were as follows: over 44(46) h postinfusion considered necessary for target distribution of PLD to tumor, patients eliminated 46 % (35–56 %) of the dose administered. Over 44(46)–47(49) h postinfusion, a single one-volume plasma filtration removed 40 % (22–45 %) (Mi5) of the remaining doxorubicin amount in the body. Total fraction eliminated attained 81 % (75–86 %). The most common treatment-related adverse events (grade 1–2) such as nausea (4/14 cycles—28 %) and vomiting (3/14 cycles—21 %) appeared during 44 h postinfusion. Hematological toxicity—anemia (5/14 cycles—35 %) was reported after cycle II termination. Symptoms of PPE-like syndrome (grade 1–2) appeared in one patient concomitantly with thrombophlebitis and malignant effusion. In this study, only one adverse reaction (1/14—7 %) as short-term malaise and nausea was reported by the investigator as probably related to PF.

Conclusion

A single one-volume PF does remove a clinically important amount of doxorubicin in a kinetic targeting approach. There were no serious signs of drug toxicity and/or PF-related adverse events. Kinetically guided therapy with pegylated liposomal doxorubicin combined with PF may be a useful tool to the higher efficacy and tolerability of therapy with PLD.

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Neuro-oncology family caregiving: review and directions for future research

CNS Oncology Ahead of Print.


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Suppression of vascular network formation by chronic hypoxia and prolyl-hydroxylase 2 (phd2) deficiency during vertebrate development

Abstract

In the adult, new vessels and red blood cells form in response to hypoxia. Here, the oxygen-sensing system (PHD–HIF) has recently been put into focus, since the prolyl-hydroxylase domain proteins (PHD) and hypoxia-inducible factors (HIF) are considered as potential therapeutic targets to treat ischemia, cancers or age-related macula degeneration. While the oxygen-sensing system (PHD–HIF) has been studied intensively in this respect, only little is known from developing vertebrate embryos since mutations within this pathway led to an early decease of embryos due to placental defects. During vertebrate embryogenesis, a progenitor cell called hemangioblast is assumed to give rise to blood cells and blood vessels in a process called hematopoiesis and vasculogenesis, respectively. Xenopus provides an ideal experimental system to address these processes in vivo, as its development does not depend on a functional placenta and thus allows analyzing the role of oxygen directly. To this end, we adopted a computer-controlled four-channel system, which allowed us to culture Xenopus embryos under defined oxygen concentrations. Our data show that the development of vascular structures and blood cells is strongly impaired under hypoxia, while general development is less compromised. Interestingly, suppression of Phd2 function using specific antisense morpholinos or a chemical inhibitor resulted in mostly overlapping vascular defects; nevertheless, blood cell was formed almost normally. Our results provide the first evidence that oxygen via Phd2 has a decisive influence on the formation of the vascular network during vertebrate embryogenesis. These findings may be considered in certain potential treatment concepts.

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A case for the use of receiver operating characteristic analysis of potential clinical efficacy biomarkers in advanced renal cell carcinoma

Future Oncology Ahead of Print.


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Effects of High Doses of Vitamin C on Cancer Patients in Singapore: Nine Cases

Introduction. Intravenous high-dose vitamin C therapy is widely used in naturopathic and integrative oncology; however, a study reviewing its effects has never been performed in Singapore. This article serves to document administration of supportive vitamin C therapy for cancer patients in Singapore. Methods. The clinical response of 9 cancer patients of differing stages to the regular administration of large doses (25-100 g/d) of intravenous vitamin C (IVC; ascorbic acid) is outlined. Tumor pathology and patient health were verified by doctors who do not practice vitamin C treatment. Results. Cases suggesting survival beyond prognosis, improvement in quality of life, safe coadministration with and improved tolerance of conventional therapy, and deterioration in clinical condition following withdrawal of vitamin C therapy are documented clinically. Some patients experience the Jarisch-Herxheimer reaction—the release of endotoxin from microorganism death resulting in pimples, fever, and body odor—for a few hours after the therapy, but these are resolved quickly with no lasting effects. Conclusion. Randomized trials of IVC therapy are recommended because it has minimal side effects and has shown promising results.

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Perceptions, Attributions, and Emotions Toward Endocrine Therapy in Young Women with Breast Cancer

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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