Objectives
To evaluate the correlation between simple planimetric measurements in axial computed tomography (CT) slices and measurements of patient body composition and anthropometric data performed ...with bioelectrical impedance analysis (BIA) and metric clinical assessments.
Methods
In this prospective cross-sectional study, we analyzed data of a cohort of 62 consecutive, untreated adult patients with advanced malignant melanoma who underwent concurrent BIA assessments at their radiologic baseline staging by CT between July 2016 and October 2017. To assess muscle and adipose tissue mass, we analyzed the areas of the paraspinal muscles as well as the cross-sectional total patient area in a single CT slice at the height of the third lumbar vertebra. These measurements were subsequently correlated with anthropometric (body weight) and body composition parameters derived from BIA (muscle mass, fat mass, fat-free mass, and visceral fat mass). Linear regression models were built to allow for estimation of each parameter based on CT measurements.
Results
Linear regression models allowed for accurate prediction of patient body weight (adjusted
R
2
= 0.886), absolute muscle mass (adjusted
R
2
= 0.866), fat-free mass (adjusted
R
2
= 0.855), and total as well as visceral fat mass (adjusted
R
2
= 0.887 and 0.839, respectively).
Conclusions
Our data suggest that patient body composition can accurately and quantitatively be determined by using simple measurements in a single axial CT slice. This could be useful in various medical and scientific settings, where the knowledge of the patient’s anthropometric parameters is not immediately or easily available.
Key Points
•
Easy to perform measurements on a single CT slice highly correlate with clinically valuable parameters of body composition.
•
Body composition data were acquired using bioelectrical impedance analysis to correlate CT measurements with a non-imaging-based method, which is frequently lacking in previous studies.
•
The obtained equations facilitate a quick, opportunistic assessment of relevant parameters of body composition.
Modern advances in technology such as next-generation sequencing and digital PCR make detection of minor circulating cell-free tumor DNA amounts in blood from cancer patients possible. Samples can be ...obtained minimal-invasively, tested for treatment-determining genetic alterations and are considered to reflect the genetic constitution of the whole tumor mass. Furthermore, tumor development can be determined by a time course of the quantified circulating cell-free tumor DNA. However, systematic studies which prove the clinical relevance of monitoring patients using liquid biopsies are still lacking. In this study, we collected 115 samples from 47 late stage melanoma patients over 1.5 years alongside therapy-associated clinical routine monitoring. Mutation status was confirmed by molecular analysis of primary tumor material. We can show that detectable levels of circulating cell-free tumor DNA correlate with clinical development over time. Increasing levels of circulating cell-free tumor DNA during melanoma treatment with either targeted therapy (BRAF/MEK inhibitors) or immunotherapy, during recovery time or the intervals between last treatment cycle and second-line treatment point towards clinical progression before the progression becomes obvious in imaging. Therefore, this is a further possibility to closely screen our patients for tumor progression during therapy, in therapy-free phases and in earlier stages before therapy initiation.
Thyroid hormones regulate mitochondrial function. As other hypothalamic–pituitary–thyroid (HPT) axis hormones, i.e., thyrotropin-releasing hormone (TRH) and thyrotropin (TSH), are expressed in human ...hair follicles (HFs) and regulate mitochondrial function in human epidermis, we investigated in organ-cultured human scalp HFs whether TRH (30 nM), TSH (10 mU ml−1), thyroxine (T4) (100 nM), and triiodothyronine (T3) (100 pM) alter intrafollicular mitochondrial energy metabolism. All HPT-axis members increased gene and protein expression of mitochondrial-encoded subunit 1 of cytochrome c oxidase (MTCO1), a subunit of respiratory chain complex IV, mitochondrial transcription factor A (TFAM), and Porin. All hormones also stimulated intrafollicular complex I/IV activity and mitochondrial biogenesis. The TSH effects on MTCO1, TFAM, and porin could be abolished by K1-70, a TSH-receptor antagonist, suggesting a TSH receptor–mediated action. Notably, as measured by calorimetry, T3 and TSH increased follicular heat production, whereas T3/T4 and TRH stimulated ATP production in cultured HF keratinocytes. HPT-axis hormones did not increase reactive oxygen species (ROS) production. Rather, T3 and T4 reduced ROS formation, and all tested HPT-axis hormones increased the transcription of ROS scavengers (catalase, superoxide dismutase 2) in HF keratinocytes. Thus, mitochondrial biology, energy metabolism, and redox state of human HFs are subject to profound (neuro-)endocrine regulation by HPT-axis hormones. The neuroendocrine control of mitochondrial biology in a complex human mini-organ revealed here may be therapeutically exploitable.
Background Composition of the intestinal microbiota has been correlated to therapeutic efficacy of immune checkpoint inhibitors (ICI) in various cancer entities including melanoma. Prediction of the ...outcome of such therapy, however, is still unavailable. This prospective, non-interventional study was conducted in order to achieve an integrated assessment of the connection between a specific intestinal microbiota profile and antitumor immune response to immune checkpoint inhibitor therapy (anti-PD-1 and/or anti-CTLA-4) in melanoma patients. Methods We assessed blood and stool samples of 29 cutaneous melanoma patients who received immune checkpoint inhibitor therapy. For functional and phenotypical immune analysis, 12-color flow cytometry and FluoroSpot assays were conducted. Gut microbiome was analyzed with shotgun metagenomics sequencing. To combine clinical, microbiome and immune variables, we applied the Random Forest algorithm. Results A total of 29 patients was analyzed in this study, among whom 51.7% (n = 15) reached a durable clinical benefit. The Immune receptor TIGIT is significantly upregulated in T cells (p = 0.0139) and CD56.sup.high NK cells (p = 0.0037) of responders. Several bacterial taxa were associated with response (e.g. Ruminococcus torques) or failure (e.g. Barnesiella intestinihominis) to immune therapy. A combination of two microbiome features (Barnesiella intestinihominis and the Enterobacteriaceae family) and one immune feature (TIGIT.sup.+ CD56.sup.high NK cells) was able to predict response to ICI already at baseline (AUC = 0.85; 95% CI: 0.841-0.853). Conclusions Our results reconfirm a link between intestinal microbiota and response to ICI therapy in melanoma patients and furthermore point to TIGIT as a promising target for future immunotherapies. Keywords: Microbiome, Melanoma, Immune checkpoint inhibitors, NK cells, TIGIT, Response, Random Forest
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Since it is unknown whether thyroid hormones (THs) regulate mitochondrial function in human epidermis, we treated organ-cultured human skin, or isolated cultured human epidermal keratinocytes, with ...triiodothyronine (100 pmol/L) or thyroxine (100 nmol/L). Both THs significantly increased protein expression of the mitochondrially encoded cytochrome C oxidase I (MTCO1), complex I activity, and the number of perinuclear mitochondria. Triiodothyronine also increased mitochondrial transcription factor A (TFAM) protein expression, and thyroxine stimulated complex II/IV activity. Increased mitochondrial function can correlate with increased reactive oxygen species production, DNA damage, and accelerated tissue aging. However, THs neither raised reactive oxygen species production or matrix metalloproteinase-1, -2 and -9 activity nor decreased sirtuin1 (Sirt1) immunoreactivity. Instead, triiodothyronine increased sirtuin-1, fibrillin-1, proliferator-activated receptor-gamma 1-alpha (PGC1α), collagen I and III transcription, and thyroxine decreased cyclin-dependent kinase inhibitor 2A (p16ink4) expression in organ-cultured human skin. Moreover, TH treatment increased intracutaneous fibrillin-rich microfibril and collagen III deposition and decreased mammalian target of rapamycin (mTORC1/2) expression ex vivo. This identifies THs as potent endocrine stimulators of mitochondrial function in human epidermis, which down-regulates rather than enhance the expression of skin aging-related biomarkers ex vivo. Therefore, topically applied THs deserve further exploration as candidate agents for treating skin conditions characterized by reduced mitochondrial function.
Although the role of sentinel lymph node biopsy (SLNB) as a prognostic factor is well established, its consequences for therapy are controversial. The aim of this study was to analyze if complete ...lymph node dissection (CLND) in patients with more than one positive sentinel lymph node (SLN) significantly improves melanoma‐specific survival (MSS) and progression‐free survival (PFS). Medical records of patients who underwent SLNB between 2001 and 2016 at the University Hospital of Cologne were reviewed, and patients with positive SLN were identified. Patient and tumor characteristics, patterns of recurrence, progression‐free and melanoma‐specific survival were analyzed. Seventy‐eight patients with multiple positive and 197 patients with one positive SLN were included in this study. Patients with multiple positive SLN had significantly more positive non‐SLN compared with patients with only one positive SLN (26.9% vs 8.6%, P = 0.01). However, in the subgroup of patients with multiple positive SLN, CLND did not significantly improve MSS (mean MSS 95 vs 75 months, P = 0.5) and PFS (mean PFS 59 vs 68 months P = 0.167). CLND did not result in a significant improvement in PFS and MSS in patients with multiple positive SLN.
Context:
Mitochondrial capacity and metabolic potential are under the control of hormones, such as thyroid hormones. The most proximal regulator of the hypothalamic-pituitary-thyroid (HPT) axis, TRH, ...is the key hypothalamic integrator of energy metabolism via its impact on thyroid hormone secretion.
Objective:
Here, we asked whether TRH directly modulates mitochondrial functions in normal, TRH-receptor-positive human epidermis.
Methods:
Organ-cultured human skin was treated with TRH (5–100 ng/ml) for 12–48 h.
Results:
TRH significantly increased epidermal immunoreactivity for the mitochondria-selective subunit I of respiratory chain complex IV (MTCO1). This resulted from an increased MTCO1 transcription and protein synthesis and a stimulation of mitochondrial biogenesis as demonstrated by transmission electron microscopy and TRH-enhanced mitochondrial DNA synthesis. TRH also significantly stimulated the transcription of several other mitochondrial key genes (TFAM, HSP60, and BMAL1), including the master regulator of mitochondrial biogenesis (PGC-1α). TRH significantly enhanced mitochondrial complex I and IV enzyme activity and enhanced the oxygen consumption of human skin samples, which shows that the stimulated mitochondria are fully vital because the main source for cellular oxygen consumption is mitochondrial endoxidation.
Conclusions:
These findings identify TRH as a potent, novel neuroendocrine stimulator of mitochondrial activity and biogenesis in human epidermal keratinocytes in situ. Thus, human epidermis offers an excellent model for dissecting neuroendocrine controls of human mitochondrial biology under physiologically relevant conditions and for exploring corresponding clinical applications.
PDF
