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Inhibitors of kinases involved in signaling and other intracellular pathways, have revolutionized cancer treatment by providing highly targeted and effective therapies. However, timely monitoring treatment response remains a considerable challenge since conventional methods such as assessing changes in tumor volume do not adequately capture early responses or resistance development, due to the predominantly cytostatic rather than cytotoxic effect of kinase inhibitors. Magnetic resonance spectroscopy (MRS) is a non-invasive imaging technique that can provide insights into cellular metabolism by detecting changes in metabolite concentrations. By measuring metabolite levels, MRS offers a means to assess treatment response in real-time, providing earlier indications of efficacy or resistance compared to conventional imaging modalities. Bruton's Tyrosine Kinase (BTK) is a critical enzyme involved in B-cell receptor signaling. BTK inhibitors have been approved for the treatment of Mantle Cell Lymphoma (MCL) and other B-cell malignancies. Recent studies involving genome-scale gene expression, metabolomic, and fluxomic analyses have demonstrated that ibrutinib, an index BTK inhibitor, profoundly affects the key metabolic pathways in MCL cells., including glycolysis, glutaminolysis, pentose shunt, TCA cycle and phospholipid metabolism. Importantly, the effects of ibrutinib on MCL cells directly and proportionately correlates with their sensitivity to the drug. Consequently, changes in specific metabolite concentrations detectable non-invasively by MRS such as lactate and alanine reflecting mostly the status of cellular glycolysis and glutaminolysis, respectively, have emerged as potential biomarkers for predicting response and resistance of MCL cells to BTK inhibition, both in vitro and in vivo. Preparations to validate the utility of these biomarkers in clinical setting are under way. These studies may pave the way to monitor therapeutic response to kinase inhibitors also in other types of cancer.
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BACKGROUND AND OBJECTIVE: At present, there is no consensus regarding the most optimal dural substitute to use for duroplasty in primary decompressive craniectomy (PDC) for traumatic brain injury (TBI). The author's objective was to conduct a retrospective analysis comparing 2 techniques of PDC: duroplasty using anterior-based vascularized galea pericranium (VP group) with synthetic dural substitute duroplasty (SR group). METHODS: From April 2015 to February 2022, 379 craniotomies were done for TBI. The outcome of eligible 97 consecutive patients receiving PDC treatment were examined. Out of 97, 60 received vascularized galea pericranium and 37 received synthetic dural graft for dural augmentation. Propensity matching generated 28 pairs (56 patients) for analysis. The primary outcome was extended Glasgow Outcome Scale (GOS-E) measured at 6 months after injury. Secondary outcomes included were incidence of surgical complications (neurosurgical site infections, and hemorrhagic and hydrodynamic complications), surgical time, days in intensive care unit, hospital length of stay, hospital mortality, and GOS-E at 1 year after injury. RESULTS: Patients in VP group, compared with those in SR group had better GOS-E score at 6 months (P = .011) and 1 year (P = .026). Hospital mortality (P = .342), days in intensive care unit (P = .574), hospital stay (P = .155), surgical time (P = .131), medical and surgical complications including neurosurgical infections, and hemorrhagic and hydrodynamic complications did not differ significantly in both groups. Complication of brain abscess was found exclusively in the SR group (P = .327). CONCLUSION: In this retrospective study, adults who underwent PDC for TBI using anterior-based vascularized galea pericranial graft were associated with better clinical outcomes at 6 months and 1 year compared with standard repair group using synthetic dural substitute (G patch).
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BACKGROUND: Inhibition of kinases is the ever-expanding therapeutic approach to various types of cancer. Typically, assessment of the treatment response is accomplished by standard, volumetric imaging procedures, performed weeks to months after the onset of treatment, given the predominantly cytostatic nature of the kinase inhibitors, at least when used as single agents. Therefore, there is a great clinical need to develop new monitoring approaches to detect the response to kinase inhibition much more promptly. Noninvasive 1H magnetic resonance spectroscopy (MRS) can measure in vitro and in vivo concentration of key metabolites which may potentially serve as biomarkers of response to kinase inhibition. METHODS: We employed mantle cell lymphoma (MCL) cell lines demonstrating markedly diverse sensitivity of inhibition of Bruton's tyrosine kinase (BTK) regarding their growth and studied in-depth effects of the inhibition on various aspects of cell metabolism including metabolite synthesis using metabolomics, glucose and oxidative metabolism by Seahorse XF technology, and concentration of index metabolites lactate, alanine, total choline and taurine by 1H MRS. RESULTS: Effective BTK inhibition profoundly suppressed key cell metabolic pathways, foremost pyrimidine and purine synthesis, the citrate (TCA) cycle, glycolysis, and pyruvate and glutamine/alanine metabolism. It also inhibited glycolysis and amino acid-related oxidative metabolism. Finally, it profoundly and quickly decreased concentration of lactate (a product of mainly glycolysis) and alanine (an indicator of amino acid metabolism) and, less universally total choline both in vitro and in vivo, in the MCL xenotransplant model. The decrease correlated directly with the degree of inhibition of lymphoma cell expansion and tumor growth. CONCLUSIONS: Our results indicate that BTK inhibition exerts a broad and profound suppressive effect on cell metabolism and that the affected index metabolites such as lactate, alanine may serve as early, sensitive, and reliable biomarkers of inhibition in lymphoma patients detectable by noninvasive MRS-based imaging method. This kind of imaging-based detection may also be applicable to other kinase inhibitors, as well as diverse lymphoid and non-lymphoid malignancies.
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Agammaglobulinemia Tirosina Quinasa , Linfoma de Células del Manto , Inhibidores de Proteínas Quinasas , Humanos , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/farmacología , Animales , Agammaglobulinemia Tirosina Quinasa/metabolismo , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Linfoma de Células del Manto/metabolismo , Linfoma de Células del Manto/patología , Linfoma de Células del Manto/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Biomarcadores de Tumor/metabolismo , Proliferación Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones , Biomarcadores/metabolismoRESUMEN
The MAPK signaling pathway with BRAF mutations has been shown to drive the pathogenesis of 40-60% of melanomas. Inhibitors of this pathway's BRAF and MEK components are currently used to treat these malignancies. However, responses to these treatments are not always successful. Therefore, identifying noninvasive biomarkers to predict treatment responses is essential for personalized medicine in melanoma. Using noninvasive 1H magnetic resonance spectroscopy (1H MRS), we previously showed that BRAF inhibition reduces lactate and alanine tumor levels in the early stages of effective therapy and could be considered as metabolic imaging biomarkers for drug response. The present work demonstrates that these metabolic changes observed by 1H MRS and those assessed by 31P MRS are also found in preclinical human melanoma models treated with MEK inhibitors. Apart from 1H and 31P MRS, additional supporting in vitro biochemical analyses are described. Our results indicate significant early metabolic correlations with response levels to MEK inhibition in the melanoma models and are consistent with our previous study of BRAF inhibition. Given these results, our study supports the potential clinical utility of noninvasive MRS to objectively image metabolic biomarkers for the early prediction of melanoma's response to MEK inhibition.
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Melanoma , Metabolómica , Inhibidores de Proteínas Quinasas , Melanoma/metabolismo , Melanoma/tratamiento farmacológico , Melanoma/patología , Humanos , Metabolómica/métodos , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Espectroscopía de Resonancia Magnética/métodos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Espectroscopía de Protones por Resonancia Magnética/métodosRESUMEN
Prostate cancer is a multi-focal disease that can be treated using surgery, radiation, androgen deprivation, and chemotherapy, depending on its presentation. Standard dose-escalated radiation therapy (RT) in the range of 70-80 Gray (GY) is a standard treatment option for prostate cancer. It could be used at different phases of the disease (e.g., as the only primary treatment when the cancer is confined to the prostate gland, combined with other therapies, or as an adjuvant treatment after surgery). Unfortunately, RT for prostate cancer is associated with gastro-intestinal and genitourinary toxicity. We have previously reported that the metabolic modulator lonidamine (LND) produces cancer sensitization through tumor acidification and de-energization in diverse neoplasms. We hypothesized that LND could allow lower RT doses by producing the same effect in prostate cancer, thus reducing the detrimental side effects associated with RT. Using the Seahorse XFe96 and YSI 2300 Stat Plus analyzers, we corroborated the expected LND-induced intracellular acidification and de-energization of isolated human prostate cancer cells using the PC3 cell line. These results were substantiated by non-invasive 31P magnetic resonance spectroscopy (MRS), studying PC3 prostate cancer xenografts treated with LND (100 mg/kg, i.p.). In addition, we found that LND significantly increased tumor lactate levels in the xenografts using 1H MRS non-invasively. Subsequently, LND was combined with radiation therapy in a growth delay experiment, where we found that 150 µM LND followed by 4 GY RT produced a significant growth delay in PC3 prostate cancer xenografts, compared to either control, LND, or RT alone. We conclude that the metabolic modulator LND radio-sensitizes experimental prostate cancer models, allowing the use of lower radiation doses and diminishing the potential side effects of RT. These results suggest the possible clinical translation of LND as a radio-sensitizer in patients with prostate cancer.
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Dabrafenib therapy for metastatic melanoma focuses on blocking growth-promoting signals produced by a hyperactive BRAF protein. We report the metabolic differences of four human melanoma cell lines with diverse responses to dabrafenib therapy (30 mg/kg; oral): WM3918 < WM9838BR < WM983B < DB-1. Our goal was to determine if metabolic changes produced by the altered signaling pathway due to BRAF mutations differ in the melanoma models and whether these differences correlate with response to treatment. We assessed metabolic changes in isolated cells using high-resolution proton magnetic resonance spectroscopy (1H MRS) and supplementary biochemical assays. We also noninvasively studied mouse xenografts using proton and phosphorus (1H/31P) MRS. We found consistent changes in lactate and alanine, either in isolated cells or mouse xenografts, correlating with their relative dabrafenib responsiveness. In xenografts, we also observed that a more significant response to dabrafenib correlated with higher bioenergetics (i.e., increased ßNTP/Pi). Notably, our noninvasive assessment of the metabolic status of the human melanoma xenografts by 1H/31P MRS demonstrated early metabolite changes preceding therapy response (i.e., tumor shrinkage). Therefore, this noninvasive methodology could be translated to assess in vivo predictive metabolic biomarkers of response in melanoma patients under dabrafenib and probably other signaling inhibition therapies.
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Lonidamine (LND) is an anti-cancer drug with great potential as a metabolic modulator of chemotherapy, radiotherapy, hyperthermia, and photodynamic therapy in cancer treatment. LND affects several important aspects of cancer cell metabolism: it inhibits Complex I and II of the electron transport chain (ETC) and pyruvate carriers (mitochondrial), and monocarboxylate transporters in the plasma membrane of the cell. Cancer cells are affected by changes in pH on the molecular level, and so are the drugs used to treat cancer, thus it is important to understand how pH affects their structures and LND is no exception. LND dissolves at a pH of 8.3 in tris-glycine buffer but has limited solubility at pH 7. To understand how pH affects the structure of LND, and its effect as a metabolic modulator on cancer therapy, we made up samples of LND at pH 2, pH 7, and pH 13, and analyzed these samples using 1H and 13C NMR. We looked for ionization sites to explain the behavior of LND in solution. Our results showed considerable chemical shifts between the extremes of our experimental pH range. LND was ionized at its indazole α-nitrogen, however, we did not directly observe the protonation of the carboxyl group oxygen that is expected at pH 2, which may be the result of a chemical-exchange phenomenon.
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PURPOSE: To monitor the metabolic turnover of ß-hydroxybutyrate (BHB) oxidation using 2 H-MRS in conjunction with intravenous administration of 2 H labeled BHB. METHODS: Nine-month-old mice were infused with [3,4,4,4]-2 H4 -BHB (d4 -BHB; 3.11 g/kg) through the tail vein using a bolus variable infusion rate for a period of 90 min. The labeling of downstream cerebral metabolites from the oxidative metabolism of d4 -BHB was monitored using 2 H-MRS spectra acquired with a home-built 2 H surface coil on a 9.4T preclinical MR scanner with a temporal resolution of 6.25 min. An exponential model was fit to the BHB and glutamate/glutamine (Glx) turnover curves to determine rate constants of metabolite turnover and to aid in the visualization of metabolite time courses. RESULTS: Deuterium label was incorporated into Glx from BHB metabolism through the tricarboxylic acid (TCA) cycle, with an increase in the level of [4,4]-2 H2 -Glx (d2 -Glx) over time and reaching a quasi-steady state concentration of â¼0.6 ± 0.1 mM following 30 min of infusion. Complete oxidative metabolic breakdown of d4 -BHB also resulted in the formation of semi-heavy water (HDO), with a four-fold (10.1 to â¼42.1 ± 7.3 mM) linear (R2 = 0.998) increase in its concentration by the end of infusion. The rate constant of Glx turnover from d4 -BHB metabolism was determined to be 0.034 ± 0.004 min-1 . CONCLUSION: 2 H-MRS can be used to monitor the cerebral metabolism of BHB with its deuterated form by measuring the downstream labeling of Glx. The integration of 2 H-MRS with deuterated BHB substrate provides an alternative and clinically promising MRS tool to detect neurometabolic fluxes in healthy and disease conditions.
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Encéfalo , Ratones , Animales , Ácido 3-Hidroxibutírico , Deuterio , Oxidación-Reducción , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismoRESUMEN
Bonded cumomers are sets of isotopomers of 13 C-labeled metabolites containing a particular sequence of contiguously or singly labeled carbon atoms. Only these isotopomers contribute to multiplet structure in the 13 C NMR spectrum. We discuss the application of this technique to the study of quantitative tumor metabolism, bioenergetics, and the Warburg effect. The advantages and sensitivity of bonded cumomer analysis over positional enrichment analysis are discussed. When sensitivity requirements are met, bonded cumomer analysis enables the extraction of fluxes through specific metabolic pathways with higher precision. In conjunction with isotopomer control analysis, we evaluate the sensitivity of experimentally measurable metabolite multiplets to determine the robustness of flux analysis in 13 C spectra of tumors. This review examines the role of glycolytic and tricarboxylic acid cycle metabolism with special emphasis on flux through the pentose phosphate pathway (PPP). The impact of reversibility of the nonoxidative branch of the PPP with various 13 C glucose tracers on fine-structure multiplets is analyzed.
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Modelos Biológicos , Neoplasias , Humanos , Espectroscopía de Resonancia Magnética/métodos , Metabolismo Energético , Ciclo del Ácido Cítrico , Glucosa/metabolismo , Isótopos de Carbono/metabolismoRESUMEN
Importance of the redox status of nicotinamide adenine dinucleotide (NAD), including its oxidized (NAD+) and reduced (NADH) forms, has been shown in many biological processes. However, NAD(H) redox status assessment is traditionally limited to biochemical assays in vitro or optical redox imaging (ORI) for superficial tissues in vivo and for deep tissues ex vivo. In recent years, phosphorous-31 magnetic resonance spectroscopy (31P-MRS) was utilized to quantify NAD+, NADH, and the redox ratio NAD+/NADH in normal tissues in vivo. The quantification is based on the spectral fitting of the upfield shoulder of the αATP peak that contains signals of NAD+ (a quartet) and NADH (a singlet), assuming pH-independence of peak positions. To evaluate the feasibility of measuring tumour NAD(H) redox status in vivo, we fitted single voxel 31P-MR spectra of subcutaneous mouse xenografts of human breast cancer cell lines acquired on a 9.4-T horizontal bore preclinical MR scanner. We found larger variations in the chemical shift offsets of NAD+ and NADH from αATP in these tumours than the literature values of normal tissues. Furthermore, our 31P-MR spectra of αATP, NAD+, and NADH solution phantoms indicated that the chemical shift of αATP and thus the offsets between NAD(H) and αATP were pH dependent. Therefore, whether tumour pH should be incorporated into the spectral fitting model should be further evaluated. Additionally, spectral resolution and signal-to-noise ratio should be improved by optimising 31P-MRS protocols, increasing data acquisition time, and using a more sensitive coil for signal detection.
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NAD , Neoplasias , Animales , Humanos , Ratones , NAD/metabolismo , Fósforo , Estudios de Factibilidad , Espectroscopía de Resonancia Magnética/métodos , Oxidación-Reducción , Neoplasias/diagnóstico por imagenRESUMEN
As a phosphorus-containing molecule, nicotinamide adenine dinucleotide is visible by phosphorus magnetic resonance spectroscopy (31P-MRS). However, the relatively low cellular levels of its oxidised (NAD+) and reduced (NADH) forms and a significant peak overlap hinder their evaluation in live tissues. This problem is critical when using 31P-MR spectroscopic imaging, where signals are localised from limited tissue volumes. We have reported improvements in spectral resolution of 31P-MRSI of human tissues in situ using a strict optimisation of the static magnetic field (B0 shimming) and 1H-irradiation during 31P acquisition. Given this, we aimed to demonstrate if these improvements allowed us to measure the in vivo intracellular levels of NAD+ and NADH at the relatively low magnetic field of 1.5 tesla (T). Our results show the feasibility of the in vivo determination of NAD+ and NADH from relatively small volumes of human tissues studied at 1.5 T. These results are clinically relevant as the currently available systems for human use mainly operate at 1.5 or 3.0.
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NAD , Fósforo , Humanos , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética/métodosRESUMEN
1H magnetic resonance spectroscopy (MRS) with the multiple quantum coherence (MQC) technique allows for the detection of lactate, an end product of glycolysis, in the environment of lipids. The method can also be used to detect alanine, a byproduct of glutaminolysis. An issue is that when both lactate and alanine are detected together by the MQC technique, a phase mismatch arises between lactate and alanine signals due to off-resonance rotations and the difference in double quantum coherence frequencies between the two molecules. Such phase mismatch can cause errors in spectral fitting and metabolite quantification. In this study, we designed two pulse sequences that eliminate such phase differences of lactate and alanine while suppressing lipid signals by modifications of the Selective Multiple Quantum Coherence (Sel-MQC) sequence, a well-known MQC technique. Using the product operator formalism and the off-resonance rotation matrices, the phase evolutions of lactate and alanine during the spectrally selective pulses and the free precession times of the sequence at the single quantum, double quantum and zero quantum coherence states of these molecules were calculated. The multiple quantum (MQ) evolution time t1 that can remove the phase difference of lactate and alanine at the echo was calculated and fine-tuned with experiments. The lactate and alanine signal intensities and the editing efficiencies from the two modified Sel-MQC sequences were theoretically predicted by using the product operator evolutions and compared with the experimental data. The J-coupled lipid signals were successfully suppressed by both sequences. One of the two developed sequences was applied to a human body with a phantom of lactate and alanine, which resulted in successful in-phase editing of lactate and alanine and suppression of the lipid signals from the body. The study sets an important foundation for the noninvasive detection of lactate and alanine from tumors of cancer patients.
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Alanina , Ácido Láctico , Humanos , Espectroscopía de Resonancia Magnética/métodos , Imagen por Resonancia Magnética/métodos , Lípidos/químicaRESUMEN
Proton magnetic resonance spectroscopy (1H-MRS) provides a non-invasive biochemical profile of brain tumors. The conventional 1H-MRS methods present a few challenges mainly related to limited spatial coverage and low spatial and spectral resolutions. In the recent past, the advent and development of more sophisticated metabolic imaging and spectroscopic sequences have revolutionized the field of neuro-oncologic metabolomics. In this review article, we will briefly describe the scientific premises of three-dimensional echoplanar spectroscopic imaging (3D-EPSI), two-dimensional correlation spectroscopy (2D-COSY), and chemical exchange saturation technique (CEST) MRI techniques. Several published studies have shown how these emerging techniques can significantly impact the management of patients with glioma by determining histologic grades, molecular profiles, planning treatment strategies, and assessing the therapeutic responses. The purpose of this review article is to summarize the potential clinical applications of these techniques in studying brain tumor metabolism.
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Pseudoprogression (PsP) refers to treatment-related clinico-radiologic changes mimicking true progression (TP) that occurs in patients with glioblastoma (GBM), predominantly within the first 6 months after the completion of surgery and concurrent chemoradiation therapy (CCRT) with temozolomide. Accurate differentiation of TP from PsP is essential for making informed decisions on appropriate therapeutic intervention as well as for prognostication of these patients. Conventional neuroimaging findings are often equivocal in distinguishing between TP and PsP and present a considerable diagnostic dilemma to oncologists and radiologists. These challenges have emphasized the need for developing alternative imaging techniques that may aid in the accurate diagnosis of TP and PsP. In this review, we encapsulate the current state of knowledge in the clinical applications of commonly used metabolic and physiologic magnetic resonance (MR) imaging techniques such as diffusion and perfusion imaging and proton spectroscopy in distinguishing TP from PsP. We also showcase the potential of promising imaging techniques, such as amide proton transfer and amino acid-based positron emission tomography, in providing useful information about the treatment response. Additionally, we highlight the role of "radiomics", which is an emerging field of radiology that has the potential to change the way in which advanced MR techniques are utilized in assessing treatment response in GBM patients. Finally, we present our institutional experiences and discuss future perspectives on the role of multiparametric MR imaging in identifying PsP in GBM patients treated with "standard-of-care" CCRT as well as novel/targeted therapies.
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Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Progresión de la Enfermedad , Glioblastoma/diagnóstico por imagen , Glioblastoma/patología , Glioblastoma/terapia , Humanos , Imagen por Resonancia Magnética/métodos , ProtonesRESUMEN
Objective.The selective multiple quantum coherence (Sel-MQC) sequence is a magnetic resonance spectroscopy (MRS) technique used to detect lactate and suppress co-resonant lipid signalsin vivo. The coherence pathways of J-coupled lipids upon the sequence, however, have not been studied, hindering a logical design of the sequence to fully attenuate lipid signals. The objective of this study is to elucidate the coherence pathways of J-coupled lipids upon the Sel-MQC sequence and find a strategy to effectively suppress lipid signals from these pathways while keeping the lactate signal.Approach.The product operator formalism was used to express the evolutions of the J-coupled spins of lipids and lactate. The transformations of the product operators by the spectrally selective pulses of the sequence were calculated by using the off-resonance rotation matrices. The coherence pathways and the conversion rates of the individual pathways were derived from them. Experiments were performed on phantoms and two human subjects at 3 T.Main results.The coherence pathways contributing to the various lipid resonance signals by the Sel-MQC sequence depending on the gradient ratios and RF pulse lengths were identified. Theoretical calculations of the signals from the determined coherence pathways and signal attenuations by gradients matched the experimental data very well. Lipid signals from fatty tissues of the subjects were successfully suppressed to the noise level by using the gradient ratio -0.8:-1:2 or 1:0.8:2. The new gradient ratios kept the lactate signal the same as with the previously used gradient ratio 0:-1:2.Significance.The study has elucidated the coherence pathways of J-coupled lipids upon the Sel-MQC sequence and demonstrated how lipid signals can be effectively suppressed while keeping lactate signals by using information from the coherence pathway analysis. The findings enable applying the Sel-MQC sequence to lactate detection in an environment of high concentrations of lipids.
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Ácido Láctico , Imagen por Resonancia Magnética , Humanos , Ácido Láctico/análisis , Ácido Láctico/química , Ácido Láctico/metabolismo , Lípidos/química , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética/métodos , Fantasmas de ImagenRESUMEN
Neurocysticercosis (NCC) is a parasitic infection caused by Cysticercus cellulosae, the metacestode of pork tapeworm (Taenia solium). NCC is one of the most common public health problems worldwide. We present a patient harboring a bilobed ring-enhancing lesion with a presumed diagnosis of brain metastasis, who returned to the USA after traveling to an endemic region. The diagnosis of NCC was established based on a characteristic resonance of succinate on proton magnetic resonance spectroscopy. Also, higher mean diffusivity and lower fractional anisotropy along with relative cerebral blood volume were observed from the lesion compared to contralateral normal brain regions. Multiparametric analysis may improve the differential diagnosis of ring-enhancing intracranial lesions such as NCC.
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Neurocisticercosis , Taenia solium , Animales , Encéfalo/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Neurocisticercosis/diagnóstico por imagen , Análisis EspectralRESUMEN
INTRODUCTION: The sensitive, specific, fast, robust and noninvasive biomarkers for the evaluation of prostate cancer (PC) remain elusive in medical research. However, efforts are in full sway to investigate and resolve these puzzles for clinical practice. Advances in modern analytical techniques, sample processing, and the emergence of multiple omics approaches have created a great hope for the development of better detection modalities for PC. The objective of the present review is to provide a concise overview of the PC metabolomics-based potential discriminating molecules in urine samples using nuclear magnetic resonance spectroscopy and mass spectrometry. AREA COVERED: A literature search was executed to find the studies reporting the noninvasive urine-based biomarkers for the diagnosis and prognosis of underlying disease. Most studies have extensivelyreported PC discriminating molecules with their respective controls. Additionally, pathophysiology and the treatment paradigm of PC are summarized and related to the insights underpinning the therapeutic intervention of PC. EXPERT OPINION: With multi-centric, global, comprehensive omics approaches via either a non- or least-invasive bio-matrix may open new avenues of research for PC biomarker discovery, backed by a molecular mechanistic outline.
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Biomarcadores de Tumor , Neoplasias de la Próstata , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , MetabolómicaRESUMEN
Glioblastoma (GBM) is the most malignant brain tumor in adults, with a dismal prognosis despite aggressive multi-modal therapy. Immunotherapy is currently being evaluated as an alternate treatment modality for recurrent GBMs in clinical trials. These immunotherapeutic approaches harness the patient's immune response to fight and eliminate tumor cells. Standard MR imaging is not adequate for response assessment to immunotherapy in GBM patients even after using refined response assessment criteria secondary to amplified immune response. Thus, there is an urgent need for the development of effective and alternative neuroimaging techniques for accurate response assessment. To this end, some groups have reported the potential of diffusion and perfusion MR imaging and amino acid-based positron emission tomography techniques in evaluating treatment response to different immunotherapeutic regimens in GBMs. The main goal of these techniques is to provide definitive metrics of treatment response at earlier time points for making informed decisions on future therapeutic interventions. This review provides an overview of available immunotherapeutic approaches used to treat GBMs. It discusses the limitations of conventional imaging and potential utilities of physiologic imaging techniques in the response assessment to immunotherapies. It also describes challenges associated with these imaging methods and potential solutions to avoid them.
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Neoplasias Encefálicas/diagnóstico por imagen , Diagnóstico por Imagen , Glioblastoma/diagnóstico por imagen , Animales , Neoplasias Encefálicas/etiología , Neoplasias Encefálicas/terapia , Toma de Decisiones Clínicas , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Diagnóstico por Imagen/métodos , Diagnóstico por Imagen/normas , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Glioblastoma/etiología , Glioblastoma/terapia , Humanos , Inmunoterapia/efectos adversos , Inmunoterapia/métodos , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Pronóstico , Resultado del TratamientoRESUMEN
Introduction: Renal cell carcinoma (RCC) is one of the most prevalent metabolic diseases and a leading cause of utmost mortality among men globally. In spite of extensive development in technology for biomarker discovery during the last 10 years, the currently used clinical biomarkers are still unable to detect RCC at early and progression stages. Hence, the development of new and precise biomarkers is most important to improve the clinical management of RCC and reduce the level of mortality.Area covered: For the detection of RCC at an early stage; a new branch of omics technology - metabolomics - has been introduced. Mainly two techniques (mass spectrometry and nuclear magnetic resonance spectroscopy) have been exploited to execute metabolomics. Precisely, metabolomics showed promising and powerful approach to identify novel RCC biomarker. The present review discussed and the literature search to narrate the outcomes of the past 10 years of studies related to RCC pathophysiology, metabolomics, advancements, and shortcomings.Expert opinion: Although, compared to mass spectrometric tactic, nuclear magnetic resonance is moving fast to achieve the aim and in vivo application for diagnosis and management of RCC, metabolomics-based research in RCC is still in its infancy stage.
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Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/metabolismo , Neoplasias Renales/metabolismo , Metabolómica/métodos , Animales , Biomarcadores de Tumor/genética , Carcinoma de Células Renales/diagnóstico , Humanos , Neoplasias Renales/diagnóstico , Espectroscopía de Resonancia Magnética/métodos , Espectrometría de Masas/métodosRESUMEN
Inhibitors of Bruton tyrosine kinase (BTK), a kinase downstream of BCR, display remarkable activity in a subset of mantle cell lymphoma (MCL) patients, but the drug resistance remains a considerable challenge. In this study, we demonstrate that aberrant expression of ROR1 (receptor tyrosine kinase-like orphan receptor 1), seen in a large subset of MCL, results in BCR/BTK-independent signaling and growth of MCL cells. ROR1 forms a functional complex with CD19 to persistently activate the key cell signaling pathways PI3K-AKT and MEK-ERK in the BCR/BTK-independent manner. This study demonstrates that ROR1/CD19 complex effectively substitutes for BCR-BTK signaling to promote activation and growth of MCL cells. Therefore, ROR1 expression and activation may represent a novel mechanism of resistance to inhibition of BCR/BTK signaling in MCL. Our results provide a rationale to screen MCL patients for ROR1 expression and to consider new therapies targeting ROR1 and/or CD19 or their downstream signaling pathways for MCL-expressing ROR1.