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The ability of CD8+ T cells to infiltrate solid tumors and reach cancer cells is associated with improved patient survival and responses to immunotherapy. Thus, identifying the factors controlling T cell migration in tumors is critical, so that strategies to intervene on these targets can be developed. Although interstitial motility is a highly energy-demanding process, the metabolic requirements of CD8+ T cells migrating in a 3D environment remain unclear. Here, we demonstrate that the tricarboxylic acid (TCA) cycle is the main metabolic pathway sustaining human CD8+ T cell motility in 3D collagen gels and tumor slices while glycolysis plays a more minor role. Using pharmacological and genetic approaches, we report that CD8+ T cell migration depends on the mitochondrial oxidation of glucose and glutamine, but not fatty acids, and both ATP and ROS produced by mitochondria are required for T cells to migrate. Pharmacological interventions to increase mitochondrial activity improve CD8+ T cell intratumoral migration and CAR T cell recruitment into tumor islets leading to better control of tumor growth in human xenograft models. Our study highlights the rationale of targeting mitochondrial metabolism to enhance the migration and antitumor efficacy of CAR T cells in treating solid tumors.The migration of T cells into tumours and how this is regulated by metabolic pathways is not completely understood. Here the authors use human and xenograft mouse models to explore the functional changes in T cells during migration in tumours and how glycolytic and TCA cycle metabolism is involved. [ABSTRACT FROM AUTHOR]

We discuss how metabolism changes during different phases of the cell cycle to sustain biosynthesis and replication in normal and cancer cells. We also highlight how several master regulators of cell cycle, such as cyclin–cyclin-dependent kinases (cyc–CDK complexes) and E3 proteasome ligases, modulate key metabolic enzymes to support cell-cycle progression. [ABSTRACT FROM AUTHOR]

Adoptive transfer of T cells genetically engineered to express chimeric antigen receptors (CAR) has demonstrated striking efficacy for the treatment of several hematological malignancies, including B-cell lymphoma, leukemia, and multiple myeloma. However, many patients still do not respond to this therapy or eventually relapse after an initial remission. In most solid tumors for which CAR T-cell therapy has been tested, efficacy has been very limited. In this context, it is of paramount importance to understand the mechanisms of tumor resistance to CAR T cells. Possible factors contributing to such resistance have been identified, including inherent CAR T-cell dysfunction, the presence of an immunosuppressive tumor microenvironment, and tumor-intrinsic factors. To control tumor growth, CAR T cells have to migrate actively enabling a productive conjugate with their targets. To date, many cells and factors contained within the tumor microenvironment have been reported to negatively control the migration of T cells and their ability to reach cancer cells. Recent evidence suggests that additional determinants, such as immune checkpoint proteins, cellular metabolism, and adhesion molecules, may modulate the motility of CAR T cells in tumors. Here, we review the potential impact of these determinants on CAR T-cell motility, and we discuss possible strategies to restore intratumoral T-cell migration with a special emphasis on approaches targeting these determinants. [ABSTRACT FROM AUTHOR]

Simple Summary: We propose that PFK1 promotes a positive feedback loop with PI3K/AKT and YAP/TAZ signaling pathways in cancer cells. Therefore, targeting PFK1 (or its product F-1,6-BP) could improve the efficacy of PI3K and YAP/TAZ inhibitors currently tested in clinical trials. To this aim, we suggest the use of citrate, which is a physiologic and potent inhibitor of PFK1. PI3K/AKT is one of the most frequently altered signaling pathways in human cancers, supporting the activation of many proteins sustaining cell metabolism, proliferation, and aggressiveness. Another important pathway frequently altered in cancer cells is the one regulating the YAP/TAZ transcriptional coactivators, which promote the expression of genes sustaining aerobic glycolysis (such as WNT, MYC, HIF-1), EMT, and drug resistance. Of note, the PI3K/AKT pathway can also regulate the YAP/TAZ one. Unfortunately, although PI3K and YAP inhibitors are currently tested in highly resistant cancers (both solid and hematologic ones), several resistance mechanisms may arise. Resistance mechanisms to PI3K inhibitors may involve the stimulation of alternative pathways (such as RAS, HER, IGFR/AKT), the inactivation of PTEN (the physiologic inhibitor of PI3K), and the expression of anti-apoptotic Bcl-xL and MCL1 proteins. Therefore, it is important to improve current therapeutic strategies to overcome these limitations. Here, we want to highlight how the glycolytic enzyme PFK1 (and its product F-1,6-BP) promotes the activation of both PI3K/AKT and YAP/TAZ pathways by several direct and indirect mechanisms. In turn, PI3K/AKT and YAP/TAZ can promote PFK1 activity and F-1,6-BP production in a positive feedback loop, thus sustaining the Warburg effect and drug resistance. Thus, we propose that the inhibition of PFK1 (and of its key activator PFK2/PFKFB3) could potentiate the sensitivity to PI3K and YAP inhibitors currently tested. Awaiting the development of non-toxic inhibitors of these enzymes, we propose to test the administration of citrate at a high dosage, because citrate is a physiologic inhibitor of both PFK1 and PFK2/PFKFB3. Consistently, in various cultured cancer cells (including melanoma, sarcoma, hematologic, and epithelial cancer cells), this "citrate strategy" efficiently inhibits the IGFR1/AKT pathway, promotes PTEN activity, reduces Bcl-xL and MCL1 expression, and increases sensitivity to standard chemotherapy. It also inhibits the development of sarcoma, pancreatic, mammary HER+ and lung RAS-driven tumors in mice without apparent toxicities. [ABSTRACT FROM AUTHOR]

COVID-19 pandemic has been characterized by a pattern of consecutive declines and regrowth in European countries in 2020. After being partially regressed during the summer, the reappearance of the infection during fall 2020 in many temperate countries strongly suggests that temperature and cold may play a role in influencing the infectivity and virulence of SARS-CoV-2. While promoting medicine as an art, Hippocrates interpreted with logical reasoning the occurrence of diseases such as epidemics, as a consequence of environmental factors, in particular climatic variations. During the Renaissance, Sanctorius was one of the first to perform quantitative measurements, and Harvey discovered the circulation of blood by performing experimental procedures in animals. We think that a reasoning mixing various observations, measurements and experiments is fundamental to understand how cold increases infectivity and virulence of SARS-CoV-2. By this review, we provide evidence linking cold, angiotensin-II, vasoconstriction, hypoxia and aerobic glycolysis (the Warburg effect) to explain how cold affects the epidemiology of COVID-19. Also, a low humidity increases virus transmissibility, while a warm atmosphere, a moderate airway humidity, and the production of vasodilator angiotensin 1-7 by ACE2 are less favorable to the virus entry and/or its development. The meteorological and environmental parameters impacting COVID-19 pandemic should be reintegrated into a whole perspective by taking into account the different factors influencing transmissibility, infectivity and virulence of SARS-CoV-2. To understand the modern enigma represented by COVID-19, an interdisciplinary approach is surely essential. • The influence of climate on COVID-19 pandemic is suspected but largely enigmatic. • Cold may increase viral infectivity by paralyzing airway defense barriers. • Angiotensin II-mediated vasoconstriction induced by cold promotes hypoxia in cells. • Hypoxia activates aerobic glycolysis promoting SARS-CoV-2 replication. • This cascade may have favored the spread of COVID-19 in European countries in 2020. [ABSTRACT FROM AUTHOR]

Background: Infection of the pleural cavity invariably leads to hospitalisation, and a fatal outcome is not uncommon. Our aim was to study the epidemiology of pleural empyema on a nationwide basis in the whole population and in three subgroups of patients, namely post-lung resection, associated cancer and those with no surgery and no cancer.Methods: Data from patients aged ≥18 years hospitalised with a diagnosis of pleural infection in France between January 2013 and December 2017 were retrieved from the medical-administrative national hospitalisation database and retrospectively analysed. Mortality, length of stay and costs were assessed.Results: There were 25 512 hospitalisations for pleural empyema. The annual rate was 7.15 cases per 100 000 habitants in 2013 and increased to 7.75 cases per 100 000 inhabitants in 2017. The mean age of patients was 62.4±15.6 years and 71.7% were men. Post-lung resection, associated cancer and no surgery-no cancer cases accounted for 9.8%, 30.1% and 60.1% of patients, respectively. These groups were significantly different in terms of clinical characteristics, mortality and risk factors for length of stay, costs and mortality. Mortality was 17.1% in the whole population, 29.5% in the associated cancer group, 17.7% in the post-lung resection group and 10.7% in the no surgery-no cancer group. In the whole population, age, presence of fistula, higher Charlson Comorbidity Index (>3), alcohol abuse, arterial hypertension, hyperlipidaemia, atheroma, atrial fibrillation, performance status >3 and three subgroups of pleural empyema independently predicted mortality.Conclusions: Empyema is increasing in incidence. Factors associated with mortality are recent lung resection and associated diagnosis of cancer. [ABSTRACT FROM AUTHOR]

We propose that fructose-1,6-bisphosphate (F-1,6-BP) promotes a feedback loop between phosphofructokinase-1 (PFK1), phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), and PFK2/PFKFB3, which enhances aerobic glycolysis and sustains effector T (T eff) cell activation, while oxidative metabolism is concomitantly downregulated. This regulation, promoted by low citrate and mitochondrial ATP synthesis, also sustains the Warburg effect in cancer cells. [ABSTRACT FROM AUTHOR]

Current mortality due to the Covid-19 pandemic (approximately 1.2 million by November 2020) demonstrates the lack of an effective treatment. As replication of many viruses - including MERS-CoV - is supported by enhanced aerobic glycolysis, we hypothesized that SARS-CoV-2 replication in host cells (especially airway cells) is reliant upon altered glucose metabolism. This metabolism is similar to the Warburg effect well studied in cancer. Counteracting two main pathways (PI3K/AKT and MAPK/ERK signaling) sustaining aerobic glycolysis inhibits MERS-CoV replication and thus, very likely that of SARS-CoV-2, which shares many similarities with MERS-CoV. The Warburg effect appears to be involved in several steps of COVID-19 infection. Once induced by hypoxia, the Warburg effect becomes active in lung endothelial cells, particularly in the presence of atherosclerosis, thereby promoting vasoconstriction and micro thrombosis. Aerobic glycolysis also supports activation of pro-inflammatory cells such as neutrophils and M1 macrophages. As the anti-inflammatory response and reparative process is performed by M2 macrophages reliant on oxidative metabolism, we speculated that the switch to oxidative metabolism in M2 macrophages would not occur at the appropriate time due to an uncontrolled pro-inflammatory cascade. Aging, mitochondrial senescence and enzyme dysfunction, AMPK downregulation and p53 inactivation could all play a role in this key biochemical event. Understanding the role of the Warburg effect in COVID-19 can be essential to developing molecules reducing infectivity, arresting endothelial cells activation and the pro-inflammatory cascade. • Enhanced aerobic glycolysis supports replication of many viruses including MERS-CoV. • PI3K/AKT and MAPK/ERK inhibitors arrest MERS-CoV replication. • This metabolism likely sustains SARS-CoV-2 replication in host cells, in particular airway cells. • The Warburg effect also supports activation of endothelial cells and pro-inflammatory cells. [ABSTRACT FROM AUTHOR]

Purpose: The widespread use of Nivolumab results in an increasing number of side effects and adverse events. Herein, we evaluated the impact of Nivolumab on crude and normalized pulmonary artery diameter (PAD).Methods: We analyzed clinical, morphometric, pathological and radiological data of lung cancer patients treated by Nivolumab in an 18-month period. Blinded radiological evaluation was performed, by three observers measuring axial PAD and Aorta diameter (AoD) in secondarily matched pre- and post-Nivolumab CT-scans. Correlation between ΔPAD and clinicopathological data was investigated.Results: 59 patients receiving Nivolumab for treatment of advanced lung carcinoma were identified. Pre-and post-Nivolumab comparison of CT-scan measures revealed that mean PAD was 26.3 ± 2.8 mm versus 28.0 ± 3.0 mm (p < 0.001), and mean PAD/AoD ratio was 0.82 ± 0.09 versus 0.87 ± 0.11 (p <  0.001), respectively. Median ΔPAD was 0.05 [0.01-0.122] was significantly higher in hypometabolic patients exhibiting low Rest Energy Expenditure (p = 0.03). Patients exhibiting ΔPAD > 1% had significantly lower serum albumin level (p = 0.03), and higher nutritional risk (p = 0.02), compared to others. Unlike Nivolumab therapy, there was no increase of PAD after chemotherapy in the same cohort of patients with available scans (n = 45, 25.9 ± 2.9 mm pre-chemotherapy versus 25.7 ± 2.4 mm post-chemotherapy, p = 0.51). Anti-PD-1 treatment was associated with immune-related adverse events in 11 (18.6%) cases including 2 cases of life-threatening acute pulmonary hypertension, both exhibiting post-treatment PAD/AoD ratio > 1.Conclusion: Nivolumab is associated to PAD enlargement, a potential marker of pulmonary hypertension, sometimes leading to lethal adverse events. Careful CT-scan and echocardiographic evaluation of PAD should be part of the therapeutic work-up of patients receiving Nivolumab, especially those suffering cancer-associated malnutrition. [ABSTRACT FROM AUTHOR]

ACLY links energy metabolism provided by catabolic pathways to biosynthesis. ACLY, which has been found to be overexpressed in many cancers, converts citrate into acetyl-CoA and OAA. The first of these molecules supports protein acetylation, in particular that of histone, and de novo lipid synthesis, and the last one sustains the production of aspartate (required for nucleotide and polyamine synthesis) and the regeneration of NADPH,H+(consumed in redox reaction and biosynthesis). ACLY transcription is promoted by SREBP1, its activity is stabilized by acetylation and promoted by AKT phosphorylation (stimulated by growth factors and glucose abundance). ACLY plays a pivotal role in cancer metabolism through the potential deprivation of cytosolic citrate, a process promoting glycolysis through the enhancement of the activities of PFK 1 and 2 with concomitant activation of oncogenic drivers such as PI3K/AKT which activate ACLY and the Warburg effect in a feed-back loop. Pending the development of specific inhibitors and tailored methods for identifying which specific metabolism is involved in the development of each tumor, ACLY could be targeted by inhibitors such as hydroxycitrate and bempedoic acid. The administration of citrate at high level mimics a strong inhibition of ACLY and could be tested to strengthen the effects of current therapies. [ABSTRACT FROM AUTHOR]

Background Esophageal gastrointestinal stromal tumors (E-GISTs) represent less than 1% of all GISTs. The rarity of this lesion precludes the realization of randomized studies, and its treatment remains a matter of debate. We aimed to evaluate the feasibility of enucleation by video-assisted thoracic surgery (VATS) for low- to intermediate-risk E-GIST. Methods We performed a retrospective review of patients treated by enucleation through VATS between January 2004 and January 2014 and reviewed the literature. Results We included five patients (four men and one woman). Mean age was 53 years (range: 49–79). Three patients were diagnosed because of dysphagia and two others incidentally. The diagnosis was made by immunostaining demonstrating CD117 expression on tumor cells. The mitotic index of all E-GISTs was low (≤ 5 per 50 high-power field). Median postoperative follow-up was 5.5 years, and there was no recurrence. Conclusion Thoracoscopic enucleation of E-GIST seems to represent a valuable option as the postoperative morbidity/mortality is low and the oncological outcome is good for low-to-intermediate grade of malignity tumors. This is a retrospective study focused on minimally invasive treatment of E-GIST. We evaluated the feasibility of VATS enucleation of low-to-medium grade of malignity E-GIST. [ABSTRACT FROM AUTHOR]

Cell cycle progression and division is regulated by checkpoint controls and sequential activation of cyclin-dependent kinases (CDKs). Understanding of how these events occur in synchrony with metabolic changes could have important therapeutic implications. For biosynthesis, cancer cells enhance glucose and glutamine consumption. Inactivation of pyruvate kinase M2 (PKM2) promotes transcription in G1 phase. Glutamine metabolism supports DNA replication in S phase and lipid synthesis in G2 phase. A boost in glycolysis and oxidative metabolism can temporarily furnish more ATP when necessary (G1/S transition, segregation of chromosomes). Recent studies have shown that a few metabolic enzymes [PKM2, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB3), GAPDH] also periodically translocate to the nucleus and oversee cell cycle regulators or oncogene expression (c-Myc). Targeting these metabolic enzymes could increase the response to CDK inhibitors (CKIs). The Warburg effect promotes a reductive metabolism that limits the production of ROS, which can be toxic for DNA replication. Aerobic glycolysis actively supports protein synthesis, in G1 phase particularly. Dimeric PKM2 promotes cellular biosynthesis and expression of cyclin D1. PFKFB3 increases ATP production at the G1 restriction checkpoint and promotes activation of cyclins D and E. The upregulation of GLS1 enhances glutaminolysis, which sustains DNA replication in S phase. Some glycolytic enzymes (PKM2, ALDO, GAPDH) periodically translocate to the nucleus upregulating the expression of genes involved in the cell cycle. [ABSTRACT FROM AUTHOR]

Icard, Philippe, and Georges Saumon. Alveolar sodium and liquid transport in mice. Am. J. Physiol. 277 (Lung Cell. Mol. Physiol. 21): L1232-L1238, 1999.--We have developed a simple isolated lung preparation for measurement of liquid and solute fluxes across mouse alveolar epithelium. Liquid instilled into air spaces was absorbed at the rate ([J.sub.w]) of 3.7 [+ or -] 0.32 ml [multiplied by] [h.sup.-1] [multiplied by] g dry lung [wt.sup.-1]. [J.sub.w] was significantly depressed by ouabain (P [is less than] 0.001) and amiloride (P [is less than] 0.001). Omission of glucose from the instillate or addition of the [Na.sup.+]-glucose cotransport inhibitor phloridzin did not affect [J.sub.w]. However, the low epithelial lining fluid glucose concentration (one-third that of plasma), the larger-than-mannitol permeability of methyl-[Alpha]-D-glucopyranoside, and the presence of [Na.sup.+]-glucose cotransporter SGLT1 mRNA in mouse lung tissue suggest that there is a [Na.sup.+]-glucose cotransporter in the mouse alveolar-airway barrier. Isoproterenol stimulated [J.sub.w] (6.5 [+ or -] 0.45 ml [multiplied by] [h.sup.-1] [multiplied by] g dry lung [wt.sup.-1]; P [is less than] 0.001), and this effect was blocked by amiloride, benzamil, ouabain, and the specific [[Beta].sub.2]-adrenergic antagonist ICI-118551 but not by atenolol. Similar stimulation was obtained with terbutaline (6.4 [+ or -] 0.46 ml [multiplied by] [h.sup.-1] [multiplied by] g dry lung [wt.sup.-1]). [Na.sup.+] unidirectional fluxes out of air spaces varied in agreement with [J.sub.w] changes. Thus alveolar liquid absorption in mice follows [Na.sup.+] transport via the amiloride-sensitive pathway, with little contribution from [Na.sup.+]-glucose cotransport, and is stimulated by [Beta]2-adrenergic agonists. glucose transport; pulmonary alveoli; pulmonary edema

Background: Ovarian carcinoma is the leading cause of death from gynecological cancer because there is risk of chemoresistance. As previously demonstrated in our laboratory, Alpha-lipoic acid (LA), a co-factor for metabolic enzymes, suppresses the tumor growth. In this study, we have researched the mechanisms that are responsible for the activity of LA. Methods: We have studied the mechanisms of LA in two ovarian cancer cell lines, a cisplatin sensitive one, IGROV1 and its resistant counterpart, IGROV1-R10. These cells have been exposed to lipoic acid at various concentrations. Cell proliferation, cell cycle repartition and nuclear staining with DAPI were recorded. Western blot analyses were performed to detect various proteins implied in apoptotic cell death pathways. To investigate the formation of ROS, the oxidation of CM-DCFH2-DA were also determined. Findings: LA suppressed growth proliferation and induced apoptosis in both ovarian cell lines. Moreover, LA provoked a down regulation of two anti-apoptotic proteins, Mcl-1 and Bcl-xL protein and a strong induction of the BH3-only protein Bim. Furthermore, LA induced ROS generation which could be involved in the CHOP induction which is known to activate the Bim translation. Conclusions: Our results reveal novel actions of LA which could explain the anti-tumoral effects of the LA. Therefore, LA seems to be a promising compound for ovarian cancer treatment. [ABSTRACT FROM AUTHOR]

The inhibition of two major anti-apoptotic proteins, Bcl-xL and Mcl-1, appears essential to destroy chemoresistant cancer cells. We have studied their concomitant inhibition, using ABT 737 or siRNA targeting XL1 and citrate, a molecule which reduces the expression level of Mcl-1. Two cisplatin-chemoresistant ovarian cell lines (SKOV3 and IGROV1-R10) were exposed to ABT 737 or siRNA targeting XL1 and citrate at various individual concentrations, or combined. Cell proliferation, cell cycle repartition and nuclear staining with DAPI were recorded. Western blot analyses were performed to detect various proteins implied in apoptotic cell death pathways. Mcl-1 expression was barely reduced when cells were exposed to citrate alone, whereas a mild reduction was observed after ABT 737 treatment. Concomitant inhibition of Bcl-xL and Mcl-1 using ABT 737 or siXL1 associated with citrate was far more effective in inhibiting cell proliferation and inducing cell death than treatment alone. Given that few, if any, specific inhibitors of Mcl-1 are currently available, anti-glycolytic agents such as citrate could be tested in association with synthetic inhibitors of Bcl-xL [ABSTRACT FROM AUTHOR]

Background: Results of bilobectomy for non-small cell lung cancer have rarely been studied. Methods: Retrospective analysis was conducted on patients with non-small cell lung cancer having undergone bilobectomy from January 1999 to June 2012 at our institution. Analysis aimed at determining perioperative mortality and morbidity, and at studying prognostic factors for long-term survival using the 7th TNM classification. Results: A total of 103 patients (85 males; mean age 62 years) underwent upper-middle bilobectomy (n = 54) or lower-middle bilobectomy (n = 49). Histologic examination revealed 51 adenocarcinomas, 43 squamous cell carcinomas and 9 other cell carcinomas. Perioperative mortality was 0.97%. The overall morbidity rate was 71%, whereas the rate of life-threatening complications was 9.6%. Complications were more frequent in men (p = 0.032), in patients with chronic pulmonary obstructive diseases (p = 0.030) and after lower-middle bilobectomy (p = 0.0016). The overall 5-year Kaplan-Meier survival rate was 57.8%. In univariate analysis, factors associated with increased survival were the following: pathologic stage (stage I 74.9%, stage II 64.1%, stage III 28.8%, p = 0.0018); nodal status (N0 vs N1, p = 0.011; N0 vs N2, p = 0.0015; N0 vs N+, p = 0.0008); R status (R0 vs R1, p = 0.0032), and smoking status (past smoker or nonsmoker vs active smoker, p = 0.00054). Multivariate analysis revealed that active smokers (RR = 3.87, CI 95% [1.83 to 8.21]; p = 0.00042) and increasing stage (stage 0: RR=1; stage I: RR = 1.98, CI 95% [1.38 to 2.83]; stage II: RR = 3.90, CI 95% [1.90 to 8.02]; stage III: RR=7.72, CI 95% [2.62 to 22.73]; stage IV: RR = 15.25, CI 95% [3.61 to 64.40]; p = 0.0042) were significantly associated with poorer survival. Conclusions: Bilobectomy can be performed with low mortality, acceptable morbidity and long term survival in accordance with TNM staging. [Copyright &y& Elsevier]

Purpose: The purpose of the study was to compare 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and 99mTc-depreotide single-photon emission computed tomography (SPECT) in the diagnosis of malignancy of solitary pulmonary nodules (SPNs). Methods: Twenty-eight patients without any history of cancer and presenting an SPN (0.8-3 cm in size) underwent FDG PET and depreotide SPECT. Depreotide SPECT and FDG PET were performed on a double-head gamma camera and a dedicated PET scanner respectively. Twenty-five out of 28 lesions were removed by thoracotomy or assessed by biopsy (n=1) and histologically examined. A strategy of serial CT scanning was adopted in the three remaining patients. Results: Histological findings revealed 18 malignant nodules and seven benign lesions. Stability over a 2-year period indicated a benign process in the remaining three cases. Both techniques yielded true positive results in 15 of the 18 cancers. FDG PET identified two additional adenocarcinomas not detected by depreotide SPECT. A carcinoid tumour not visualised on FDG PET was identified by depreotide SPECT. Seven of the ten benign lesions did not reveal tracer uptake on either depreotide SPECT or FDG PET. Both techniques showed false positive results for the same two lesions. One more false positive was seen on FDG PET. FDG PET and depreotide SPECT had a sensitivity of 94.4% and 88.9% respectively; this difference was not significant. In our experience, depreotide SPECT and FDG PET are equally sensitive (92.3%) for large (>1.5 cm) and equally specific (85.7%) for small (up to 1.5 cm) SPNs suspicious for malignancy. Conclusion: This study showed 18F-FDG PET to be more sensitive than 99mTc-depreotide SPECT in the diagnosis of malignancy of SPNs. However, the combination of both techniques may provide additional accuracy. [ABSTRACT FROM AUTHOR]

: BackgroundSuperior vena cava syndrome (SVCS) is often seen in the natural history of malignant thoracic diseases. SVCS is characterized by unpleasant symptoms that usually lead to death. The purpose of our study is to show the efficiency of percutaneous stenting in the superior vena cava for relieving SVCS and the possibility of repeated stenting after recurrence.: MethodsTwenty patients with SVCS caused by malignant diseases who had one or more stents placed in the superior vena cava or its main tributaries were evaluated.: ResultsOut of 20 patients, 1 died of myocardial infarction 24 hours after the procedure without any signs of pulmonary embolus, hemorrhage, or malposition of the stent. SVCS was successfully controlled in 94% of patients until death or completion of the study. In 3 patients the procedure was repeated (3 to 20 weeks later) because of the recurrence of symptoms.: ConclusionsPercutaneous venous stent placement in the superior vena cava is a simple and effective technique to relieve rapid SVCS caused by malignancies. When recurrence occurs, repeated stenting can be performed successfully. [Copyright &y& Elsevier]

Citrate plays a central role in cancer cells' metabolism and regulation. Derived from mitochondrial synthesis and/or carboxylation of α-ketoglutarate, it is cleaved by ATP-citrate lyase into acetyl-CoA and oxaloacetate. The rapid turnover of these molecules in proliferative cancer cells maintains a low-level of citrate, precluding its retro-inhibition on glycolytic enzymes. In cancer cells relying on glycolysis, this regulation helps sustain the Warburg effect. In those relying on an oxidative metabolism, fatty acid β-oxidation sustains a high production of citrate, which is still rapidly converted into acetyl-CoA and oxaloacetate, this latter molecule sustaining nucleotide synthesis and gluconeogenesis. Therefore, citrate levels are rarely high in cancer cells. Resistance of cancer cells to targeted therapies, such as tyrosine kinase inhibitors (TKIs), is frequently sustained by aerobic glycolysis and its key oncogenic drivers, such as Ras and its downstream effectors MAPK/ERK and PI3K/Akt. Remarkably, in preclinical cancer models, the administration of high doses of citrate showed various anti-cancer effects, such as the inhibition of glycolysis, the promotion of cytotoxic drugs sensibility and apoptosis, the neutralization of extracellular acidity, and the inhibition of tumors growth and of key signalling pathways (in particular, the IGF-1R/AKT pathway). Therefore, these preclinical results support the testing of the citrate strategy in clinical trials to counteract key oncogenic drivers sustaining cancer development and resistance to anti-cancer therapies. [ABSTRACT FROM AUTHOR]