Phosphoinositide 3-Kinase Regulates Glycolysis through Mobilization of Aldolase from the Actin Cytoskeleton.

The phosphoinositide 3-kinase (PI3K) pathway regulates multiple steps in glucose metabolism and also cytoskeletal functions, such as cell movement and attachment. Here, we show that PI3K directly coordinates glycolysis with cytoskeletal dynamics in an AKT-independent manner. Growth factors or insulin stimulate the PI3K-dependent activation of Rac, leading to disruption of the actin cytoskeleton, release of filamentous actin-bound aldolase A, and an increase in aldolase activity. Consistently, PI3K inhibitors, but not AKT, SGK, or mTOR inhibitors, cause a significant decrease in glycolysis at the step catalyzed by aldolase, while activating PIK3CA mutations have the opposite effect. These results point toward a master regulatory function of PI3K that integrates an epithelial cell's metabolism and its form, shape, and function, coordinating glycolysis with the energy-intensive dynamics of actin remodeling.

Tuning MPL signaling to influence hematopoietic stem cell differentiation and inhibit essential thrombocythemia progenitors.

Thrombopoietin (TPO) and the TPO-receptor (TPO-R, or c-MPL) are essential for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Agents that can modulate TPO-R signaling are highly desirable for both basic research and clinical utility. We developed a series of surrogate protein ligands for TPO-R, in the form of diabodies (DBs), that homodimerize TPO-R on the cell surface in geometries that are dictated by the DB receptor binding epitope, in effect "tuning" downstream signaling responses. These surrogate ligands exhibit diverse pharmacological properties, inducing graded signaling outputs, from full to partial TPO agonism, thus decoupling the dual functions of TPO/TPO-R. Using single-cell RNA sequencing and HSC self-renewal assays we find that partial agonistic diabodies preserved the stem-like properties of cultured HSCs, but also blocked oncogenic colony formation in essential thrombocythemia (ET) through inverse agonism. Our data suggest that dampening downstream TPO signaling is a powerful approach not only for HSC preservation in culture, but also for inhibiting oncogenic signaling through the TPO-R.

13 C NMR quantification of polyamine syntheses in rat prostate.

Currently, many prostate cancer patients, detected through the prostate specific antigen test, harbor organ-confined indolent disease that cannot be differentiated from aggressive cancer according to clinically and pathologically known measures. Spermine has been considered as an endogenous inhibitor for prostate-confined cancer growth and its expression has shown correlation with prostate cancer growth rates. If established clinically, measurements of spermine bio-synthesis rates in prostates may predict prostate cancer growth and patient outcomes. Using rat models, we tested the feasibility of quantifying spermine bio-synthesis rates with 13 C NMR. Male Copenhagen rats (10 weeks, n = 6) were injected with uniformly 13 C-labeled L-ornithine HCl, and were sacrificed in pairs at 10, 30, and 60 min after injection. Another two rats were injected with saline and sacrificed at 30 min as controls. Prostates were harvested and extracted with perchloric acid and the neutralized solutions were examined by 13 C NMR at 600 MHz. 13 C NMR revealed measurable ornithine, as well as putrescine-spermidine-spermine syntheses in rat prostates, allowing polyamine bio-synthetic and ornithine bio-catabolic rates to be calculated. Our study demonstrated the feasibility of 13 C NMR for measuring bio-synthesis rates of ornithine to spermine enzymatic reactions in rat prostates. The current study established a foundation upon which future investigations of protocols that differentiate prostate cancer growth rates according to the measure of ornithine to spermine bio-synthetic rates may be developed.

Tracing the origins of relapse in acute myeloid leukaemia to stem cells.

In acute myeloid leukaemia, long-term survival is poor as most patients relapse despite achieving remission. Historically, the failure of therapy has been thought to be due to mutations that produce drug resistance, possibly arising as a consequence of the mutagenic properties of chemotherapy drugs. However, other lines of evidence have pointed to the pre-existence of drug-resistant cells. For example, deep sequencing of paired diagnosis and relapse acute myeloid leukaemia samples has provided direct evidence that relapse in some cases is generated from minor genetic subclones present at diagnosis that survive chemotherapy, suggesting that resistant cells are generated by evolutionary processes before treatment and are selected by therapy. Nevertheless, the mechanisms of therapy failure and capacity for leukaemic regeneration remain obscure, as sequence analysis alone does not provide insight into the cell types that are fated to drive relapse. Although leukaemia stem cells have been linked to relapse owing to their dormancy and self-renewal properties, and leukaemia stem cell gene expression signatures are highly predictive of therapy failure, experimental studies have been primarily correlative and a role for leukaemia stem cells in acute myeloid leukaemia relapse has not been directly proved. Here, through combined genetic and functional analysis of purified subpopulations and xenografts from paired diagnosis/relapse samples, we identify therapy-resistant cells already present at diagnosis and two major patterns of relapse. In some cases, relapse originated from rare leukaemia stem cells with a haematopoietic stem/progenitor cell phenotype, while in other instances relapse developed from larger subclones of immunophenotypically committed leukaemia cells that retained strong stemness transcriptional signatures. The identification of distinct patterns of relapse should lead to improved methods for disease management and monitoring in acute myeloid leukaemia. Moreover, the shared functional and transcriptional stemness properties that underlie both cellular origins of relapse emphasize the importance of developing new therapeutic approaches that target stemness to prevent relapse.

Palladium-Catalyzed γ,γ'-Diarylation of Free Alkenyl Amines.

The direct difunctionalization of alkenes is an effective way to construct multiple C-C bonds in one-pot using a single functional group. The regioselective dicarbofunctionalization of alkenes is therefore an important area of research to rapidly obtain complex organic molecules. Herein, we report a palladium-catalyzed γ,γ'-diarylation of free alkenyl amines through interrupted chain walking for the synthesis of Z-selective alkenyl amines. Notably, while 1,3-dicarbofunctionalization of allyl groups is well precedented, the present disclosure allows 1,3-dicarbofunctionalization of highly substituted allylamines to give highly Z-selective trisubsubstituted olefin products. This cascade reaction operates via an unprotected amine-directed Mizoroki-Heck (MH) pathway featuring a ß-hydride elimination to selectively chain walk to furnish a new terminal olefin which then generates the cis-selective alkenyl amines around the sterically crowded allyl moiety. This operationally simple protocol is applicable to a variety of cyclic, branched, and linear secondary and tertiary alkenylamines, and has a broad substrate scope with regard to the arene coupling partner as well. Mechanistic studies have been performed to help elucidate the mechanism, including the presence of a likely unproductive side C-H activation pathway.

Visualizing the effects of lactate dehydrogenase (LDH) inhibition and LDH-A genetic ablation in breast and lung cancer with hyperpolarized pyruvate NMR.

In many tumors, cancer cells take up large quantities of glucose and metabolize it into lactate, even in the presence of sufficient oxygen to support oxidative metabolism. It has been hypothesized that this malignant metabolic phenotype supports cancer growth and metastasis, and that reversal of this so-called "Warburg effect" may selectively harm cancer cells. Conversion of glucose to lactate can be reduced by ablation or inhibition of lactate dehydrogenase (LDH), the enzyme responsible for conversion of pyruvate to lactate at the endpoint of glycolysis. Recently developed inhibitors of LDH provide new opportunities to investigate the role of this metabolic pathway in cancer. Here we show that magnetic resonance spectroscopic imaging of hyperpolarized pyruvate and its metabolites in models of breast and lung cancer reveal that inhibition of LDH was readily visualized through reduction in label exchange between pyruvate and lactate, while genetic ablation of the LDH-A isoform alone had smaller effects. During the acute phase of LDH inhibition in breast cancer, no discernible bicarbonate signal was observed and small signals from alanine were unchanged.

In vivo measurement of a new source of contrast, the dipolar relaxation time, T1D , using a modified inhomogeneous magnetization transfer (ihMT) sequence.

PURPOSE: This paper describes a technique that can be used in vivo to measure the dipolar relaxation time, T1D , of macromolecular protons contributing to magnetization transfer (MT) in tissues and to produce quantitative T1D maps. THEORY AND METHODS: The technique builds upon the inhomogeneous MT (ihMT) technique that is particularly sensitive to tissue components with long T1D . A standard ihMT experiment was altered to introduce a variable time for switching between positive and negative offset frequencies for RF saturation. A model for the dependence of ihMT was developed and used to fit data acquired in vivo. RESULTS: Application of the method to images from brains of healthy volunteers produced values of T1D = (5.9 ± 1.2) ms in gray matter and T1D = (6.2 ± 0.4) ms in white matter regions and provided maps of the T1D parameter. CONCLUSION: The model and experiments described provide access to a new relaxation characteristic of tissue with potentially unique diagnostic information. Magn Reson Med 78:1362-1372, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Selective spectroscopic imaging of hyperpolarized pyruvate and its metabolites using a single-echo variable phase advance method in balanced SSFP.

PURPOSE: In balanced steady state free precession (bSSFP), the signal intensity has a well-known dependence on the off-resonance frequency, or, equivalently, the phase advance between successive radiofrequency (RF) pulses. The signal profile can be used to resolve the contributions from the spectrally separated metabolites. This work describes a method based on use of a variable RF phase advance to acquire spatial and spectral data in a time-efficient manner for hyperpolarized 13C MRI. THEORY AND METHODS: The technique relies on the frequency response from a bSSFP acquisition to acquire relatively rapid, high-resolution images that may be reconstructed to separate contributions from different metabolites. The ability to produce images from spectrally separated metabolites was demonstrated in vitro, as well as in vivo following administration of hyperpolarized 1-13C pyruvate in mice with xenograft tumors. RESULTS: In vivo images of pyruvate, alanine, pyruvate hydrate, and lactate were reconstructed from four images acquired in 2 s with an in-plane resolution of 1.25 × 1.25 mm(2) and 5 mm slice thickness. CONCLUSION: The phase advance method allowed acquisition of spectroscopically selective images with high spatial and temporal resolution. This method provides an alternative approach to hyperpolarized 13C spectroscopic MRI that can be combined with other techniques such as multiecho or fluctuating equilibrium bSSFP. Magn Reson Med 76:1102-1115, 2016. © 2015 Wiley Periodicals, Inc.

A Practical Guide to MR Imaging Safety: What Radiologists Need to Know.

Magnetic resonance (MR) imaging can provide critical diagnostic and anatomic information while avoiding the use of ionizing radiation, but it has a unique set of safety risks associated with its reliance on large static and changing magnetic fields, high-powered radiofrequency coil systems, and exogenous contrast agents. It is crucial for radiologists to understand these risks and how to mitigate them to protect themselves, their colleagues, and their patients from avoidable harm and to comply with safety regulations at MR imaging sites. Basic knowledge of MR imaging physics and hardware is necessary for radiologists to understand the origin of safety regulations and to avoid common misconceptions that could compromise safety. Each of the components of the MR imaging unit can be a factor in injuries to patients and personnel. Safety risks include translational force and torque, projectile injury, excessive specific absorption rate, burns, peripheral neurostimulation, interactions with active implants and devices, and acoustic injury. Standards for MR imaging device safety terminology were first issued in 2005 and are required by the U.S. Food and Drug Administration, with devices labeled as "MR safe," "MR unsafe," or "MR conditional." MR imaging contrast agent safety is also discussed. Additional technical and safety policies relate to pediatric, unconscious, incapacitated, or pregnant patients and pregnant imaging personnel. Division of the MR imaging environment into four distinct, clearly labeled zones--with progressive restriction of entry and increased supervision for higher zones--is a mandatory and key aspect in avoidance of MR imaging-related accidents. All MR imaging facilities should have a documented plan to handle emergencies within zone IV, including cardiac arrest or code, magnet quench, and fires. Policies from the authors' own practice are provided for additional reference. Online supplemental material is available for this article.

Development of a Tool to Assess Surgical Resident Competence On-Call: The Western University Call Assessment Tool (WUCAT).

BACKGROUND: A central tenet of competency-based medical education is the formative assessment of trainees. There are currently no assessments designed to examine resident competence on-call, despite the on-call period being a significant component of residency, characterized by less direct supervision compared to daytime. The purpose of this study was to design a formative on-call assessment tool and collect valid evidence on its application. METHODS: Nominal group technique was used to identify critical elements of surgical resident competence on-call to inform tool development. The tool was piloted over six months in the Division of Plastic & Reconstructive Surgery at our institution. Quantitative and qualitative evidence was collected to examine tool validity. RESULTS: A ten-item tool was developed based on the consensus group results. Sixty-three assessments were completed by seven staff members on ten residents during the pilot. The tool had a reliability coefficient of 0.67 based on a generalizability study and internal item consistency was 0.92. Scores were significantly associated with years of training. We found the tool improved the quantity and structure of feedback given and that the tool was considered feasible and acceptable by both residents and staff members. CONCLUSIONS: The Western University Call Assessment Tool (WUCAT) has multiple sources of evidence supporting its use in assessing resident competence on-call.

Characterizing Metabolic Heterogeneity of Hepatocellular Carcinoma with Hyperpolarized 13C Pyruvate MRI and Mass Spectrometry.

Purpose To characterize the metabolomic profiles of two hepatocellular carcinoma (HCC) rat models, track evolution of these profiles to a stimulated tumor state, and assess their effect on lactate flux with hyperpolarized (HP) carbon 13 (13C) MRI. Materials and Methods Forty-three female adult Fischer rats were implanted with N1S1 or McA-RH7777 HCC tumors. In vivo lactate-to-pyruvate ratio (LPR) was measured with HP 13C MRI at 9.4 T. Ex vivo mass spectrometry was used to measure intratumoral metabolites, and Ki67 labeling was used to quantify proliferation. Tumors were first compared with three normal liver controls. The tumors were then compared with stimulated variants via off-target hepatic thermal ablation treatment. All comparisons were made using the Mann-Whitney test. Results HP 13C pyruvate MRI showed greater LPR in N1S1 tumors compared with normal liver (mean [SD], 0.564 ± 0.194 vs 0.311 ± 0.057; P < .001 [n = 9]), but not for McA-RH7777 (P = .44 [n = 8]). Mass spectrometry confirmed that the glycolysis pathway was increased in N1S1 tumors and decreased in McA-RH7777 tumors. The pentose phosphate pathway was also decreased only in McA-RH7777 tumors. Increased proliferation in stimulated N1S1 tumors corresponded to a net increase in LPR (six stimulated vs six nonstimulated, 0.269 ± 0.148 vs 0.027 ± 0.08; P = .009), but not in McA-RH7777 (eight stimulated vs six nonstimulated, P = .13), despite increased proliferation and metastases. Mass spectrometry demonstrated relatively increased lactate production with stimulation in N1S1 tumors only. Conclusion Two HCC subtypes showed divergent glycolytic dependency at baseline and during transformation to a high proliferation state. This metabolic heterogeneity in HCC should be considered with use of HP 13C MRI for diagnosis and tracking. Keywords: Molecular Imaging-Probe Development, Liver, Abdomen/GI, Oncology, Hepatocellular Carcinoma © RSNA, 2024 See also commentary by Ohliger in this issue.

The eye in pregnancy: ophthalmologic and neuro-ophthalmologic changes.

A variety of changes in the eye can occur during pregnancy. These can be physiological, pathologic related to the pregnancy, or pathologic unrelated to the pregnancy. Pregnancy also can affect preexisting conditions. Pregnant women often discuss changes in their health first with their obstetrician; therefore, knowledge of common ophthalmic complaints during pregnancy is of particular concern for the practicing obstetrician. We reviewed the literature for ophthalmic and neuro-ophthalmic conditions that occur during pregnancy or in the postpartum period. Results are presented anatomically, first discussing general ophthalmologic conditions, then neuro-ophthalmic conditions follow. Effects of ocular medications on the fetus are reviewed.

"Influential" Intraoperative Educators and Variability of Teaching Styles.

OBJECTIVES: Academic surgeons manage their role as intraoperative educators in a variety of ways. Such variability is neither idiosyncratic nor is there a single best approach. This study sought to explore the practices of surgeons deemed influential by their residents, allowing insight into a variety of potentially effective practices. PARTICIPANTS: Constructivist grounded theory guided data collection and analysis. Data sources included surveys from senior surgical residents (PGY3-6) and recent graduates from an academic hospital in Canada (36% response rate), intraoperative observations of teaching interactions, and semi-structured interviews with observed surgeons. Rigour was supported by data triangulation, constant comparison, and collection to theoretical sufficiency. DESIGN: We developed a framework grouping effective teaching into three overlapping approaches: exacting, empowering, and fostering. The approaches differ based on the level of independence granted and the degree of expectation placed on individual residents. Each demonstrates different strategies for balancing the multiple supervisory roles and patient care obligations faced by academic surgeons. We also identified strategies that could be used across approaches to enhance learning. CONCLUSIONS: For surgical educators seeking to improve upon the quality of the intraoperative supervision they provide, frameworks such as this may serve as models of effective supervision. Enhancing surgeons' knowledge of proven strategies, combined with reflecting on how they teach and how they balance responsibilities to patients and trainees, may allow them to broaden their educational practice.

PFKFB3-mediated Pro-glycolytic Shift in Hepatocellular Carcinoma Proliferation.

BACKGROUND & AIMS: Metabolic reprogramming, in particular, glycolytic regulation, supports abnormal survival and growth of hepatocellular carcinoma (HCC) and could serve as a therapeutic target. In this study, we sought to identify glycolytic regulators in HCC that could be inhibited to prevent tumor progression and could also be monitored in vivo, with the goal of providing a theragnostic alternative to existing therapies. METHODS: An orthotopic HCC rat model was used. Tumors were stimulated into a high-proliferation state by use of off-target liver ablation and were compared with lower-proliferating controls. We measured in vivo metabolic alteration in tumors before and after stimulation, and between stimulated tumors and control tumors using hyperpolarized 13C magnetic resonance imaging (MRI) (h13C MRI). We compared metabolic alterations detected by h13C MRI to metabolite levels from ex vivo mass spectrometry, mRNA levels of key glycolytic regulators, and histopathology. RESULTS: Glycolytic lactate flux increased within HCC tumors 3 days after tumor stimulation, correlating positively with tumor proliferation as measured with Ki67. This was associated with a shift towards aerobic glycolysis and downregulation of the pentose phosphate pathway detected by mass spectrometry. MRI-measured lactate flux was most closely coupled with PFKFB3 expression and was suppressed with direct inhibition using PFK15. CONCLUSIONS: Inhibition of PFKFB3 prevents glycolytic-mediated HCC proliferation, trackable by in vivo h13C MRI.

Reprogramming Cancer into Antigen-Presenting Cells as a Novel Immunotherapy.

Therapeutic cancer vaccination seeks to elicit activation of tumor-reactive T cells capable of recognizing tumor-associated antigens (TAA) and eradicating malignant cells. Here, we present a cancer vaccination approach utilizing myeloid-lineage reprogramming to directly convert cancer cells into tumor-reprogrammed antigen-presenting cells (TR-APC). Using syngeneic murine leukemia models, we demonstrate that TR-APCs acquire both myeloid phenotype and function, process and present endogenous TAAs, and potently stimulate TAA-specific CD4+ and CD8+ T cells. In vivo TR-APC induction elicits clonal expansion of cancer-specific T cells, establishes cancer-specific immune memory, and ultimately promotes leukemia eradication. We further show that both hematologic cancers and solid tumors, including sarcomas and carcinomas, are amenable to myeloid-lineage reprogramming into TR-APCs. Finally, we demonstrate the clinical applicability of this approach by generating TR-APCs from primary clinical specimens and stimulating autologous patient-derived T cells. Thus, TR-APCs represent a cancer vaccination therapeutic strategy with broad implications for clinical immuno-oncology. SIGNIFICANCE: Despite recent advances, the clinical benefit provided by cancer vaccination remains limited. We present a cancer vaccination approach leveraging myeloid-lineage reprogramming of cancer cells into APCs, which subsequently activate anticancer immunity through presentation of self-derived cancer antigens. Both hematologic and solid malignancies derive significant therapeutic benefit from reprogramming-based immunotherapy. This article is highlighted in the In This Issue feature, p. 1027.

Stat3 is a positive regulator of gap junctional intercellular communication in cultured, human lung carcinoma cells.

BACKGROUND: Neoplastic transformation of cultured cells by a number of oncogenes such as src suppresses gap junctional, intercellular communication (GJIC); however, the role of Src and its effector Signal transducer and activator of transcription-3 (Stat3) upon GJIC in non small cell lung cancer (NSCLC) has not been defined. Immunohistochemical analysis revealed high Src activity in NSCLC biopsy samples compared to normal tissues. Here we explored the potential effect of Src and Stat3 upon GJIC, by assessing the levels of tyr418-phosphorylated Src and tyr705-phosphorylated Stat3, respectively, in a panel of NSCLC cell lines. METHODS: Gap junctional communication was examined by electroporating the fluorescent dye Lucifer yellow into cells grown on a transparent electrode, followed by observation of the migration of the dye to the adjacent, non-electroporated cells under fluorescence illumination. RESULTS: An inverse relationship between Src activity levels and GJIC was noted; in five lines with high Src activity GJIC was absent, while two lines with extensive GJIC (QU-DB and SK-LuCi6) had low Src levels, similar to a non-transformed, immortalised lung epithelial cell line. Interestingly, examination of the mechanism indicated that Stat3 inhibition in any of the NSCLC lines expressing high endogenous Src activity levels, or in cells where Src was exogenously transduced, did not restore GJIC. On the contrary, Stat3 downregulation in immortalised lung epithelial cells or in the NSCLC lines displaying extensive GJIC actually suppressed junctional permeability. CONCLUSIONS: Our findings demonstrate that although Stat3 is generally growth promoting and in an activated form it can act as an oncogene, it is actually required for gap junctional communication both in nontransformed lung epithelial cells and in certain lung cancer lines that retain extensive GJIC.

Incidence of major and minor brain injuries in facial fractures.

BACKGROUND: Facial fractures can be associated with brain and cervical spine injuries because impact forces are transmitted through the head and neck. Although major brain injury is commonly recognized in these patients, incidence of minor brain injury is not well-known, despite potential morbidity and mortality. OBJECTIVES: This prospective study aimed to determine the incidence of both major and minor brain injuries in 100 patients presenting to a craniofacial surgery service with facial fractures and to identify characteristics associated with brain injury. METHODS: Data were collected for a 9-month period by a craniofacial surgeon at a level I trauma center. A questionnaire and checklist were designed to capture information about major and minor brain injury in patients with facial fractures. Assessments were completed in the outpatient clinic, emergency department, hospital ward, or intensive care unit during the first patient encounters. RESULTS: The average age of patients was 34 years; 79% were male. Time between injury and assessment ranged from less than a few hours to 4 months. Incidence of brain injury was 67% overall: 29% with major brain injury and 38% with minor injury. Major brain injury was commonly diagnosed early in the emergency department or intensive care unit. Conversely, minor brain injury tended to be diagnosed late in the clinic. Patient age, mechanism of injury, and type of facial fracture predicted brain injuries overall, but mechanism of injury was the sole predictor of minor brain injury. CONCLUSIONS: Facial fractures are often associated with brain injury. A high level of suspicion is warranted for minor traumatic brain injuries.

Outcomes of Immediate Alloplastic Breast Reconstruction in Patients Receiving Post-Mastectomy Radiotherapy.

Background: Immediate alloplastic breast reconstruction is traditionally avoided in patients who require post-mastectomy radiation therapy (PMRT). However, a subset of patients who undergo alloplastic reconstruction may unpredictably require adjuvant radiation. The purpose of this study was to compare outcomes and complications in patients at our institution who had undergone immediate alloplastic breast reconstruction and received PMRT to either the permanent implant or temporary tissue expander. Materials and Methods: A retrospective cohort study was performed looking at patients who underwent immediate alloplastic breast reconstruction over a 10-year period (2009-2019) at our regional breast centre. All patients who underwent immediate alloplastic breast reconstruction and had PMRT were included in the study. Major (wound dehiscence with device exposure, or reconstructive failure) and minor (infection, capsular contracture, revision surgery) complication rates between those patients receiving radiation to a tissue expander versus implant were compared using Fisher exact test (P < .05). Results: Six-hundred ninety-two patients were identified, and 43 patients met inclusion criteria. Of this group, 29 received PMRT to implants and 14 received PMRT to tissue expanders. Complication rates were similar between groups for superficial wound infection (3.4% vs 7.1%), periprosthetic infection (3.4% vs 7.1%), capsular contracture (41.4% vs 21.4%), revision surgery for aesthetics (41.4% vs 21.4%), wound dehiscence and device exposure (3.4% vs 21.3%), and reconstructive failure (10.3% vs 6.7%). Total complication rates were similar between groups (51.7% vs 42.9%). Discussion: Overall 6.4% of patients who underwent immediate alloplastic breast reconstruction required PMRT over a 10-year period. Complication rates for infection, capsular contracture, revision surgery, wound dehiscence and device exposure, and reconstructive failure were similar between both groups. Total complication rates were similar between groups. This information will help to inform decision-making regarding immediate alloplastic reconstruction and expected complications when PMRT is needed.

Historique: D'habitude, on évite la reconstruction mammaire alloplastique immédiate chez les patientes qui ont besoin d'une radiothérapie après la mastectomie (RTAM). Toutefois, un sous-groupe de patientes peut avoir besoin de radiation adjuvante non planifiée. La présente étude visait à comparer les résultats cliniques et les complications chez les patientes de l'établissement des chercheurs, après une reconstruction mammaire alloplastique immédiate et une RTAM sur l'implant permanent ou les expanseurs tissulaires permanents. Matériaux et méthodologie: Les chercheurs ont procédé à une étude de cohorte rétrospective sur une période de dix ans (2009 à 2019) auprès de patientes qui avaient subi une reconstruction mammaire alloplastique immédiate à leur centre régional de traitement du cancer du sein. Toutes les patientes qui avaient subi une telle reconstruction et une RTAM en ont fait partie. Au moyen du test exact de Fisher (p < 0,05), les chercheurs ont comparé les complications majeures (déhiscence des plaies et exposition du dispositif ou échec de la reconstruction) et mineures (infection, contracture capsulaire, chirurgie de reprise) entre les patientes recevant une radiation sur les expanseurs tissulaires et sur l'implant, respectivement. Résultats: Les chercheurs ont extrait 692 patientes, dont 43 respectaient les critères d'inclusion. De ce groupe, 29 ont reçu une RTAM sur les implants et 14, sur les expanseurs tissulaires. Le taux de complication était semblable entre les groupes pour ce qui était de l'infection superficielle de la plaie (3,4 % par rapport à 7,1 %), de l'infection périprosthétique (3,4 % par rapport à 7,1 %), de la contracture capsulaire (41,4 % par rapport à 21,4 %), de la reprise de l'intervention pour des raisons esthétiques (41,4 % par rapport à 21,4 %), de la déhiscence de la plaie et de l'exposition du dispositif (3,4 % par rapport à 21,3 %) et de l'échec de la reconstruction (10,3 % par rapport à 6,7 %). Le taux total de complications était semblable entre les groupes (51,7 % par rapport à 42,9 %). Discussion: Dans l'ensemble, 6,4 % des patients qui ont subi une reconstruction mammaire alloplastique immédiate ont eu besoin d'une RTAM sur une période de dix ans. Le taux de complications d'infection, de contracture capsulaire, de chirurgie de reprise, de déhiscence de la plaie, d'exposition du dispositif et d'échec de la reconstruction était semblable dans les deux groupes, de même que le taux total de complications. Ces données contribueront à éclairer la décision de procéder à une reconstruction alloplastique immédiate et à évaluer les complications possibles en cas de RTAM.

Hyperpolarized [1-13C]Pyruvate Magnetic Resonance Spectroscopic Imaging for Evaluation of Early Response to Tyrosine Kinase Inhibition Therapy in Gastric Cancer.

PURPOSE: To evaluate the use of hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopic imaging (HP-13C MRSI) for quantitative measurement of early changes in glycolytic metabolism and its ability to predict response to pan-tyrosine kinase inhibitor (Pan-TKI) therapy in gastric cancer (GCa). PROCEDURES: Pan-TKI afatinib-sensitive NCI-N87 and resistant SNU16 human GCa cells were assessed for GLUT1, hexokinase-II (HKII), lactate dehydrogenase (LDHA), phosphorylated AKT (pAKT), and phosphorylated MAPK (pMAPK) at 0-72 h of treatment with 0.1 µM afatinib. Subcutaneous NCI-N87 tumor-bearing nude mice underwent [18F]FDG PET/MRI and HP-13C MRSI at baseline and 4 days after treatment with afatinib 10 mg/kg/day or vehicle (n = 10/group). Changes in PET and HP-13C MRSI metabolic parameters were compared between the two groups. Imaging findings were correlated with tumor growth and histopathology over 3 weeks of treatment. RESULTS: In vitro analysis showed a continuous decrease in LDHA, pAKT, and pMAPK in NCI-N87 compared to SNU16 cells within 72 h of treatment with afatinib, without a significant change in GLUT1 and HKII in either cell type. [18F]FDG PET of NCI-N87 tumors showed no significant change in PET measures at baseline and day 4 of treatment in either treatment group (SUVmean day 4/day 0: 2.7 ± 0.42/2.34 ± 0.38, p = 0.57 in the treated group vs. 1.73 ± 0.66/2.24 ± 0.43, p = 0.4 in the control group). HP-13C MRSI demonstrated significantly decreased lactate-to-pyruvate ratio (L/P) in treated tumors (L/P day 4/day 0: 0.83 ± 0.30/1.10 ± 0.20, p = 0.012 vs. 0.94 ± 0.20/0.98 ± 0.30, p = 0.75, in the treated vs. control group, respectively). Response to afatinib was confirmed with decreased tumor size over 3 weeks (11.10 ± 16.50 vs. 293.00 ± 79.30 mm3, p < 0.001, treated group vs. control group, respectively) and histopathologic evaluation. CONCLUSIONS: HP-13C MRSI is a more representative biomarker of early metabolic changes in response to pan-TKI in GCa than [18F]FDG PET and could be used for early prediction of response to targeted therapies.