Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2.

OBJECTIVE: The hallmark oncogene MYC drives the progression of most tumours, but direct inhibition of MYC by a small-molecule drug has not reached clinical testing. MYC is a transcription factor that depends on several binding partners to function. We therefore explored the possibility of targeting MYC via its interactome in pancreatic ductal adenocarcinoma (PDAC). DESIGN: To identify the most suitable targets among all MYC binding partners, we constructed a targeted shRNA library and performed screens in cultured PDAC cells and tumours in mice. RESULTS: Unexpectedly, many MYC binding partners were found to be important for cultured PDAC cells but dispensable in vivo. However, some were also essential for tumours in their natural environment and, among these, the ATPases RUVBL1 and RUVBL2 ranked first. Degradation of RUVBL1 by the auxin-degron system led to the arrest of cultured PDAC cells but not untransformed cells and to complete tumour regression in mice, which was preceded by immune cell infiltration. Mechanistically, RUVBL1 was required for MYC to establish oncogenic and immunoevasive gene expression identifying the RUVBL1/2 complex as a druggable vulnerability in MYC-driven cancer. CONCLUSION: One implication of our study is that PDAC cell dependencies are strongly influenced by the environment, so genetic screens should be performed in vitro and in vivo. Moreover, the auxin-degron system can be applied in a PDAC model, allowing target validation in living mice. Finally, by revealing the nuclear functions of the RUVBL1/2 complex, our study presents a pharmaceutical strategy to render pancreatic cancers potentially susceptible to immunotherapy.

Does indocyanine green fluorescence angiography impact the intraoperative choice of procedure in free vascularized medial femoral condyle grafting for scaphoid nonunions?

Background: Free vascularized medial femoral condyle (MFC) bone grafts can lead to increased vascularity of the proximal pole and restore scaphoid architecture in scaphoid nonunions. The intraoperative perfusion assessment of the bone graft is challenging because the conventional clinical examination is difficult. Indocyanine green (ICG) angiography has previously been shown to provide a real-time intraoperative evaluation of soft tissue perfusion in reconstructive surgery. The present study investigated the utility of ICG angiography in patients treated with a free medial femoral condyle graft for scaphoid nonunions. Methods: We performed a retrospective analysis of patients with scaphoid nonunions, in which ICG angiography was used intraoperatively for perfusion assessment. The medical records, radiographs, intraoperative imaging, and operative reports of all patients were reviewed. Intraoperative ICG dye was administered intravenously, and laser angiography was performed to assess bone perfusion. The scaphoid union was examined using postoperative CT scans. Results: Two patients had documented osteonecrosis of the proximal pole at the time of surgery. Four patients received a nonvascularized prior bone graft procedure, and a prior spongiosa graft procedure was performed in one patient. The mean time from injury to the MFC bone graft surgery was 52.7 months, and the mean time from prior failed surgery was 10.4 months. Perfusion of the vascular pedicle of the MFC and the periosteum could be detected in all patients. In two patients, even perfusion of the cancellous bone could be demonstrated by ICG angiography. Following transplantation of the bone graft, patency of the vascular anastomosis and perfusion of the periost were confirmed by ICG angiography in the assessed cases. No additional surgery regarding a salvage procedure for a scaphoid nonunion advanced collapse was necessary for the further course. Conclusion: ICG-angiography has shown to be a promising tool in the treatment of scaphoid nonunion with medial femoral condyle bone grafts. It enables intraoperative decision making by assessment of the microvascular blood supply of the periosteum and the vascular pedicle of the MFC bone graft. Further studies need to evaluate the impact on union rates in a long-term follow-up.

An Innovative Arteriovenous (AV) Loop Breast Cancer Model Tailored for Cancer Research.

Animal models are important tools to investigate the pathogenesis and develop treatment strategies for breast cancer in humans. In this study, we developed a new three-dimensional in vivo arteriovenous loop model of human breast cancer with the aid of biodegradable materials, including fibrin, alginate, and polycaprolactone. We examined the in vivo effects of various matrices on the growth of breast cancer cells by imaging and immunohistochemistry evaluation. Our findings clearly demonstrate that vascularized breast cancer microtissues could be engineered and recapitulate the in vivo situation and tumor-stromal interaction within an isolated environment in an in vivo organism. Alginate-fibrin hybrid matrices were considered as a highly powerful material for breast tumor engineering based on its stability and biocompatibility. We propose that the novel tumor model may not only serve as an invaluable platform for analyzing and understanding the molecular mechanisms and pattern of oncologic diseases, but also be tailored for individual therapy via transplantation of breast cancer patient-derived tumors.

Improving the Safety of DIEP Flap Transplantation: Detailed Perforator Anatomy Study Using Preoperative CTA.

Background: Deep inferior epigastric perforator and muscle sparing transverse rectus abdominis muscle flaps are commonly used flaps for autologous breast reconstruction. CT-angiography allows to analyse the perforator course preoperatively. Our aim was to compare the different aspects of perforator anatomy in the most detailed study. Methods: CT-angiographies of 300 female patients with autologous breast reconstruction of 10 years were analysed regarding the anatomy of the deep inferior epigastric artery and every perforator. Results: Overall, 2260 perforators were included. We identified correlations regarding the DIEA branching point and number of perforators and their intramuscular course. The largest perforator emerged more often from the medial branch of the DIEA than the smaller perforators (70% (416/595) vs. 54% (878/1634), p < 0.001) and more often had a direct connection to the SIEV (large 67% (401/595) vs. small 39% (634/1634), p < 0.01). Medial row perforators were larger than the laterals (lateral 1.44 mm ± 0.43 (n = 941) vs. medial 1.58 mm ± 0.52 (n = 1304) (p < 0.001)). The larger and more medial the perforator, the more likely it was connected to the SIEV: perforators with direct connection to the SIEV had a diameter of 1.65 mm ± 0.53 (n = 1050), perforators with indirect connection had a diameter of 1.43 ± 0.43 (n = 1028), perforators without connection had a diameter of 1.31 mm ± 0.37 (n = 169) (p < 0.001). Medial perforators were more often directly connected to the SIEV than lateral perforators (medial 56% (723/1302) vs. lateral 35% (327/941), p < 0.001). A lateral perforator more often had a short intramuscular course than medial perforators (69% (554/800) vs. 45% (474/1055), p < 0.001), which was also more often observed in the case of a small perforator and a caudal exit of the rectus sheath. Conclusion: The largest perforator emerges more often from the medial branch of the DIEA and frequently has a direct connection to the SIEV, making medial row perforators ideal for DIEP flap transplantation.

Influence of the autotaxin-lysophosphatidic acid axis on cellular function and cytokine expression in different breast cancer cell lines.

Previous studies provide high evidence that autotaxin (ATX)-lysophosphatidic acid (LPA) signaling through LPA receptors (LPAR) plays an important role in breast cancer initiation, progression, and invasion. However, its specific role in different breast cancer cell lines remains to be fully elucidated to offer improvements in targeted therapies. Within this study, we analyzed in vitro the effect of LPA 18:1 and the LPAR1, LPAR3 (and LPAR2) inhibitor Ki16425 on cellular functions of different human breast cancer cell lines (MDA-MB-231, MDA-MB-468, MCF-7, BT-474, SKBR-3) and the human breast epithelial cell line MCF-10A, as well as Interleukin 8 (IL-8), Interleukin 6 (IL-6) and tumor necrosis factor (TNF)-alpha cytokine secretion after LPA-incubation. ATX-LPA signaling showed a dose-dependent stimulatory effect especially on cellular functions of triple-negative and luminal A breast cancer cell lines. Ki16425 inhibited the LPA-induced stimulation of triple-negative breast cancer and luminal A cell lines in variable intensity depending on the functional assay, indicating the interplay of different LPAR in those assays. IL-8, IL-6 and TNF-alpha secretion was induced by LPA in MDA-MB-468 cells. This study provides further evidence about the role of the ATX-LPA axis in different breast cancer cell lines and might contribute to identify subtypes suitable for a future targeted therapy of the ATX-LPA axis.

Corrigendum: Does indocyanine green fluorescence angiography impact the intraoperative choice of procedure in free vascularized medial femoral condyle grafting for scaphoid non-unions?

[This corrects the article DOI: 10.3389/fsurg.2022.962450.].

The third dimension in perforator mapping-Comparison of Cinematic Rendering and maximum intensity projection in abdominal-based autologous breast reconstruction.

BACKGROUND: Cinematic Rendering (CR) is a recently introduced post-processing three-dimensional (3D) visualization imaging tool. The aim of this study was to assess its clinical value in the preoperative planning of deep inferior epigastric artery perforator (DIEP) or muscle-sparing transverse rectus abdominis myocutaneous (MS-TRAM) flaps, and to compare it with maximum intensity projection (MIP) images. The study presents the first application of CR for perforator mapping prior to autologous breast reconstruction. METHODS: Two senior surgeons independently analyzed CR and MIP images based on computed tomography angiography (CTA) datasets of 20 patients in terms of vascular pedicle characteristics, the possibility to harvest a DIEP or MS-TRAM flap, and the side of the flap harvest. We calculated inter- and intra-observer agreement in order to examine the accordance of both image techniques. RESULTS: We observed a good inter- and intra-observer agreement concerning the type of flap and the side of the flap harvest. However, the agreement on the pedicle characteristics varies depending on the considered variable. Both investigators identified a significantly higher number of perforators with MIP compared with CR (observer 1, p<0.0001 and observer 2, p<0.0385). CONCLUSION: The current study serves as an explorative study, showing first experiences with CR in abdominal-based autologous breast reconstruction. In addition to MIP images, CR might improve the surgeon's understanding of the individual's anatomy. Future studies are required to compare CR with other 3D visualization tools and its possible effects on operative parameters.

Abdominal Panniculectomy Can Simplify Kidney Transplantation in Obese Patients.

BACKGROUND: Obesity is frequently present in patients suffering from end-stage renal disease (ESRD). However, overweight kidney transplant candidates are a challenge for the transplant surgeon. Obese patients tend to develop a large abdominal panniculus after weight loss creating an area predisposed to wound-healing disorders. Due to concerns about graft survival and postoperative complications after kidney transplantation, obese patients are often refused in this selective patient cohort. The study aimed to analyze the effect of panniculectomies on postoperative complications and transplant candidacy in an interdisciplinary setting. METHODS: A retrospective database review of 10 cases of abdominal panniculectomies performed in patients with ESRD prior to kidney transplantation was conducted. RESULTS: The median body mass index was 35.2 kg/m2 (range 28.5-53.0 kg/m2) at first transplant-assessment versus 31.0 kg/m2 (range 28.0-34.4 kg/m2) at panniculectomy, and 31.6 kg/m2 (range 30.3-32.4 kg/m2) at kidney transplantation. We observed no major postoperative complications following panniculectomy and minor wound-healing complications in 2 patients. All aside from 1 patient became active transplant candidates 6 weeks after panniculectomy. No posttransplant wound complications occurred in the transplanted patients. CONCLUSION: Abdominal panniculectomy is feasible in patients suffering ESRD with no major postoperative complications, thus converting previously ineligible patients into kidney transplant candidates. An interdisciplinary approach is advisable in this selective patient cohort.

Novel imaging methods reveal positive impact of topical negative pressure application on tissue perfusion in an in vivo skin model.

The influence of topical negative pressure application (TNPA) on tissue perfusion still remains controversial. TNPA was applied for 30 minutes on intact skin of 21 healthy participants. Measurements of tissue oxygen saturation and tissue temperature as signs of tissue perfusion were performed before application of the TNPA, directly after removal of the TNPA and 5, 10, 15, 20, and 30 minutes after removal of the dressing using the near infrared imaging (NIRI) and a thermal imaging camera. Tissue oxygen saturation showed an increase from 67.7% before applying the TNPA to 76.1% directly after removal of TNPA, followed by a decrease of oxygen saturation 30 minutes after removal of TNPA. The measured temperature of the treated skin area increased from 32.1°C to 36.1°C after removal of TNPA with a consecutive decrease of the temperature 30 minutes after removal. TNPA resulted in both a higher tissue oxygen saturation and a higher skin temperature after 30 minutes compared to the beginning. TNPA increases both tissue oxygen saturation and skin temperature as sign of an increase of tissue perfusion. NIRI and thermal imaging proved to be useful for measuring changes in tissue perfusion.

Topical negative-pressure wound therapy: emerging devices and techniques.

Introduction: The treatment of chronic wounds constitutes a massive financial burden to society and our health-care system. Therefore, efficient wound care is of great importance to all kinds of medical fields. The implementation and modification of negative-pressure wound therapy can be seen as a major improvement in wound healing. Many different NPWT applications evolved trying to address various wound etiologies.Areas covered: This review aims to give an overview of various NPWT applications, show its effects on wound healing, and discuss future modifications.Expert opinion: NPWT as a delivery device for cold plasma, growth factors, or targeted stem cells to the wound bed and the ability to monitor the inflammatory activity, bacterial load and wound healing factors can be seen as possible future steps to individualized wound care. In addition, it requires high-quality experimental studies to develop the ideal foam in terms of microstructure, pore size, and material properties.

Body Contouring Surgery Improves Physical Activity in Patients After Massive Weight Loss-a Retrospective Study.

BACKGROUND: The aim of the study was to compare physical activity (PA) in patients who had undergone massive weight loss (MWL), before and after body contouring procedures. METHODS: All patients undergoing body contouring surgery after MWL between 2007 and 2017 with a minimum follow-up of 6 months after the last procedure were included in this retrospective study. Excluded were those with a body mass index > 35 kg/m2 and those with comorbidities leading to impaired PA. Quality of life (QOL) was assessed using the Moorehead-Ardelt QOL Questionnaire II. Evaluation of PA was obtained with the International Physical Activity Questionnaire (IPAQ) short form and the Freiburg PA Questionnaire. Functional impairment during exercise was analyzed using a self-designed functional impairment score (FIS). RESULTS: In the 45 patients completing the survey (37 female, 8 male), an improvement in QOL (p < 0.001) and PA scored by the IPAQ (p = 0.017) was found. The Freiburg PA Questionnaire showed no difference in PA before and after body contouring surgery (p = 0,274). Furthermore, scores of the FIS indicated a decrease of functional impairment during physical activity after body contouring surgery (p < 0.001). CONCLUSION: Body contouring improves QOL and PA in patients after massive weight loss. The results of our study confirm the important role of plastic surgery in the treatment and maintenance of health of patients with former obesity.

Operating on the Edge? Body Contouring Procedures in Patients with Body Mass Index Greater 35.

BACKGROUND: Body contouring surgery after massive weight loss was shown to ameliorate the patient's quality of life and to enhance physical and psychological well-being. However, numerous patients are still obese when presenting for body contouring surgery, not able to lose additional weight for various reasons. Data regarding general feasibility, outcome, and postoperative complications in obese patients is rare. The aim of this study was to investigate the outcome in body contouring procedures in obese patients. METHODS: A retrospective chart review of 65 cases in 42 patients was performed. Patients with a body mass index (BMI) > 35 kg/m2 at the time of operation were enrolled and all different types of body contouring surgery were included. Complications were classified as major (need for surgical intervention) and minor complications. RESULTS: The median BMI of all patients was 38 kg/m2 (range 35.1-65.1 kg/m2). The majority of performed types of body contouring was abdominal body contouring (panniculectomy n = 27 (42%), abdominoplasty n = 12 (18%)). Complications occurred in 27 cases (41.5%). Twenty-one cases (32.3%) were classified as minor complications, six (9.2%) as major complications. The most common major complications were hematoma and wound dehiscence; the most common minor complication was seroma. CONCLUSION: A reasonable risk for complications is well known in body contouring surgery especially in obese patients. It is imperative to discuss related risks and expected results. Taking several points into account concerning the perioperative management, reduction of major complications is possible even in still obese patients, making body contouring surgery a discussible option.

Language function shows comparable cortical patterns by functional MRI and repetitive nTMS in healthy volunteers.

In preoperative planning, fMRI and repetitive navigated transcranial magnetic stimulation (rTMS) repeatedly revealed differences in the detected language sites, which can be attributed to tumor-induced oxygenation changes impairing the accuracy of fMRI. We therefore compared the accordance of those techniques in healthy subjects using exactly the same tasks in both investigations. 19 healthy right-handed subjects performed object naming, pseudoword reading, verb generation, and action naming during fMRI at 3 T and rTMS. For rTMS language mapping, we stimulated 46 cortical spots over the left hemisphere; each site was stimulated for three times. Language positive points during rTMS for one, two, or three errors out the three stimulations per spot (1/3, 2/3, 3/3) were exported via DICOM, and compared to the positive fMRI clusters. As a result of this comparison, the best correlation was observed between 3/3 errors and fMRI for pseudoword reading and verb generation with t-values of pu < 0.001, uncorrected for multiple comparisons, on average across the whole rTMS-spot map. We found a close spatial agreement between several rTMS-spots (2/3 and 3/3 errors) and fMRI clusters accentuated in the frontal lobe, followed by the parietal lobe and less in the temporal lobe. Compared to the fMRI clusters, there was a higher congruence for 2/3 and 3/3 errors than for 1/3 errors. Overall, results of language mapping in healthy subjects by fMRI and rTMS correspond well yet depending on the used language task.

Non-invasive Mapping of Face Processing by Navigated Transcranial Magnetic Stimulation.

Background: Besides motor and language function, tumor resections within the frontal and parietal lobe have also been reported to cause neuropsychological impairment like prosopagnosia. Objective: Since non-navigated transcranial magnetic stimulation (TMS) has previously been used to map neuropsychological cortical function, this study aims to evaluate the feasibility and spatial discrimination of repetitive navigated TMS (rTMS) mapping for detection of face processing impairment in healthy volunteers. The study was also designed to establish this examination for preoperative mapping in brain tumor patients. Methods: Twenty healthy and purely right-handed volunteers (11 female, 9 male) underwent rTMS mapping for cortical face processing function using 5 Hz/10 pulses. Both hemispheres were investigated randomly with an interval of 2 weeks between mapping sessions. Fifty-two predetermined cortical spots of the whole hemispheres were mapped after baseline measurement. The task consisted of 80 portraits of popular persons, which had to be named while rTMS was applied. Results: In 80% of all subjects rTMS elicited naming errors in the right middle middle frontal gyrus (mMFG). Concerning anomia errors, the highest error rate (35%) was achieved in the bilateral triangular inferior frontal gyrus (trIFG). With regard to similarly or wrongly named persons, we observed 10% error rates mainly in the bilateral frontal lobes. Conclusion: It seems feasible to map the cortical face processing function and to generate face processing impairment via rTMS. The observed localizations are well in accordance with the contemporary literature, and the mapping did not interfere with rTMS-induced language impairment. The clinical usefulness of preoperative mapping has to be evaluated subsequently.

Interhemispheric connectivity revealed by diffusion tensor imaging fiber tracking derived from navigated transcranial magnetic stimulation maps as a sign of language function at risk in patients with brain tumors.

OBJECTIVE Resection of brain tumors in language-eloquent areas entails the risk of postoperative aphasia. It has been demonstrated via navigated transcranial magnetic stimulation (nTMS) that language function can partially shift to the unaffected hemisphere due to tumor-induced plasticity. Therefore, this study was designed to evaluate whether interhemispheric connectivity (IC) detected by nTMS-based diffusion tensor imaging-fiber tracking (DTI-FT) can be used to predict surgery-related aphasia in patients with brain tumors. METHODS Thirty-eight patients with left-sided perisylvian brain lesions underwent cortical language mapping of both hemispheres by nTMS prior to awake surgery. Then, nTMS-based DTI-FT was conducted with a fractional anisotropy (FA) of 0.01 and 0.2 to visualize nTMS-based IC. Receiver operating characteristics were calculated for the prediction of a postoperative (irrespective of the preoperative state) and a new surgery-related aphasia by the presence of detectable IC. RESULTS Language mapping by nTMS was possible in all patients. Seventeen patients (44.7%) suffered from surgery-related worsening of language performance (transient aphasia according to 3-month follow-up in 16 subjects [42.1%]; new permanent aphasia according to 3-month follow-up in 1 patient [2.6%]). Regarding the correlation of aphasia to nTMS-based IC, statistically significant differences were revealed for both evaluated FA values. However, better results were observed for tractography with an FA of 0.2, which led to a specificity of 93% (postoperative aphasia) and 90% (surgery-related aphasia). For postoperative aphasia, the corresponding OR was 0.1282 (95% CI 0.0143-1.1520), and for surgery-related aphasia the OR was 0.1184 (95% CI 0.0208-0.6754). CONCLUSIONS According to these results, IC detected by preoperative nTMS-based DTI-FT might be regarded as a risk factor for surgery-related aphasia, with a specificity of up to 93%. However, because the majority of enrolled patients suffered from transient aphasia postoperatively, it has to be evaluated whether this approach distinctly leads to similar results among patients with permanent language deficits. Despite this restriction, this approach might contribute to individualized patient consultation prior to tumor resection in clinical practice.

Language pathway tracking: comparing nTMS-based DTI fiber tracking with a cubic ROIs-based protocol.

OBJECTIVE Diffusion tensor imaging (DTI) fiber tracking (FT) has been widely used in glioma surgery in recent years. It can provide helpful information about subcortical structures, especially in patients with eloquent space-occupying lesions. This study compared the newly developed navigated transcranial magnetic stimulation (nTMS)-based DTI FT of language pathways with the most reproducible protocol for language pathway tractography, using cubic regions of interest (ROIs) for the arcuate fascicle. METHODS Thirty-seven patients with left-sided perisylvian lesions underwent language mapping by repetitive nTMS. DTI FT was performed using the cubic ROIs-based protocol and the authors' nTMS-based DTI FT approach. The same minimal fiber length and fractional anisotropy were chosen (50 mm and 0.2, respectively). Both protocols were performed with standard clinical tractography software. RESULTS Both methods visualized language-related fiber tracts (i.e., corticonuclear tract, arcuate fascicle, uncinate fascicle, superior longitudinal fascicle, inferior longitudinal fascicle, arcuate fibers, commissural fibers, corticothalamic fibers, and frontooccipital fascicle) in all 37 patients. Using the cubic ROIs-based protocol, 39.9% of these language-related fiber tracts were detected in the examined patients, as opposed to 76.0% when performing nTMS-based DTI FT. For specifically tracking the arcuate fascicle, however, the cubic ROIs-based approach showed better results (97.3% vs 75.7% with nTMS-based DTI FT). CONCLUSIONS The cubic ROIs-based protocol was designed for arcuate fascicle tractography, and this study shows that it is still useful for this intention. However, superior results were obtained using the nTMS-based DTI FT for visualization of other language-related fiber tracts.

Visualization of subcortical language pathways by diffusion tensor imaging fiber tracking based on rTMS language mapping.

Diffusion tensor imaging fiber tracking (DTI FT) is used to visualize subcortical fiber tracts. Yet, there is no standard at hand to visualize language-involved subcortical fibers reliably. Thus, this study investigates the feasibility of using language-related cortical areas identified via repetitive navigated transcranial magnetic stimulation (rTMS) to seed DTI FT of subcortical language tracts. From 2011 to 2014, 37 patients with left-hemispheric perisylvian lesions were examined. Language-positive rTMS stimulation spots were integrated in the deterministic tractography software (BrainLAB, iPlanNet 3.0) as objects and used as seed regions for DTI FT. Tractography was then performed in each patient with 77 different combinations of fiber lengths (40 - 100 mm) and fractional anisotropy (FA; 0.01 - 0.5). The rTMS-based DTI FT identified all commonly known subcortical language tracts, such as the corticonuclear tract, arcuate fascicle, uncinate fascicle, superior longitudinal fascicle, inferior longitudinal fascicle, arcuate fibers, commissural fibers, corticothalamic fibers, and the fronto-occipital fascicle. In 32 patients (86.5 %), each above-named tract could be visualized, while at least 6 out of these 9 tracts were identified in each patient. A fiber length of 100 mm and an FA of 0.1 or 0.15 provided optimal visualization by revealing 125 and 61 individually tracked fibers per visualized language tract and 90 % and 73 % of all language-related tracts, respectively. This study proves the feasibility of rTMS-based DTI FT for subcortical language tracts, provides suitable settings, and shows its easy and standardizable application for the visualization of every language tract in 86.5 % of patients.