From early motor ability to global cognitive development seven years after neonatal arterial ischemic stroke.

The developmental condition of children after neonatal arterial ischemic stroke (NAIS) is characterized by cognitive and motor impairments. We hypothesized that independent walking age would be a predictor of later global cognitive functioning in this population. Sixty-one children with an available independent walking age and full-scale IQ score seven years after NAIS were included in this study. Full-scale IQ was assessed using the fourth edition of the Wechsler Intelligence Scale for Children (WISC-IV). Independent walking age was negatively correlated with full-scale IQ score at seven years of age (Pearson correlation coefficient of -0.27; 95% confidence interval from 0.48 to -0.01; p <0.05). Early motor function is correlated with later global cognitive functioning in children after NAIS. Assessing and promoting early motor ability is essential in this population.

Perivascular Macrophages Regulate Blood Flow Following Tissue Damage.

[Figure: see text].

Perinatal inflammation exposure and developmental outcomes 7 years after neonatal arterial ischaemic stroke.

AIM: To test the association between perinatal inflammation exposure and Full-Scale IQ (FSIQ) score 7 years after neonatal arterial ischaemic stroke (NAIS). METHOD: We conducted a cross-sectional ancillary study nested in a multicentric longitudinal French cohort of infants born at term with NAIS between November 2003 and October 2006. Seventy-three children were included (45 males, 28 females). The a priori defined primary outcome measure was the FSIQ score assessed with the Wechsler Intelligence Scale for Children, Fourth Edition at 7 years of age. RESULTS: Seventeen (23%) of the included children were exposed to perinatal inflammation. Exposure to perinatal inflammation was independently associated with an increase of FSIQ score (coefficient 13.4, 95% confidence interval 1.3-25.4; p = 0.03). Children exposed to perinatal inflammation had a higher median cerebral volume, a lower median lesion volume, and less extensive lesion distributions compared to non-exposed children. INTERPRETATION: We propose the existence of two NAIS categories: arteritis-associated NAIS in children exposed to perinatal inflammation and embolism-associated NAIS in children non-exposed to perinatal inflammation. Identifying these two NAIS categories would open the possibility for specific curative strategies: anti-inflammatory strategy in arteritis-associated NAIS and recanalization strategy in embolism-associated NAIS.

The impact of perinatal inflammation on the electroencephalogram in preterm infants: a systematic review.

BACKGROUND: To summarise the association between perinatal inflammation (PI) exposure and electroencephalography (EEG) features in preterm infants. METHODS: This systematic review included clinical studies of preterm infants born <37 weeks of gestational age (GA), who had both a PI exposure and an EEG assessment performed during the neonatal period. Studies were identified from Medline and Embase databases on the 15th of September 2021. PI was defined by histological chorioamnionitis, clinical chorioamnionitis, or early-onset neonatal infection (EONI). The risk of bias in included studies was assessed using the Joanna Briggs Institute (JBI) appraisal tool. A narrative approach was used to synthesise results. This review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 statement. RESULTS: Two cross-sectional studies enrolling 130 preterm children born <32 weeks of GA assessed with one-channel amplitude-integrated EEG (aEEG) during the first four days of life were included. A PI exposure was described in 39 (30%) infants and was associated with a decrease in amplitude and a reduced incidence of sleep-wake cycling patterns. CONCLUSION: These results should be interpreted with caution because of the small number of included studies and their heterogeneity. Further clinical studies evaluating the association of PI with EEG findings are needed. IMPACT: A method to assess developmental trajectories following perinatal inflammation is required. Insufficient data exist to determine EEG features associated with perinatal inflammation. Further clinical studies evaluating this association are needed.

A subset of epithelioid and spindle cell rhabdomyosarcomas is associated with TFCP2 fusions and common ALK upregulation.

Rhabdomyosarcomas with TFCP2 fusions represent an emerging subtype of tumors, initially discovered by RNA-sequencing. We report herein the clinicopathological, transcriptional, and genomic features of a series of 14 cases. Cases were retrospectively and prospectively recruited and studied by immunohistochemistry (MYF4, MYOD1, S100, AE1/E3, ALK), fluorescence in situ hybridization with TFCP2 break-apart probe (n = 10/14), array-comparative genomic hybridization (Agilent), whole RNA-sequencing (Truseq Exome, Illumina), or anchored multiplex PCR-based targeted next-generation sequencing (Archer® FusionPlex® Sarcoma kit). Patient's age ranged between 11 and 86 years, including 5 pediatric cases. Tumors were located in the bone (n = 12/14) and soft tissue (n = 2/14). Most bone tumors invaded surrounding soft tissue. Craniofacial bones were over-represented (n = 8/12). Median survival was 8 months and five patients are currently alive with a median follow-up of 20 months. Most tumors displayed a mixed spindle cell and epithelioid pattern with frequent vesicular nuclei. All tumors expressed keratins and showed a rhabdomyogenic phenotype (defined as expression of MYF4 and/or MYOD1). ALK was overexpressed in all but three cases without underlying ALK fusion on break-apart FISH (n = 5) nor next-generation sequencing (n = 14). ALK upregulation was frequently associated with an internal deletion at genomic level. TFCP2 was fused in 5' either to EWSR1 (n = 6) or FUS (n = 8). EWSR1 was involved in both soft tissue cases. FISH with TFCP2 break-apart probe was positive in all tested cases (n = 8), including one case with unbalanced signal. On array-CGH, all tested tumors displayed complex genetic profiles with genomic indexes ranging from 13 to 107.55 and recurrent CDKN2A deletions. FET-TFCP2 rhabdomyosarcomas clustered together and distinctly from other rhabdomyosarcomas subgroups. Altogether, our data confirm and expand the spectrum of the new family of FET-TFCP2 rhabdomyosarcomas, which are associated with a predilection for the craniofacial bones, an aggressive course, and recurrent pathological features. Their association with ALK overexpression might represent a therapeutic vulnerability.

Presentation and outcome of frequent and rare sarcoma histologic subtypes: A study of 10,262 patients with localized visceral/soft tissue sarcoma managed in reference centers.

BACKGROUND: The objective of this study was to describe characteristics at diagnosis and outcomes of adults with soft tissue sarcoma. METHODS: The authors conducted a retrospective multicenter study of 12,262 patients who were treated between January 1980 and 31 December 2013 in French Sarcoma Group centers and enrolled in the "Conticabase." Diagnoses were systematically reviewed by expert pathologists, and entities were classified according to the 2013 World Health Organization classification. Diagnostic characteristics, treatments, and outcomes are described for the entire cohort, for the subgroup of patients with translocation-related sarcomas, and for 9 different histologic subtypes. RESULTS: The results stressed the magnitude of heterogeneity among adult sarcomas. For example, compared with other sarcomas, translocation-related sarcomas (2143 tumors; 20.8%) were associated with a younger age at presentation (40.6 vs 60.0 years; P < .0001), a low rate of predisposing conditions (0.01% vs 22.3%; P < .0001), a higher rate of lymph node involvement (4.7% vs 1.3%; P < .0001), and a higher rate of synchronous metastasis (11.9% vs 6.7%; P < .001); and complete (R0) resection (41.6% vs 31.9%; P < .0001), receipt of (neo)adjuvant radiation therapy (62.6% vs 42.2%; P < .0001), and receipt of (neo)adjuvant chemotherapy (36.6% vs 22.3%; P < .0001) were significantly more frequent. Overall, translocation-related sarcomas were associated with a lower rate of local relapse (18.1% vs 26.0%; P < .0001) but a higher rate of metastatic relapse (42.0% vs 30.7%; P < .0001). CONCLUSIONS: Collaborative efforts are urgently needed to better assess the natural history and management options for every histologic subtype of sarcoma. Cancer 2018;124:1179-87. © 2017 American Cancer Society.

Patterns of care and outcomes of patients with METAstatic soft tissue SARComa in a real-life setting: the METASARC observational study.

BACKGROUND: Well-designed observational studies of individuals with rare tumors are needed to improve patient care, clinical investigations, and the education of healthcare professionals. METHODS: The patterns of care, outcomes, and prognostic factors of a cohort of 2225 patients with metastatic soft tissue sarcomas who were diagnosed between 1990 and 2013 and documented in the prospectively maintained database of the French Sarcoma Group were analyzed. RESULTS: The median number of systemic treatments was 3 (range, 1-6); 27% of the patients did not receive any systemic treatment and 1054 (49%) patients underwent locoregional treatment of the metastasis. Half of the patients who underwent chemotherapy (n = 810) received an off-label drug. Leiomyosarcoma was associated with a significantly better outcome than the other histological subtypes. With the exception of leiomyosarcomas, the benefit of a greater than third-line regimen was very limited, with a median time to next treatment (TNT) and overall survival (OS) ranging between 2.3 and 3.7 months and 5.4 and 8.5 months, respectively. The TNT was highly correlated with OS. Female sex, leiomyosarcoma histology, locoregional treatment of metastases, inclusion in a clinical trial, and treatment with first-line polychemotherapy were significantly associated with improved OS in the multivariate analysis. CONCLUSIONS: The combination of doxorubicin with a second drug, such as ifosfamide, represents a valid option, particularly when tumor shrinkage is expected to provide clinical benefits. After failure of the second-line therapy, best supportive care should be considered, particularly in patients with non-leiomyosarcoma histology who are not eligible to participate in a clinical trial. Locoregional treatment of metastasis should always be included in the therapeutic strategy when feasible. TNT may represent a useful surrogate endpoint for OS in clinical studies.

Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans.

Vascular endothelial growth factor A (VEGF-A) is upregulated during hypoxia and is the major regulator of angiogenesis. VEGF-A expression has also been found to recruit myeloid cells to ischemic tissues where they contribute to angiogenesis. This study investigates the mechanisms underlying neutrophil recruitment to VEGF-A as well as the characteristics of these neutrophils. A previously undefined circulating subset of neutrophils shown to be CD49d(+)VEGFR1(high)CXCR4(high) was identified in mice and humans. By using chimeric mice with impaired VEGF receptor 1 (VEGFR1) or VEGFR2 signaling (Flt-1tk(-/-), tsad(-/-)), we found that parallel activation of VEGFR1 on neutrophils and VEGFR2 on endothelial cells was required for VEGF-A-induced recruitment of circulating neutrophils to tissue. Intravital microscopy of mouse microcirculation revealed that neutrophil recruitment by VEGF-A versus by the chemokine macrophage inflammatory protein 2 (MIP-2 [CXCL2]) involved the same steps of the recruitment cascade but that an additional neutrophil integrin (eg, VLA-4 [CD49d/CD29]) played a crucial role in neutrophil crawling and emigration to VEGF-A. Isolated CD49d(+) neutrophils featured increased chemokinesis but not chemotaxis compared with CD49d(-) neutrophils in the presence of VEGF-A. Finally, by targeting the integrin α4 subunit (CD49d) in a transplantation-based angiogenesis model that used avascular pancreatic islets transplanted to striated muscle, we demonstrated that inhibiting the recruitment of circulating proangiogenic neutrophils to hypoxic tissue impairs vessel neoformation. Thus, angiogenesis can be modulated by targeting cell-surface receptors specifically involved in VEGF-A-dependent recruitment of proangiogenic neutrophils without compromising recruitment of the neutrophil population involved in the immune response to pathogens.

Handling missing covariates in observational studies: an illustration with the assessment of prognostic factors of survival outcomes in soft-tissue or visceral sarcomas in irradiated fields (SIF).

Background: Missing covariates are common in observational research and can lead to bias and loss of statistical power. Limited data regarding prognostic factors of survival outcomes of sarcomas in irradiated fields (SIF) are available. Because of the long lag time between irradiation of first cancer and scarcity of SIF, missing data are a critical issue when analyzing long-term outcomes. We assessed prognostic factors of overall (OS), progression-free (PFS), and metastatic-progression-free (MPFS) survivals in SIF using three methods to account for missing covariates. Methods: We relied on the NETSARC French Sarcoma Group database, Cox (OS/PFS), and competitive hazards (MPFS) survival models. Covariates investigated were age, sex, histological subtype, tumor size, depth and grade, metastasis, surgery, surgical resection, surgeon's expertise, imaging, and neo-adjuvant treatment. We first applied multiple imputation (MI): observed data were used to estimate the missing covariate. With the missing-data modality approach, a category missing was created for qualitative variables. With the complete-case (CC) approach, analysis was restricted to patients without missing covariates. Results: CC subjects (N = 167; 33%) presented more often with soft-tissue sarcoma (versus visceral sarcoma) and grade I-II tumors as compared to the 504 eligible cases. With MI (N = 504), factors associated with the worst outcome included metastasis (p = 0.04) and R1/R2 resection (p < 0.001) for OS; higher grade/non-gradable tumors (p = 0.002) and R1/R2 resection (p < 0.001) for PFS; and metastasis (p = 0.01) for M-PFS. The 'missing-data modality' approach (N = 504) led to different associations, including significance reached due to variables with the modality 'missing'. The CC analysis led to different results and reduced precision. Conclusion: The CC population was not representative of the eligible population, introducing bias, in addition to worst precision. The 'missing-data modality method' results in biased estimates in non-randomized studies, as outcomes may be related to variables with missing values. Appropriate statistical methods for missing covariates, for example, MI, should therefore be considered.

Corrigendum: Serum D-dimer is not predictive of placenta-mediated complications in pregnancy at high risk: the multicentric prospective cohort AngioPred study.

[This corrects the article DOI: 10.3389/fcell.2023.1115622.].

Why, when and how to assess autonomic nervous system maturation in neonatal care units: A practical overview.

The evaluation of the autonomic reactivity of newborns by heart rate variability (HRV) analysis is a simple and essential aid to identifying pathological situations of dysautonomia. Thanks to this relatively simple and reproducible analytic tool, the pediatrician can identify and target children at high risk of life-threatening events, i.e., those with insufficient intrinsic capacity for cardiorespiratory self-regulation, who should benefit from close cardiorespiratory monitoring. Different mathematical algorithms integrate delayed or real-time variations in the length of the RR interval to better understand the state of autonomic maturation of the newborn. HRV analysis, as a non-invasive tool for assessing autonomic balance, is essential to assess the functioning of the autonomic nervous system and, more specifically, parasympathetic/sympathetic balance. Despite many recognized diagnostic and therapeutic implications, its application to neonatal medicine is not yet well understood.

Mean 3D Dispersion for Automatic General Movement Assessment of Preterm Infants.

The General Movement assessment (GMA) is a validated assessment of brain maturation primarily based on the qualitative analysis of the complexity and the variation of spontaneous motor activity. The GMA can identify preterm infants presenting an early abnormal developmental trajectory before term-equivalent age, which permits a personalized early developmental intervention. However, GMA is time-consuming and relies on a qualitative analysis; these limitations restrict the implementation of GMA in clinical practice. In this study based on a validated dataset of 183 videos from 92 premature infants (54 males, 38 females) born <33 weeks of gestational age (GA) and acquired between 32 and 40 weeks of GA, we introduce the mean 3D dispersion (M3D) for objective quantification and classification of normal and abnormal GMA. Moreover, we have created a new 3D representation of skeleton joints which allows an objective comparison of spontaneous movements of infants of different ages and sizes. Preterm infants with normal versus abnormal GMA had a distinct M3D distribution (p <0.001). The M3D has shown a good classification performance for GMA (AUC=0.7723) and presented an accuracy of 74.1%, a sensitivity of 75.8%, and a specificity of 70.1% when using an M3D of 0.29 as a classification threshold.Clinical relevance- Our study paves the way for the development of quantitative analysis of GMA within the Neonatal Unit.

Mode of delivery after labor induction with vaginal dinoprostone versus oral misoprostol for women with unfavorable cervix at term.

OBJECTIVE: To compare the delivery mode after labor induction with 10 mg vaginal dinoprostone insert versus oral misoprostol 50 µg/4 h for women with an unfavorable cervix. MATERIAL AND METHODS: This is a retrospective observational study comparing the before/after introduction of oral misoprostol for labor induction, conducted at the Saint-Étienne University Hospital on a cohort of 396 women with a Bishop score <6. One hundred and twelve women (28.3%) were treated with a 10 mg vaginal dinoprostone insert versus 284 (71.7%) with oral misoprostol 50 µg/4 h. The primary outcome was the cesarean section rate. RESULTS: Labor induction with vaginal dinoprostone was independently associated with an increased rate of cesarean sections compared to oral misoprostol (aOR = 2.44; CI95% from 1.35 to 4.40; p = 0.003). The use of vaginal dinoprostone increased the induction rate during more than 48 h (18.8% versus 9.9%; p = 0.02), and the occurrence of fetal heart rate changes (34.8% versus 21.1%; p = 0.005). The maternofetal morbidity was similar. CONCLUSION: Labor induction with vaginal dinoprostone was independently associated with an increased rate of cesarean sections compared to oral misoprostol in women with an unfavorable cervix.

Long-term developmental condition following neonatal arterial ischemic stroke: A systematic review.

BACKGROUND: Neonatal arterial ischemic stroke (NAIS) is the most frequent subtype of perinatal stroke. Its elusive pathophysiology, its abrupt and unexpected occurrence, and the uncertainty of the post-NAIS developmental condition may lead to parental emotional distress and psychological difficulties. The aim of this study was to summarize the current data on long-term developmental conditions following NAIS to support parental information given within the neonatal unit. METHODS: This systematic review included clinical studies of term infants with NAIS, who had a developmental assessment at ≥5 years of age. Studies were identified from the Medline and Embase databases on June 1, 2022. The Joanna Briggs Institute (JBI) appraisal tool was used to assess the risk of bias. Results were synthesized using a narrative approach. The 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was followed to report this work. RESULTS: Three cohort studies enrolling 205 children assessed from 5 to 7 years after NAIS were included. Most of the children presented long-term developmental conditions allowing them to be integrated into a regular school program, to participate in physical activities, and to have a good quality of life. Global intellectual deficiency and moderate-to-severe cerebral palsy occurred in less than 10% of the children. CONCLUSION: Physicians should not overestimate the incidence of moderate-to-severe developmental outcome following NAIS when discussing the prognosis with parents. A parental information sheet about NAIS and its long-term developmental conditions is provided.

Serum D-dimer is not predictive of placenta-mediated complications in pregnancy at high risk: The multicentric prospective cohort AngioPred study.

Background: The theory that D-dimer level might has a predictive or diagnostic role in preeclampsia needs to be explored. Aim of the study was to evaluate the association between serum D-dimer level and the occurrence of placenta-mediated complications (PMC) in a pregnant population at high risk. Methods: A prospective multicenter cohort study including 200 pregnant women was conducted. Results: Serum D-dimer increases throughout pregnancy, with the highest levels at the end of gestation. Serum D-dimer level was similar for women with PMC and with no complication. Serum D-dimer level was not different in women with preeclampsia versus uncomplicated women. Serum D-dimer level was not different in women with early or late preeclampsia versus uncomplicated women. Conclusion: This result suggests that serum D-dimer level was not predictive of the PMC occurrence. This corroborates the fact that the origin of PMC based more on immunity than in hemostasis.

High dose (54 Gy) pre-operative helical tomotherapy for retroperitoneal liposarcoma: Results of a phase II multicenter study.

PURPOSE: To evaluate efficacy and feasibility of high-dose intensity-modulated radiotherapy (RT) with pre-operative helical tomotherapy, delivering 54 Gy/30 fractions in patients with retroperitoneal liposarcomas (RPLS). MATERIALS AND METHODS: Patients with operable, biopsy-proven, RPLS were included in this phase II multicenter study (ClinicalTrials.gov: NCT01841047). The primary objectives were to analyze loco-regional relapse free survival (LRFS), overall survival (OS) and toxicities, graded according to CTCAE V3.0. RESULTS: From April 2009 to September 2013, 48 patients were included. Histological types were: 20 well differentiated and 28 dedifferentiated liposarcomas. Median clinical target volume (CTV) was 2570 cc (range, 230-8734 cc). The radio-surgical schedule was completed as planned in all patients apart from one. A monobloc wide excision was achieved for all patients. Surgical margins were R0 (16; 34%), R1 (28; 60%), R2 (2; 4%) or missing (1, 2%).With a median follow-up of 5.5 years, 3-year LRFS rate was 74.2% (95%CI: [59.1%; 84.5%]). At 5 years, cumulative incidence of loco-regional relapse for well differentiated and dedifferentiated RPLS was 10% and 18%, respectively. The 5-year OS was 73.9% [95%CI: 58.7-84.3%]. During RT, the most common grade 3-4 adverse events were hematological (N = 20; 41.6%). After surgery and during follow-up, 17 patients (35.4%) presented a grade 3-4 toxicity. Two patients (4.1%) died due to a duodenal toxicity. Nine second cancers were observed. CONCLUSION: From this phase II trial of preoperative RT in RPLS patients, the dose level proposed cannot be considered safe, leading to non-negligible toxicity and second cancers rates. Our results, combined with STRASS-1 study, suggest that the ideal indication of RT for patients with RPLS still remains to be determined.

Classification Performance of the Ages and Stages Questionnaire: Influence of Maternal Education Level.

(1) Background: The Ages and Stages Questionnaire-Third Edition (ASQ-3) is a parental screening questionnaire increasingly being used to evaluate the development of preterm children. We aimed to assess the classification performance of the ASQ-3 in preterm infant follow-up. (2) Methods: In this cross-sectional study, we included 185 children from the SEVE longitudinal cohort born <33 weeks of gestational age between November 2011 and January 2018, who had both an ASQ-3 score at 24 months of corrected age (CA) and a revised Brunet-Lézine (RBL) scale score at 30 months of CA. The ASQ-3 overall score and sub-scores were compared to the RBL developmental quotient (DQ) scores domain by domain. The diagnostic performance of the ASQ-3 was evaluated with the RBL as the reference method by calculating sensitivity, specificity, and positive and negative likelihood ratios. A multivariate analysis assessed the association between low maternal education level and incorrect evaluation with the ASQ-3. (3) Results: The ASQ-3 overall score had a specificity of 91%, a sensitivity of 34%, a positive likelihood ratio of 3.82, and a negative likelihood ratio of 0.72. Low maternal education level was a major risk factor for incorrectly evaluating children with the ASQ-3 (odds ratio 4.16, 95% confidence interval 1.47-12.03; p < 0.01). (4) Conclusions: Regarding the low sensitivity and the impact of a low maternal education level on the classification performance of the ASQ-3, this parental questionnaire should not be used alone to follow the development of preterm children.

EG-VEGF maternal levels predict spontaneous preterm birth in the second and third trimesters in pregnant women with risk factors for placenta-mediated complications.

Prediction of spontaneous preterm birth in asymptomatic women remains a great challenge for the public health system. The aim of the study was to determine the informational value of EG-VEGF circulating levels for prediction of spontaneous preterm birth in the second and third trimesters in pregnant women at high risk for placenta-mediated complications. A prospective multicenter cohort study including 200 pregnant patients with five-serum sampling per patient. Women with spontaneous preterm birth have higher concentrations of serum EG-VEGF than uncomplicated patients at 24 weeks, 28 weeks and 32 weeks (p = 0.03, 0.02 and < 0.001). The areas under the curve reached 0.9 with 100% sensitivity at 32 weeks for the prediction of spontaneous preterm birth. Serum EG-VEGF concentrations could be considered as a reliable biomarker of spontaneous preterm birth in high-risk for placenta-mediated complications pregnant women.

Deep learning predicts patients outcome and mutations from digitized histology slides in gastrointestinal stromal tumor.

Risk assessment of gastrointestinal stromal tumor (GIST) according to the AFIP/Miettinen classification and mutational profiling are major tools for patient management. However, the AFIP/Miettinen classification depends heavily on mitotic counts, which is laborious and sometimes inconsistent between pathologists. It has also been shown to be imperfect in stratifying patients. Molecular testing is costly and time-consuming, therefore, not systematically performed in all countries. New methods to improve risk and molecular predictions are hence crucial to improve the tailoring of adjuvant therapy. We have built deep learning (DL) models on digitized HES-stained whole slide images (WSI) to predict patients' outcome and mutations. Models were trained with a cohort of 1233 GIST and validated on an independent cohort of 286 GIST. DL models yielded comparable results to the Miettinen classification for relapse-free-survival prediction in localized GIST without adjuvant Imatinib (C-index=0.83 in cross-validation and 0.72 for independent testing). DL splitted Miettinen intermediate risk GIST into high/low-risk groups (p value = 0.002 in the training set and p value = 0.29 in the testing set). DL models achieved an area under the receiver operating characteristic curve (AUC) of 0.81, 0.91, and 0.71 for predicting mutations in KIT, PDGFRA and wild type, respectively, in cross-validation and 0.76, 0.90, and 0.55 in independent testing. Notably, PDGFRA exon18 D842V mutation, which is resistant to Imatinib, was predicted with an AUC of 0.87 and 0.90 in cross-validation and independent testing, respectively. Additionally, novel histological criteria predictive of patients' outcome and mutations were identified by reviewing the tiles selected by the models. As a proof of concept, our study showed the possibility of implementing DL with digitized WSI and may represent a reproducible way to improve tailoring therapy and precision medicine for patients with GIST.