Object-oriented hand dexterity and grasping abilities, from the animal quarters to the neurosurgical OR: a systematic review of the underlying neural correlates in non-human, human primate and recent findings in awake brain surgery.

Introduction: The sensorimotor integrations subserving object-oriented manipulative actions have been extensively investigated in non-human primates via direct approaches, as intracortical micro-stimulation (ICMS), cytoarchitectonic analysis and anatomical tracers. However, the understanding of the mechanisms underlying complex motor behaviors is yet to be fully integrated in brain mapping paradigms and the consistency of these findings with intraoperative data obtained during awake neurosurgical procedures for brain tumor removal is still largely unexplored. Accordingly, there is a paucity of systematic studies reviewing the cross-species analogies in neural activities during object-oriented hand motor tasks in primates and investigating the concordance with intraoperative findings during brain mapping. The current systematic review was designed to summarize the cortical and subcortical neural correlates of object-oriented fine hand actions, as revealed by fMRI and PET studies, in non-human and human primates and how those were translated into neurosurgical studies testing dexterous hand-movements during intraoperative brain mapping. Methods: A systematic literature review was conducted following the PRISMA guidelines. PubMed, EMBASE and Web of Science databases were searched. Original articles were included if they: (1) investigated cortical activation sites on fMRI and/or PET during grasping task; (2) included humans or non-human primates. A second query was designed on the databases above to collect studies reporting motor, hand manipulation and dexterity tasks for intraoperative brain mapping in patients undergoing awake brain surgery for any condition. Due to the heterogeneity in neurosurgical applications, a qualitative synthesis was deemed more appropriate. Results: We provided an updated overview of the current state of the art in translational neuroscience about the extended frontoparietal grasping-praxis network with a specific focus on the comparative functioning in non-human primates, healthy humans and how the latter knowledge has been implemented in the neurosurgical operating room during brain tumor resection. Discussion: The anatomical and functional correlates we reviewed confirmed the evolutionary continuum from monkeys to humans, allowing a cautious but practical adoption of such evidence in intraoperative brain mapping protocols. Integrating the previous results in the surgical practice helps preserve complex motor abilities, prevent long-term disability and poor quality of life and allow the maximal safe resection of intrinsic brain tumors.

The parietal architecture binding cognition to sensorimotor integration: a multimodal causal study.

Despite human's praxis abilities are unique among primates, comparative observations suggest that these cognitive motor skills could have emerged from exploitation and adaptation of phylogenetically older building blocks, namely the parieto-frontal networks subserving prehension and manipulation. Within this framework, investigating to which extent praxis and prehension-manipulation overlap and diverge within parieto-frontal circuits could help in understanding how human cognition shapes hand actions. This issue has never been investigated by combining lesion mapping and direct electrophysiological approaches in neurosurgical patients. To this purpose, 79 right-handed left-brain tumour patient candidates for awake neurosurgery were selected based on inclusion criteria. First, a lesion mapping was performed in the early postoperative phase to localize the regions associated with an impairment in praxis (imitation of meaningless and meaningful intransitive gestures) and visuo-guided prehension (reaching-to-grasping) abilities. Then, lesion results were anatomically matched with intraoperatively identified cortical and white matter regions, whose direct electrical stimulation impaired the Hand Manipulation Task. The lesion mapping analysis showed that prehension and praxis impairments occurring in the early postoperative phase were associated with specific parietal sectors. Dorso-mesial parietal resections, including the superior parietal lobe and precuneus, affected prehension performance, while resections involving rostral intraparietal and inferior parietal areas affected praxis abilities (covariate clusters, 5000 permutations, cluster-level family-wise error correction P < 0.05). The dorsal bank of the rostral intraparietal sulcus was associated with both prehension and praxis (overlap of non-covariate clusters). Within praxis results, while resection involving inferior parietal areas affected mainly the imitation of meaningful gestures, resection involving intraparietal areas affected both meaningless and meaningful gesture imitation. In parallel, the intraoperative electrical stimulation of the rostral intraparietal and the adjacent inferior parietal lobe with their surrounding white matter during the hand manipulation task evoked different motor impairments, i.e. the arrest and clumsy patterns, respectively. When integrating lesion mapping and intraoperative stimulation results, it emerges that imitation of praxis gestures first depends on the integrity of parietal areas within the dorso-ventral stream. Among these areas, the rostral intraparietal and the inferior parietal area play distinct roles in praxis and sensorimotor process controlling manipulation. Due to its visuo-motor 'attitude', the rostral intraparietal sulcus, putative human homologue of monkey anterior intraparietal, might enable the visuo-motor conversion of the observed gesture (direct pathway). Moreover, its functional interaction with the adjacent, phylogenetic more recent, inferior parietal areas might contribute to integrate the semantic-conceptual knowledge (indirect pathway) within the sensorimotor workflow, contributing to the cognitive upgrade of hand actions.

Multidisciplinary treatment of hepatocellular carcinoma in 2023: Italian practice Treatment Guidelines of the Italian Association for the Study of the Liver (AISF), Italian Association of Medical Oncology (AIOM), Italian Association of Hepato-Bilio-Pancreatic Surgery (AICEP), Italian Association of Hospital Gastroenterologists (AIGO), Italian Association of Radiology and Clinical Oncology (AIRO), Italian Society of Pathological Anatomy and Diagnostic Cytology (SIAPeC-IAP), Italian Society of Surgery (SIC), Italian Society of Gastroenterology (SIGE), Italian Society of Medical and Interventional Radiology (SIRM), Italian Organ Transplant Society (SITO), and Association of Patients with Hepatitis and Liver Disease (EpaC) - Part II - Non-surgical treatments.

Worldwide, hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death. The remarkable improvements in treating HCC achieved in the last years have increased the complexity of its management. Following the need to have updated guidelines on the multidisciplinary treatment management of HCC, the Italian Scientific Societies involved in the management of this cancer have promoted the drafting of a new dedicated document. This document was drawn up according to the GRADE methodology needed to produce guidelines based on evidence. Here is presented the second part of guidelines, focused on the multidisciplinary tumor board of experts and non-surgical treatments of HCC.

Multidisciplinary Treatment of Hepatocellular Carcinoma in 2023: Italian practice Treatment Guidelines of the Italian Association for the Study of the Liver (AISF), Italian Association of Medical Oncology (AIOM), Italian Association of Hepato-Bilio-Pancreatic Surgery (AICEP), Italian Association of Hospital Gastroenterologists (AIGO), Italian Association of Radiology and Clinical Oncology (AIRO), Italian Society of Pathological Anatomy and Diagnostic Cytology (SIAPeC-IAP), Italian Society of Surgery (SIC), Italian Society of Gastroenterology (SIGE), Italian Society of Medical and Interventional Radiology (SIRM), Italian Organ Transplant Society (SITO), and Association of Patients with Hepatitis and Liver Disease (EpaC) - Part I - Surgical treatments.

Worldwide, hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death. The remarkable improvements in treating HCC achieved in the last years have increased the complexity of HCC management. Following the need to have updated guidelines on the multidisciplinary treatment management of HCC, the Italian Scientific Societies involved in the management of this cancer have promoted the drafting of a new dedicated document. This document was drawn up according to the GRADE methodology needed to produce guidelines based on evidence. Here is presented the first part of guidelines, focused on the multidisciplinary tumor board of experts and surgical treatments of HCC.

Radiomic Analysis of Intrahepatic Cholangiocarcinoma: Non-Invasive Prediction of Pathology Data: A Multicenter Study to Develop a Clinical-Radiomic Model.

Standard imaging cannot assess the pathology details of intrahepatic cholangiocarcinoma (ICC). We investigated whether CT-based radiomics may improve the prediction of tumor characteristics. All consecutive patients undergoing liver resection for ICC (2009-2019) in six high-volume centers were evaluated for inclusion. On the preoperative CT, we segmented the ICC (Tumor-VOI, i.e., volume-of-interest) and a 5-mm parenchyma rim around the tumor (Margin-VOI). We considered two types of pathology data: tumor grading (G) and microvascular invasion (MVI). The predictive models were internally validated. Overall, 244 patients were analyzed: 82 (34%) had G3 tumors and 139 (57%) had MVI. For G3 prediction, the clinical model had an AUC = 0.69 and an Accuracy = 0.68 at internal cross-validation. The addition of radiomic features extracted from the portal phase of CT improved the model performance (Clinical data+Tumor-VOI: AUC = 0.73/Accuracy = 0.72; +Tumor-/Margin-VOI: AUC = 0.77/Accuracy = 0.77). Also for MVI prediction, the addition of portal phase radiomics improved the model performance (Clinical data: AUC = 0.75/Accuracy = 0.70; +Tumor-VOI: AUC = 0.82/Accuracy = 0.73; +Tumor-/Margin-VOI: AUC = 0.82/Accuracy = 0.75). The permutation tests confirmed that a combined clinical-radiomic model outperforms a purely clinical one (p < 0.05). The addition of the textural features extracted from the arterial phase had no impact. In conclusion, the radiomic features of the tumor and peritumoral tissue extracted from the portal phase of preoperative CT improve the prediction of ICC grading and MVI.

Personalised management of patients with hepatocellular carcinoma: a multiparametric therapeutic hierarchy concept.

Advances in the surgical and systemic therapeutic landscape of hepatocellular carcinoma have increased the complexity of patient management. A dynamic adaptation of the available staging-based algorithms is required to allow flexible therapeutic allocation. In particular, real-world hepatocellular carcinoma management increasingly relies on factors independent of oncological staging, including patients' frailty, comorbid burden, critical tumour location, multiple liver functional parameters, and specific technical contraindications impacting the delivery of treatment and resource availability. In this Policy Review we critically appraise how treatment allocation strictly based on pretreatment staging features has shifted towards a more personalised treatment approach, in which expert tumour boards assume a central role. We propose an evidence-based framework for hepatocellular carcinoma treatment based on the novel concept of multiparametric therapeutic hierarchy, in which different therapeutic options are ordered according to their survival benefit (ie, from surgery to systemic therapy). Moreover, we introduce the concept of converse therapeutic hierarchy, in which therapies are ordered according to their conversion abilities or adjuvant abilities (ie, from systemic therapy to surgery).

A virtual biopsy of liver parenchyma to predict the outcome of liver resection.

The preoperative risk assessment of liver resections (LR) is still an open issue. Liver parenchyma characteristics influence the outcome but cannot be adequately evaluated in the preoperative setting. The present study aims to elucidate the contribution of the radiomic analysis of non-tumoral parenchyma to the prediction of complications after elective LR. All consecutive patients undergoing LR between 2017 and 2021 having a preoperative computed tomography (CT) were included. Patients with associated biliary/colorectal resection were excluded. Radiomic features were extracted from a virtual biopsy of non-tumoral liver parenchyma (a 2 mL cylinder) outlined in the portal phase of preoperative CT. Data were internally validated. Overall, 378 patients were analyzed (245 males/133 females-median age 67 years-39 cirrhotics). Radiomics increased the performances of the preoperative clinical models for both liver dysfunction (at internal validaton, AUC = 0.727 vs. 0.678) and bile leak (AUC = 0.744 vs. 0.614). The final predictive model combined clinical and radiomic variables: for bile leak, segment 1 resection, exposure of Glissonean pedicles, HU-related indices, NGLDM_Contrast, GLRLM indices, and GLZLM_ZLNU; for liver dysfunction, cirrhosis, liver function tests, major hepatectomy, segment 1 resection, and NGLDM_Contrast. The combined clinical-radiomic model for bile leak based on preoperative data performed even better than the model including the intraoperative data (AUC = 0.629). The textural features extracted from a virtual biopsy of non-tumoral liver parenchyma improved the prediction of postoperative liver dysfunction and bile leak, implementing information given by standard clinical data. Radiomics should become part of the preoperative assessment of candidates to LR.

Mapping Tumor Heterogeneity via Local Entropy Assessment: Making Biomarkers Visible.

Advanced imaging and analysis improve prediction of pathology data and outcomes in several tumors, with entropy-based measures being among the most promising biomarkers. However, entropy is often perceived as statistical data lacking clinical significance. We aimed to generate a voxel-by-voxel visual map of local tumor entropy, thus allowing to (1) make entropy explainable and accessible to clinicians; (2) disclose and quantitively characterize any intra-tumoral entropy heterogeneity; (3) evaluate associations between entropy and pathology data. We analyzed the portal phase of preoperative CT of 20 patients undergoing liver surgery for colorectal metastases. A three-dimensional core kernel (5 × 5 × 5 voxels) was created and used to compute the local entropy value for each voxel of the tumor. The map was encoded with a color palette. We performed two analyses: (a) qualitative assessment of tumors' detectability and pattern of entropy distribution; (b) quantitative analysis of the entropy values distribution. The latter data were compared with standard Hounsfield data as predictors of post-chemotherapy tumor regression grade (TRG). Entropy maps were successfully built for all tumors. Metastases were qualitatively hyper-entropic compared to surrounding parenchyma. In four cases hyper-entropic areas exceeded the tumor margin visible at CT. We identified four "entropic" patterns: homogeneous, inhomogeneous, peripheral rim, and mixed. At quantitative analysis, entropy-derived data (percentiles/mean/median/root mean square) predicted TRG (p < 0.05) better than Hounsfield-derived ones (p = n.s.). We present a standardized imaging technique to visualize tumor heterogeneity built on a voxel-by-voxel entropy assessment. The association of local entropy with pathology data supports its role as a biomarker.

Transversal hepatectomies: Classification and intention-to-treat validation of new parenchyma-sparing procedures for deep-located hepatic tumors.

BACKGROUND: Deep-located liver tumors involving hepatic veins at the caval confluence or main Glissonean pedicles generally require a major hepatectomy. An intraoperative ultrasound guidance policy opened a possibility to opt for parenchyma-sparing procedures as alternatives to major hepatectomy, called transversal hepatectomies. We ought to standardize the procedure and analyze the surgical outcome, oncological suitability, and salvageability. METHODS: This is a retrospective cohort study. All consecutive patients undergoing hepatectomies for liver tumors between January 2005 and August 2020 were reviewed. Transversal hepatectomies were classified as follows: upper transversal hepatectomy: resection of the posterosuperior segments along with at least 1 hepatic vein and preservation of the anteroinferior ones; roller coaster hepatectomy: transversal hepatectomy with tumor vessel detachment from at least 2 hepatic veins; and lower transversal hepatectomy: amputation of the distal portion of at least 1 hepatic vein with tumor vessel detachment from first/second-order Glissonean pedicles. Morbidity, mortality, local recurrences, and salvageability in cases of relapse were considered. RESULTS: A total of 61 transversal hepatectomies were performed: 40 (66%) upper transversal hepatectomies, 19 (31%) roller coaster hepatectomies, and 2 (3%) lower transversal hepatectomies. The median preserved liver volume was 67% (range 41-86). Mortality was 0, and major morbidity was 6%. Local recurrence occurred in 7 (11%) patients. Ten out of 34 (29%) patients with liver-only recurrence received redo surgery. CONCLUSION: Transversal hepatectomies offer a new parenchyma-sparing perspective for the management of complex tumor presentation, which would otherwise demand major tissue removal or even unresectability. Safety, adequate local control, and salvageability are further pillars of this approach herein systematized.

Transcranial versus direct electrical stimulation for intraoperative motor-evoked potential monitoring: Prognostic value comparison in asleep brain tumor surgery.

Objective: Safe resection of gliomas involving motor pathways in asleep-anesthesia requires the combination of brain mapping, to identify and spare essential motor sites, and continuous monitoring of motor-evoked potentials (MEPs), to detect possible vascular damage to the corticospinal tract (CST). MEP monitoring, according to intraoperative neurophysiology societies, is generally recommended by transcranial electrodes (TES), and no clear indications of direct cortical stimulation (DCS) or the preferential use of one of the two techniques based on the clinical context is available. The main aim of the study was to identify the best technique(s) based on different clinical conditions, evaluating the efficacy and prognostic value of both methodologies. Methods: A retrospective series of patients with tumors involving the motor pathways who underwent surgical resection with the aid of brain mapping and combined MEP monitoring via TES and DCS was evaluated. Irreversible MEP amplitude reduction (>50% compared to baseline) was used as an intraoperative warning and correlated to the postoperative motor outcome. Selectivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were computed for both techniques. Results: Four hundred sixty-two patients were retrospectively analyzed, and only 1.9% showed a long-term motor impairment. Both TES and DCS obtained high specificity and NPV for the acute and 1-month motor deficit. Sensitivity was rather low for the acute deficit but excellent considering the 1-month follow-up for both techniques. DCS was extremely reliable in predicting a postoperative motor decline (PPV of 100% and 90% for acute and long-term deficit, respectively). Conversely, TES produced a high number of false-positive results, especially for long-term deficits (65, 87.8% of all warnings) therefore obtaining poor PPV values (18% and 12% for acute and 1-month deficits, respectively). TES false-positive results were significantly associated with parietal tumors and lateral patient positioning. Conclusions: Data support the use of mapping and combined monitoring via TES and DCS. The sole TES monitoring is reliable in most procedures but not in parietal tumors or those requiring lateral positioning. Although no indications are available in international guidelines, DCS should be recommended, particularly for cases approached by a lateral position.

Functional Investigation of the Tumoural Heterogeneity of Intrahepatic Cholangiocarcinoma by In Vivo PET-CT Navigation: A Proof-of-Concept Study.

Intra-tumoural heterogeneity (IH) is a major determinant of resistance to therapy and outcomes but remains poorly translated into clinical practice. Intrahepatic cholangiocarcinoma (ICC) often presents as large heterogeneous masses at imaging. The present study proposed an innovative in vivo technique to functionally assess the IH of ICC. Preoperative 18F-FDG PET-CT and intraoperative ultrasonography were merged to perform the intraoperative navigation of functional tumour heterogeneity. The tumour areas with the highest and the lowest metabolism (SUV) at PET-CT were selected, identified during surgery, and sampled. Three consecutive patients underwent the procedure. The areas with the highest uptake at PET-CT had higher proliferation index (KI67) values and higher immune infiltration compared to areas with the lowest uptake. One of the patients showed a heterogeneous presence of FGFR2 translocation within the samples. Tumour heterogeneity at PET-CT may drive biopsy to sample the most informative ICC areas. Even more relevant, these preliminary data show the possibility of achieving a non-invasive evaluation of IH in ICC, paving the way for an imaging-based precision-medicine approach.

Radiomics of Biliary Tumors: A Systematic Review of Current Evidence.

Biliary tumors are rare diseases with major clinical unmet needs. Standard imaging modalities provide neither a conclusive diagnosis nor robust biomarkers to drive treatment planning. In several neoplasms, texture analyses non-invasively unveiled tumor characteristics and aggressiveness. The present manuscript aims to summarize the available evidence about the role of radiomics in the management of biliary tumors. A systematic review was carried out through the most relevant databases. Original, English-language articles published before May 2021 were considered. Three main outcome measures were evaluated: prediction of pathology data; prediction of survival; and differential diagnosis. Twenty-seven studies, including a total of 3605 subjects, were identified. Mass-forming intrahepatic cholangiocarcinoma (ICC) was the subject of most studies (n = 21). Radiomics reliably predicted lymph node metastases (range, AUC = 0.729−0.900, accuracy = 0.69−0.83), tumor grading (AUC = 0.680−0.890, accuracy = 0.70−0.82), and survival (C-index = 0.673−0.889). Textural features allowed for the accurate differentiation of ICC from HCC, mixed HCC-ICC, and inflammatory masses (AUC > 0.800). For all endpoints (pathology/survival/diagnosis), the predictive/prognostic models combining radiomic and clinical data outperformed the standard clinical models. Some limitations must be acknowledged: all studies are retrospective; the analyzed imaging modalities and phases are heterogeneous; the adoption of signatures/scores limits the interpretability and applicability of results. In conclusion, radiomics may play a relevant role in the management of biliary tumors, from diagnosis to treatment planning. It provides new non-invasive biomarkers, which are complementary to the standard clinical biomarkers; however, further studies are needed for their implementation in clinical practice.

Is precision medicine for colorectal liver metastases still a utopia? New perspectives by modern biomarkers, radiomics, and artificial intelligence.

The management of patients with liver metastases from colorectal cancer is still debated. Several therapeutic options and treatment strategies are available for an extremely heterogeneous clinical scenario. Adequate prediction of patients' outcomes and of the effectiveness of chemotherapy and loco-regional treatments are crucial to reach a precision medicine approach. This has been an unmet need for a long time, but recent studies have opened new perspectives. New morphological biomarkers have been identified. The dynamic evaluation of the metastases across a time interval, with or without chemotherapy, provided a reliable assessment of the tumor biology. Genetics have been explored and, thanks to their strong association with prognosis, have the potential to drive treatment planning. The liver-tumor interface has been identified as one of the main determinants of tumor progression, and its components, in particular the immune infiltrate, are the focus of major research. Image mining and analyses provided new insights on tumor biology and are expected to have a relevant impact on clinical practice. Artificial intelligence is a further step forward. The present paper depicts the evolution of clinical decision-making for patients affected by colorectal liver metastases, facing modern biomarkers and innovative opportunities that will characterize the evolution of clinical research and practice in the next few years.

PET/CT-based radiomics of mass-forming intrahepatic cholangiocarcinoma improves prediction of pathology data and survival.

PURPOSE: Intrahepatic cholangiocarcinoma (IHC) is an aggressive disease with few reliable preoperative biomarkers. This study aims to elucidate if radiomics extracted from preoperative [18F]FDG PET/CT may grant a non-invasive biological characterization of IHC and predict outcome after complete resection of the tumor. METHODS: All patients preoperatively imaged by [18F]FDG PET/CT who underwent hepatectomy for mass-forming IHC in the period 2010-2019 were retrospectively evaluated. On PET images, manual slice-by-slice segmentation of IHC was performed (Tumor-VOI). A 5-mm margin region was semi-automatically generated around the tumor (Margin-VOI). Textural analysis was performed using the LifeX software. Analyzed outcomes included tumor grading (G3 vs. G1-2), microvascular invasion (MVI), overall survival (OS), and progression-free survival (PFS). The performances of the combined clinical-radiomic models were compared with those of standard clinical models. RESULTS: Overall, 74 patients (40 females, median age 68 years) were included. Considering tumor grading and MVI, the models combining the clinical data and radiomics of the Tumor-VOI had better performances than the clinical ones (AUC = 0.78 vs. 0.72 for grading; 0.87 vs. 0.78 for MVI). The inclusion into the models of radiomics of the Margin-VOI further improved the prediction of grading (AUC = 0.83), but not of MVI. Considering OS and PFS, the models including the preoperative clinical data and radiomics of the Tumor-VOI and Margin-VOI had better performances than the pure clinical ones (C-index = 0.81 vs. 0.76 for OS; 0.81 vs. 0.72 for PFS) and similar to the models including the pathology and postoperative data (C-index = 0.81 for OS; 0.79 for PFS). No model retained the standard SUV measures. CONCLUSION: The PET-based radiomics of IHC can predict pathology data and allow a reliable preoperative evaluation of prognosis. The radiomics of both the tumoral and peritumoral areas had clinical relevance. The combined clinical-radiomic models outperformed the pure preoperative clinical ones and achieved performances non-inferior to the postoperative models.

The added value of artificial intelligence to LI-RADS categorization: A systematic review.

PURPOSE: The objective of this systematic review was to critically assess the available literature on deep learning (DL) and radiomics applied to the Liver Imaging Reporting and Data System (LI-RADS) in terms of 1) automatic LI-RADS classification of liver nodules; 2) the contribution of DL and radiomics to human evaluation in the classification of liver nodules following LI-RADS protocol. MATERIALS AND METHODS: A literature search was conducted to identify original research studies published up to April 2021. The inclusion criteria were: English language, focus on computed tomography (CT) and/or magnetic resonance (MR) with specified number of patients and lesions, adoption of LI-RADS classification for the detected hepatic lesions, and application of AI in the classification of liver nodules. Review articles, conference papers, editorials and commentaries, animal studies or studies with absence of AI and/or LI-RADS were excluded. After screening 221 articles, 11 studies were included in this review. RESULTS: All the included studies proved that DL and radiomics have high performances in liver nodules classification, sometimes similar or better than human evaluation. The best performances of DL was an AUC of 0.95 on MR and the best performance of radiomics was AUC of 0.98 either on CT and MR, while the lower ones were respectively AUC of 0.63 either on CT and MR for DL and AUC of 0.70 on CT for radiomics. CONCLUSION: DL and radiomics could be a useful tool in assisting radiologists in the diagnosis and classification of liver nodules according to LI-RADS.

Very Early Recurrence After Liver Resection for Colorectal Metastases: Incidence, Risk Factors, and Prognostic Impact.

BACKGROUND: Liver resection for colorectal metastases is affected by a non-negligible recurrence rate. The earlier the recurrence, the worse the prognosis. We analyzed an unexplored topic, i.e., the incidence, predictive factors, and prognostic impact of very early recurrence (≤ 3 months after hepatectomy). METHODS: All consecutive liver resections for colorectal metastases performed between 2004 and 2017 were retrospectively reviewed. Inclusion criteria were available recurrence status at 3 months after resection and follow-up ≥ 12 months. RESULTS: Overall, 484 patients were analyzed; 56 (11.6%) had very early recurrence. Independent predictors were number of metastases (very early recurrence in 3.7% of patients with solitary metastasis, 8.1% of those with 2-9 metastases; 20.0% of those with 10-14 metastases; 44.4% of those with ≥ 15 metastases, p < 0.001) and extrahepatic disease (very early recurrence in 23.2% of patients with vs. 10.1% of those without extrahepatic disease, p = 0.017). Very early recurrence rate in patients with ≥ 15 metastases and simultaneous extrahepatic disease was 71.4%. Patients with very early recurrence had poor survival (5-year survival 17.3% vs. 44.5% of non-very early recurrence patients, p < 0.001), worse than patients with 3-to-6 months recurrence (p = 0.070), and no different from unresected patients (p = 0.114). Fifteen patients with very early recurrence (26.8%) underwent repeated treatment with adequate survival (at 3 years 42.2%), but seven had a further recurrence within 3 months. CONCLUSIONS: Very early recurrence occurs in about 12% of patients undergoing aggressive surgery for colorectal metastases. The risk is increased in patients with numerous metastases or extrahepatic disease. Very early recurrence is associated with very poor prognosis, similar to that of unresected patients, and a low chance of effective repeated treatment.

Stimulation of frontal pathways disrupts hand muscle control during object manipulation.

The activity of frontal motor areas during hand-object interaction is coordinated by dense communication along specific white matter pathways. This architecture allows the continuous shaping of voluntary motor output but, despite extensive investigation in non-human primate studies, remains poorly understood in humans. Disclosure of this system is crucial for predicting and treatment of motor deficits after brain lesions. For this purpose, we investigated the effect of direct electrical stimulation on white matter pathways within the frontal lobe on hand-object manipulation. This was tested in 34 patients (15 left hemisphere, mean age 42 years, 17 male, 15 with tractography) undergoing awake neurosurgery for frontal lobe tumour removal with the aid of the brain mapping technique. The stimulation outcome was quantified based on hand-muscle activity required by task execution. The white matter pathways responsive to stimulation with an interference on muscles were identified by means of probabilistic density estimation of stimulated sites, tract-based lesion-symptom (disconnectome) analysis and diffusion tractography on the single patient level. Finally, we assessed the effect of permanent tract disconnection on motor outcome in the immediate postoperative period using a multivariate lesion-symptom mapping approach. The analysis showed that stimulation disrupted hand-muscle activity during task execution at 66 sites within the white matter below dorsal and ventral premotor regions. Two different EMG interference patterns associated with different structural architectures emerged: (i) an 'arrest' pattern, characterized by complete impairment of muscle activity associated with an abrupt task interruption, occurred when stimulating a white matter area below the dorsal premotor region. Local middle U-shaped fibres, superior fronto-striatal, corticospinal and dorsal fronto-parietal fibres intersected with this region. (ii) a 'clumsy' pattern, characterized by partial disruption of muscle activity associated with movement slowdown and/or uncoordinated finger movements, occurred when stimulating a white matter area below the ventral premotor region. Ventral fronto-parietal and inferior fronto-striatal tracts intersected with this region. Finally, only resections partially including the dorsal white matter region surrounding the supplementary motor area were associated with transient upper-limb deficit (P = 0.05; 5000 permutations). Overall, the results identify two distinct frontal white matter regions possibly mediating different aspects of hand-object interaction via distinct sets of structural connectivity. We suggest the dorsal region, associated with arrest pattern and postoperative immediate motor deficits, to be functionally proximal to motor output implementation, while the ventral region may be involved in sensorimotor integration required for task execution.