Risk Profile of Patients with Spontaneous Cervical Artery Dissection.

OBJECTIVE: Epidemiological data to characterize the individual risk profile of patients with spontaneous cervical artery dissection (sCeAD) are rather inconsistent. METHODS AND RESULTS: In the setting of the Italian Project on Stroke in Young Adults Cervical Artery Dissection (IPSYS CeAD), we compared the characteristics of 1,468 patients with sCeAD (mean age = 47.3 ± 11.3 years, men = 56.7%) prospectively recruited at 39 Italian centers with those of 2 control groups, composed of (1) patients whose ischemic stroke was caused by mechanisms other than dissection (non-CeAD IS) selected from the prospective IPSYS registry and Brescia Stroke Registry and (2) stroke-free individuals selected from the staff members of participating hospitals, matched 1:1:1 by sex, age, and race. Compared to stroke-free subjects, patients with sCeAD were more likely to be hypertensive (odds ratio [OR] = 1.65, 95% confidence interval [CI] = 1.37-1.98), to have personal history of migraine with aura (OR = 2.45, 95% CI = 1.74-3.34), without aura (OR = 2.67, 95% CI = 2.15-3.32), and family history of vascular disease in first-degree relatives (OR = 1.69, 95% CI = 1.39-2.05), and less likely to be diabetic (OR = 0.65, 95% CI = 0.47-0.91), hypercholesterolemic (OR = 0.75, 95% CI = 0.62-0.91), and obese (OR = 0.41, 95% CI = 0.31-0.54). Migraine without aura was also associated with sCeAD (OR = 1.81, 95% CI = 1.47-2.22) in comparison with patients with non-CeAD IS. In the subgroup of patients with migraine, patients with sCeAD had higher frequency of migraine attacks and were less likely to take anti-migraine preventive medications, especially beta-blockers, compared with the other groups. INTERPRETATION: The risk of sCeAD is influenced by migraine, especially migraine without aura, more than by other factors, increases with increasing frequency of attacks, and seems to be reduced by migraine preventive medications, namely beta-blockers. ANN NEUROL 2023;94:585-595.

Antithrombotic therapy in the postacute phase of cervical artery dissection: the Italian Project on Stroke in Young Adults Cervical Artery Dissection.

OBJECTIVE: To explore the impact of antithrombotic therapy discontinuation in the postacute phase of cervical artery dissection (CeAD) on the mid-term outcome of these patients. METHODS: In a cohort of consecutive patients with first-ever CeAD, enrolled in the setting of the multicentre Italian Project on Stroke in Young Adults Cervical Artery Dissection, we compared postacute (beyond 6 months since the index CeAD) outcomes between patients who discontinued antithrombotic therapy and patients who continued taking antithrombotic agents during follow-up. Primary outcome was a composite of ischaemic stroke and transient ischaemic attack. Secondary outcomes were (1) Brain ischaemia ipsilateral to the dissected vessel and (2) Recurrent CeAD. Associations with the outcome of interest were assessed by the propensity score (PS) method. RESULTS: Of the 1390 patients whose data were available for the outcome analysis (median follow-up time in patients who did not experience outcome events, 36.0 months (25th-75th percentile, 62.0)), 201 (14.4%) discontinued antithrombotic treatment. Primary outcome occurred in 48 patients in the postacute phase of CeAD. In PS-matched samples (201 vs 201), the incidence of primary outcomes among patients taking antithrombotics was comparable with that among patients who discontinued antithrombotics during follow-up (5.0% vs 4.5%; p(log rank test)=0.526), and so was the incidence of the secondary outcomes ipsilateral brain ischaemia (4.5% vs 2.5%; p(log rank test)=0.132) and recurrent CeAD (1.0% vs 1.5%; p(log rank test)=0.798). CONCLUSIONS: Discontinuation of antithrombotic therapy in the postacute phase of CeAD does not appear to increase the risk of brain ischaemia during follow-up.

Clinical Features of Patients With Cervical Artery Dissection and Fibromuscular Dysplasia.

BACKGROUND AND PURPOSE: Observational studies have suggested a link between fibromuscular dysplasia and spontaneous cervical artery dissection (sCeAD). However, whether patients with coexistence of the two conditions have distinctive clinical characteristics has not been extensively investigated. METHODS: In a cohort of consecutive patients with first-ever sCeAD, enrolled in the setting of the multicenter IPSYS CeAD study (Italian Project on Stroke in Young Adults Cervical Artery Dissection) between January 2000 and June 2019, we compared demographic and clinical characteristics, risk factor profile, vascular pathology, and midterm outcome of patients with coexistent cerebrovascular fibromuscular dysplasia (cFMD; cFMD+) with those of patients without cFMD (cFMD-). RESULTS: A total of 1283 sCeAD patients (mean age, 47.8±11.4 years; women, 545 [42.5%]) qualified for the analysis, of whom 103 (8.0%) were diagnosed with cFMD+. In multivariable analysis, history of migraine (odds ratio, 1.78 [95% CI, 1.13-2.79]), the presence of intracranial aneurysms (odds ratio, 8.71 [95% CI, 4.06-18.68]), and the occurrence of minor traumas before the event (odds ratio, 0.48 [95% CI, 0.26-0.89]) were associated with cFMD. After a median follow-up of 34.0 months (25th to 75th percentile, 60.0), 39 (3.3%) patients had recurrent sCeAD events. cFMD+ and history of migraine predicted independently the risk of recurrent sCeAD (hazard ratio, 3.40 [95% CI, 1.58-7.31] and 2.07 [95% CI, 1.06-4.03], respectively) in multivariable Cox proportional hazards analysis. CONCLUSIONS: Risk factor profile of sCeAD patients with cFMD differs from that of patients without cFMD. cFMD and migraine are independent predictors of midterm risk of sCeAD recurrence.

Age-dependent effect of susceptibility factors on the risk of intracerebral haemorrhage: Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy).

OBJECTIVE: To investigate the age-dependent impact of traditional stroke risk factors on the occurrence of intracerebral haemorrhage (ICH). METHODS: We performed a case-control analysis, comparing consecutive patients with ICH with age-matched and sex-matched stroke-free controls, enrolled in the setting of the Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy) between 2002 and 2014 by multivariable logistic regression model within subgroups stratified by age quartiles (Q1-Q4). RESULTS: We analysed 3492 patients and 3492 controls. The impact of untreated hypertension on the risk of ICH was higher in the lower than in the upper age quartile (OR 11.64, 95% CI 7.68 to 17.63 in Q1 vs OR 6.05, 95% CI 3.09 to 11.85 in Q4 with intermediate ORs in Q2 and Q3), while the opposite trend was observed for untreated hypercholesterolaemia (OR 0.63, 95% CI 0.45 to 0.97 in Q1 vs OR 0.36, 95% CI 0.26 to 0.56 in Q4 with intermediate ORs in Q2 and Q3). The effect of untreated diabetes and excessive alcohol intake was detected only in the older age group (OR 3.63, 95% CI 1.22 to 10.73, and OR 1.69, 95% CI 1.13 to 2.51, respectively). CONCLUSIONS: Our findings provide evidence of age-dependent differences in the effects of susceptibility factors on the risk of ICH.

Magnetic resonance imaging of pilocytic astrocytomas in adults with histopathologic correlation: a report of six consecutive cases.

Pilocytic astrocytoma is a WHO grade I tumor usually diagnosed in pediatric patients, and rarely encountered in the adult population. Therefore, available information about the magnetic resonance imaging characteristics of adult pilocytic astrocytoma is scarce. We report on the MRI features and corresponding histopathologic findings of six consecutive aPA cases diagnosed. The tumors were encountered in both infra- and supratentorial compartments, and their MRI characteristics were quite heterogeneous. Features included the typical solid-cystic appearance located in the cerebellum as well as the relatively unusual multifocal and/or hemorrhagic features located intra-ventricularly. The aPA MRI characteristics are remarkably variable, and might mimic those of higher grade tumors in adult patients.

Primary seminoma arising in the posterior mediastinum: a diagnostic challenge.

Primary mediastinal germ cell tumors are a rare finding, and one third of them are seminomas. Seminomas are found in the anterior mediastinum, whereas they are extremely rare within the posterior compartment. Most clinicians would not consider a primary seminoma in the differential diagnosis of a posterior mediastinal mass, as only two cases have been reported in literature. Here we present the case of a 57-year-old male with a primary seminoma arising in the left posterior mediastinum. He was asymptomatic and the mass was an incidental finding. Positron emission tomography (PET) revealed a small area with an avid tracer uptake. Transthoracic needle aspiration led to a non-diagnostic result. Due to the strong suspect of malignancy, a surgical excision was chosen to obtain a diagnosis. He underwent complete excision, and pathology report demonstrated a mediastinal seminoma. Subsequent further staging did not reveal any other location of the disease. Given the complete excision of the primary tumor, active surveillance was the treatment of choice. The patient is free of disease 48 months after diagnosis.

Long-term outcome of cervical artery dissection : IPSYS CeAD: study protocol, rationale, and baseline data of an Italian multicenter research collaboration.

Long-term consequences of cervical artery dissection (CeAD), a major cause of ischemic stroke in young people, have been poorly investigated. The Italian Project on Stroke at Young Age - Cervical Artery Dissection (IPSYS CeAD) project is a multicenter, hospital-based, consecutively recruiting, observational, cohort study aimed to address clinically important questions about long-term outcome of CeAD patients, which are not covered by other large-scale registries. Patients with radiologically diagnosed CeAD were consecutively included in the registry. Baseline demographic and clinical variables, as well as information on risk factors, were systematically collected for each eligible patient. Follow-up evaluations were conducted between 3 and 6 months after the initial event (t1) and then annually (t2 at 1 year, t3 at 2 years , and so on), in order to assess outcome events (long-term recurrent CeAD, any fatal/nonfatal ischemic stroke, transient ischemic attack (TIA), or other arterial thrombotic event, and death from any cause). Between 2000 and 2019, data from 1530 patients (age at diagnosis, 47.2 ± 11.5 years; women, 660 [43.1%]) have been collected at 39 Italian neurological centers. Dissection involved a single vessel in 1308 (85.5%) cases and caused brain ischemia in 1303 (85.1%) (190 TIA/1113 ischemic stroke). Longitudinal data are available for 1414 (92.4%) patients (median follow-up time in patients who did not experience recurrent events, 36.0 months [25th to 75th percentile, 63.0]). The collaborative IPSYS CeAD effort will provide novel information on the long-term outcome of CeAD patients. This could allow for tailored treatment approaches based on patients' individual characteristics.

Overlapping polyclonal lymphoproliferative disorders.

Multicentric Castleman disease (MCD) is a rare clinical entity characterized by a polyclonal lymphoid proliferation, leading to generalized lymphadenopathy, organomegaly and systemic symptoms. It has been reported in association with either other monoclonal or polyclonal lymphoid disorders, such as POEMS syndrome and immunoglobulin (Ig)G4-related disease. We present a patient showing a variant of MCD, sharing common features with POEMS syndrome and associated with the proliferation of IgG4-producing plasma cells.

Clinical implications of heterogeneity in PD-L1 immunohistochemical detection in hepatocellular carcinoma: the Blueprint-HCC study.

Programmed cell death ligand-1 immunohistochemical detection (PD-L1 IHC) is a putative predictor of response to PD-1/PD-L1-targeted checkpoint inhibitors. However, there is no gold standard assay in hepatocellular carcinoma (HCC). We evaluated 5 PD-L1 IHC assay platforms (E1LN3, 28-8, 22c3, SP263 and SP142) in 100 HCCs reporting PD-L1 expression in malignant (M) and tumour-infiltrating immune cells (TICs) and non-tumorous cirrhotic tissues (NTICs). We found substantial inter-assay heterogeneity in detecting PD-L1 expression in M (R2 = 0.080-0.921), TICs (Cohen's κ = 0.175-0.396) and NTICs (κ = 0.004-0.505). Such diversity may impact on the reliability and reproducibility of PD-L1 IHC assays as a predictor of response to immune checkpoint inhibitors.

Eating habits in the population of the Aeolian Islands: an observational study.

OBJECTIVE: We conducted a study to describe food profile, health status and stroke risk factors in the population of the Aeolian Islands. DESIGN: Self-administrated questionnaires regarding eating habits, health status and stroke risk factors were obtained from a sample of the general Aeolian population. We analysed the difference from common healthy eating habits indicated by the Italian Institute of Nutrition. SETTING: Current evidence finds the Mediterranean diet is a protective factor for cardio- and cerebrovascular diseases. The Aeolian Islands are an interesting study setting because of their peculiarity in the epidemiology of cerebrovascular and neurodegenerative diseases. PARTICIPANTS: Individuals (n 586; age range 15-93 years; mean 52 (sd 18) years) living in the Aeolian Islands. RESULTS: We found low fish consumption in 13·3% and vitamin intake deficiency in 5·8% of participants. A marked excess of saturated fats was observed in 71·0% of participants. Sodium excess was reported almost in half of participants (49·0%). Eating habits were characterized by high consumption of fruits and vegetables, consistent use of olive oil and scanty use of cured meat. Health status as evaluated by the General Health Questionnaire was characterized by 'normal distress' level in the majority of participants. CONCLUSIONS: Study findings show the eating habits and health status of the Aeolian people in an interesting setting of low incidence of cerebrovascular disease. This nutrition regimen has been proved to be protective against cerebrovascular disease. Nutrition is likely to contribute to the low incidence of stroke in this population.

Serum cholesterol levels, HMG-CoA reductase inhibitors and the risk of intracerebral haemorrhage. The Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy).

OBJECTIVE: Although a concern exists that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) might increase the risk of intracerebral haemorrhage (ICH), the contribution of these agents to the relationship between serum cholesterol and disease occurrence has been poorly investigated. METHODS: We compared consecutive patients having ICH with age and sex-matched stroke-free control subjects in a case-control analysis, as part of the Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy), and tested the presence of interaction effects between total serum cholesterol levels and statins on the risk of ICH. RESULTS: A total of 3492 cases (mean age, 73.0±12.7 years; males, 56.6%) and 3492 control subjects were enrolled. Increasing total serum cholesterol levels were confirmed to be inversely associated with ICH. We observed a statistical interaction between total serum cholesterol levels and statin use for the risk of haemorrhage (Interaction OR (IOR), 1.09; 95% CI 1.05 to 1.12). Increasing levels of total serum cholesterol were associated with a decreased risk of ICH within statin strata (average OR, 0.87; 95% CI 0.86 to 0.88 for every increase of 0.26 mmol/l of total serum cholesterol concentrations), while statin use was associated with an increased risk (OR, 1.54; 95% CI 1.31 to 1.81 of the average level of total serum cholesterol). The protective effect of serum cholesterol against ICH was reduced by statins in strictly lobar brain regions more than in non-lobar ones. CONCLUSIONS: Statin therapy and total serum cholesterol levels exhibit interaction effects towards the risk of ICH. The magnitude of such effects appears higher in lobar brain regions.

Calcified uterine leiomyoma from an 18th-century nunnery in North Italy.

OBJECTIVE: To develop a differential diagnosis of a mass retrieved alongside skeletal remains in the crypt of the church of Santissima Annunziata of Valenza (Province of Alessandria, Northern Italy). MATERIAL: A calcified mass measuring 40 × 39 mm and 17.62 × 16.3817.62 × 16.38 mm. METHOD: The analysis utilized macroscopic assessment and histologic examination (including histochemical and immunohistochemical analyses). RESULTS: Morphological traits include an irregular and spongy external surface. Holes of different sizes lead toward the inner part of the object. A section of the mass shows an "intertwined bundle" pattern, confirmed by microscopic examination. CONCLUSIONS: Differential diagnosis determined the mass to be consistent with calcified leiomyoma. SIGNIFICANCE: Identifying uterine leiomyoma adds to the paucity of paleopathological literature on the condition and to calcified tumors more broadly. It also allows for an important discussion of women's gynecological health in the past and potentially among nulliparous women. LIMITATIONS: Neither histochemical staining nor immunohistochemical analysis demonstrated the certain muscular nature of the specimens due to the rehydration and decalcification processes, for which there are no gold standards. SUGGESTIONS FOR FURTHER RESEARCH: Calcified masses are common in the clinical literature but remain rare in paleopathological literature. Careful excavation and improved recognition of apparently calcified masses are necessary to improve recognition, diagnosis, and interpretation.

Clinical Relevance and Interplay between miRNAs in Influencing Glioblastoma Multiforme Prognosis.

Glioblastoma multiforme (GBM) is usually treated with surgery followed by adjuvant partial radiotherapy combined with temozolomide (TMZ) chemotherapy. Recent studies demonstrated a better survival and good response to TMZ in methylguanine-DNA methyltransferase (MGMT)-methylated GBM cases. However, approximately 20% of patients with MGMT-unmethylated GBM display an unexpectedly favorable outcome. Therefore, additional mechanisms related to the TMZ response need to be investigated. As such, we decided to investigate the clinical relevance of six miRNAs involved in brain tumorigenesis (miR-181c, miR-181d, miR-21, miR-195, miR-196b, miR-648) as additional markers of response and survival in patients receiving TMZ for GBM. We evaluated miRNA expression and the interplay between miRNAs in 112 IDH wt GBMs by applying commercial assays. Then, we correlated the miRNA expression with patients' clinical outcomes. Upon bivariate analyses, we found a significant association between the expression levels of the miRNAs analyzed, but, more interestingly, the OS curves show that the combination of low miR-648 and miR-181c or miR-181d expressions is associated with a worse prognosis than cases with other low-expression miRNA pairs. To conclude, we found how specific miRNA pairs can influence survival in GBM cases treated with TMZ.

A possible case of orbital osteomyelitis from the medieval cemetery of Sant' Agostino in Caravate (Varese, Northern Italy).

OBJECTIVES: This paper aims to present one of the first osteoarchaeological cases of orbital osteomyelitis and provides the best diagnostic criteria to identify its pathophysiological changes. MATERIALS: A well-preserved skeleton of an adult male from the medieval cemetery of Sant' Agostino in Caravate, Italy. METHODS: Macroscopic, tomographic, and histological analyses were performed using standard methods. RESULTS: The skeleton shows irregularities in the architecture of the left supraorbital margin. CT analysis reveals the presence of a radiotransparent area involving the diploe and the external cranial table. This area is lateromedially oval-shaped and bordered by a thick irregular radiodense rim, associated with the presence of a cloaca on the roof of the orbit and surrounding periosteal reaction. Microscopic examination shows the formation of a thin layer of cortical bone and an osteoid-like matrix. CONCLUSION: A careful differential diagnosis based on macroscopic, radiological, and histological evidence suggests a case of orbital osteomyelitis. SIGNIFICANCE: This case study represents one of the few osteoarchaeological evaluations of ocular chronic osteomyelitis diagnosed using macroscopic skeletal, computed tomography, and histological analysis. As such, it provides a reference and an investigative criterion for future cases. LIMITATIONS: The diagnosis cannot be stated with certainty, and only probable diagnoses can be proposed. Although we referred especially to clinical literature, it is necessary to consider that the severity of conditions may be modified by modern medical intervention. SUGGESTION FOR FURTHER RESEARCH: This case provides further insights into the presence of this condition in the past.

Shell Technique with a Xenogeneic Cortical Bone Lamina and Particulate Bone Graft for Horizontal Ridge Augmentation: A Case Series

The aim of this prospective case series was to evaluate the efficacy and safety of a xenogeneic cortical bone lamina utilized as a "shell" on the buccal aspect of narrow alveolar ridges for horizontal bone augmentation. Fifteen patients requiring multiple implant restorations at sites with moderate to severe horizontal bone deficiency were consecutively enrolled. Horizontal bone augmentation was performed using a xenogeneic cortical bone lamina (XCBL), that was fixed on the buccal aspect of the ridge using titanium screws, and a mixture of particulate autogenous bone graft and porcine hydroxyapatite. Cone-beam computed tomography (CBCT) scans were taken at baseline and 6 months after bone augmentation. The healing was uneventful, with no intra- or post-operative complications. Twenty-seven dental implants were placed in the augmented sites. The calculated average horizontal bone gain from CBCT scans was 4.79 ± 1.64 mm, 5.59 ± 1.51 mm, and 5.79 ± 2.53 mm at 1-, 3- and 5-mm reference points apical to the buccal bone crest, respectively. The present case series demonstrated that the shell technique with the xenogeneic cortical bone lamina and particulate bone graft can be an effective approach for horizontal bone augmentation prior to implant placement.

A qPCR technology for direct quantification of methylation in untreated DNA.

DNA methylation is important for gene expression and alterations in DNA methylation are involved in the development and progression of cancer and other major diseases. Analysis of DNA methylation patterns has until now been dependent on either a chemical or an enzymatic pre-treatment, which are both time consuming procedures and potentially biased due to incomplete treatment. We present a qPCR technology, EpiDirect®, that allows for direct PCR quantification of DNA methylations using untreated DNA. EpiDirect® is based on the ability of Intercalating Nucleic Acids (INA®) to differentiate between methylated and unmethylated cytosines in a special primer design. With this technology, we develop an assay to analyze the methylation status of a region of the MGMT promoter used in treatment selection and prognosis of glioblastoma patients. We compare the assay to two bisulfite-relying, methyl-specific PCR assays in a study involving 42 brain tumor FFPE samples, revealing high sensitivity, specificity, and the clinical utility of the method.

Identification of MGMT Downregulation Induced by miRNA in Glioblastoma and Possible Effect on Temozolomide Sensitivity.

Glioblastoma multiforme (GBM) remains one of the tumors with the worst prognosis. In recent years, a better overall survival (OS) has been described in cases subjected to Gross Total Resection (GTR) that were presenting hypermethylation of Methylguanine-DNA methyltransferase (MGMT) promoter. Recently, also the expression of specific miRNAs involved in MGMT silencing has been related to survival. In this study, we evaluate MGMT expression by immunohistochemistry (IHC), MGMT promoter methylation and miRNA expression in 112 GBMs and correlate the data to patients' clinical outcomes. Statistical analyses demonstrate a significant association between positive MGMT IHC and the expression of miR-181c, miR-195, miR-648 and miR-767.3p between unmethylated cases and the low expression of miR-181d and miR-648 and between methylated cases and the low expression of miR-196b. Addressing the concerns of clinical associations, a better OS has been described in presence of negative MGMT IHC, in methylated patients and in the cases with miR-21, miR-196b overexpression or miR-767.3 downregulation. In addition, a better progression-free survival (PFS) is associated with MGMT methylation and GTR but not with MGMT IHC and miRNA expression. In conclusion, our data reinforce the clinical relevance of miRNA expression as an additional marker to predict efficacy of chemoradiation in GBM.

Abdominal Kikuchi-Fujimoto lymphadenopathy: an uncommon presentation of a rare disease.

A 34-year-old man presented to our hospital with a 5-day history of progressive abdominal pain and fever. A CT scan identified extensive mesenteric lymphadenopathy. Initial diagnostic tests were inconclusive. Abdominal lymph node biopsy showed histiocytic necrotising lymphadenitis, compatible with Kikuchi-Fujimoto disease (KFD). This benign and self-limiting disease generally resolves following supportive treatment. In this case, remission occurred within 3 weeks of initial presentation. KFD is a very uncommon cause of lymphadenopathy, and selective mesenteric involvement is rare. Definitive diagnosis often requires lymph node biopsy. It is important to exclude more common and serious differential diagnoses associated with mesenteric lymphadenopathy, while maintaining a minimally invasive diagnostic approach, before progressing to nodal biopsy.

A Pilot, Prospective, Observational Study to Investigate the Value of NGS in Liquid Biopsies to Predict Tumor Response After Neoadjuvant Chemo-Radiotherapy in Patients With Locally Advanced Rectal Cancer: The LiBReCa Study.

Introduction: Circulating tumor DNA (ctDNA) correlates with the response to therapy in different types of cancer. However, in patients with locally advanced rectal cancer (LARC), little is known about how ctDNA levels change with neoadjuvant chemoradiation (Na-ChRT) and how they correlate with treatment response. This work aimed to explore the value of serial liquid biopsies in monitoring response after Na-ChRT with the hypothesis that this could become a reliable biomarker to identify patients with a complete response, candidates for non-operative management. Materials and Methods: Twenty-five consecutive LARC patients undergoing long-term Na-ChRT therapy were included. Applying next-generation sequencing (NGS), we characterized DNA extracted from formalin-fixed paraffin embedded diagnostic biopsy and resection tissue and plasma ctDNA collected at the following time points: the first and last days of radiotherapy (T0, Tend), at 4 (T4), 7 (T7) weeks after radiotherapy, on the day of surgery (Top), and 3-7 days after surgery (Tpost-op). On the day of surgery, a mesenteric vein sample was also collected (TIMV). The relationship between the ctDNA at those time-points and the tumor regression grade (TRG) of the surgical specimen was statistically explored. Results: We found no association between the disappearance of ctDNA mutations in plasma samples and pathological complete response (TRG1) as ctDNA was undetectable in the majority of patients from Tend on. However, we observed that the poor (TRG 4) response to Na-ChRT was significantly associated with a positive liquid biopsy at the Top. Conclusions: ctDNA evaluation by NGS technology may identify LARC patients with poor response to Na-ChRT. In contrast, this technique does not seem useful for identifying patients prone to developing a complete response.