Needleless inhaled anesthesia with sevoflurane: Advantages of a simplified approach for children with spinal muscular atrophy undergoing intrathecal administration of nusinersen.

BACKGROUND: Intrathecal nusinersen administration, a fundamental step in the treatment of spinal muscular atrophy, is challenging in children. AIMS: This retrospective monocentric analysis of prospectively collected data evaluated the feasibility of needleless general anesthesia exclusively with sevoflurane, without imaging guidance, for children undergoing nusinersen administration in a 24-month period. METHODS: Clinical data included demographics, type of spinal muscular atrophy, presence and severity of scoliosis. Primary outcome was defined by the number of predefined sentinel adverse events related to anesthesia. Secondary outcomes were assessed by duration of the procedure, number of lumbar puncture attempts, and number of failures. Other measures included number and type of moderate, minor and minimal adverse events, as well as number and type of puncture-related adverse events. RESULTS: 116 patients (mean age: 8.7 (SD 6.9) years; with scoliosis: 49.1%) underwent 250 lumbar punctures; two cases of prolonged desaturation, considered as sentinel adverse events, (0.8%) were recorded during anesthesia (primary outcome). None of the patients underwent orotracheal intubation nor required an unplanned admission in the Pediatric Intensive Care Unit. No patient required an unplanned or prolonged hospitalization after the procedure. Mean number of puncture attempts was 1.6 (SD 1.3), and mean duration of the procedure was 14.1 (SD 8.3) minutes. No failure in the drug administration occurred (secondary outcomes). CONCLUSION: In this single-center experience, needleless general anesthesia with inhaled sevoflurane without imaging guidance has been shown to be feasible for children with spinal muscular atrophy undergoing lumbar puncture for nusinersen administration.

Children and neonates anesthesia in magnetic resonance environment in Italy: an active call survey.

BACKGROUND: Pediatric anesthesia care in the Magnetic Resonance Imaging is a challenge for clinicians. The recent debate about the role of anesthetic agent on neural development, encouraged an evaluation of their actual activity in this environment. In this active call survey, the authors sought to delineate the Italian situation regarding national centers, staff involved, monitoring tools available and sedation techniques. METHODS: A complete sample of all national centers performing almost a pediatric discharge in the 2014 was obtained from Health Ministry registers. All Institutions were contacted for a prospective phone investigation and a three-section survey was fill out with the Physician in charge. A descriptive and exploratory analyzes about the organization setting of the Centers were performed. RESULTS: Among 876 Institution screened, only 106 (37%) met minimal criteria for inclusion. Children are managed by anesthesiologists in the 95% of cases, while neonates in the 54%. A dedicated nurse is present in 74% of centers. While a pulse oximetry is present in 100% of centers, the rate of prevalence of other monitoring is lower. A specific MRI-compatible ventilator is available in the 95% of Centers, but many tools are not equally homogenously distributed. Pharmacological approach is preferred in pediatric age (98%), but its use for newborns is reduced to 43%. CONCLUSIONS: We found significant heterogeneity in the daily clinical practice of sedation in MRI. Our results could be a starting point to evaluate the further evolution of approach to children and neonates in magnetic resonance setting. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04775641.

Personalized therapeutic strategies in HER2-driven gastric cancer.

BACKGROUND: Trastuzumab is the only approved targeted therapy in patients with HER2-amplified metastatic gastric cancer (GC). Regrettably, in clinical practice, only a fraction of them achieves long-term benefit from trastuzumab-based upfront strategy. To advance precision oncology, we investigated the therapeutic efficacy of different HER2-targeted strategies, in HER2 "hyper"-amplified (≥ 8 copies) tumors. METHODS: We undertook a prospective evaluation of HER2 targeting with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates, in a selected subgroup of HER2 "hyper"-amplified gastric patient-derived xenografts (PDXs), through the design of ad hoc preclinical trials. RESULTS: Despite the high level of HER2 amplification, trastuzumab elicited a partial response only in 2 out of 8 PDX models. The dual-HER2 blockade with trastuzumab plus either pertuzumab or lapatinib led to complete and durable responses in 5 (62.5%) out of 8 models, including one tumor bearing a concomitant HER2 mutation. In a resistant PDX harboring KRAS amplification, the novel antibody-drug conjugate trastuzumab deruxtecan (but not trastuzumab emtansine) overcame KRAS-mediated resistance. We also identified a HGF-mediated non-cell-autonomous mechanism of secondary resistance to anti-HER2 drugs, responsive to MET co-targeting. CONCLUSION: These preclinical randomized trials clearly indicate that in HER2-driven gastric tumors, a boosted HER2 therapeutic blockade is required for optimal efficacy, leading to complete and durable responses in most of the cases. Our results suggest that a selected subpopulation of HER2-"hyper"-amplified GC patients could strongly benefit from this strategy. Despite the negative results of clinical trials, the dual blockade should be reconsidered for patients with clearly HER2-addicted cancers.

The scalp block for postoperative pain control in craniosynostosis surgery: a case control study.

PURPOSE: Postoperative analgesia after corrective surgery of pediatric craniosynostosis is crucial in terms of short- and long-term outcomes. The objective of this observational study was to evaluate the effectiveness of an analgesic technique based on the scalp block versus traditional pharmacological approach. METHODS: Thirteen patients, aged between 3 months and 2 years, undergoing surgical correction of craniosynostosis, received scalp nerve block before awakening (scalp block group). This group of patients was compared to a second group of 13 patients, retrieved from our database, treated with the traditional pharmacological approach (control group). Pain scores, need of rescue therapy, resumption of oral nutrition, degree of parent satisfaction at discharge, and length of stay in the Pediatric Intensive Care Unit (PICU) and in the hospital were compared between the two groups. RESULTS: Objective Pain Score values were significantly lower in patients treated with scalp block at 30 min and at 8 h after extubation. The number of pharmacological interventions for the treatment of pain in PICU was significantly higher in Control group. Children in Scalp block group started earlier oral feeding than in Control group, both for clear fluids and milk. Length of stay in PICU was longer in Scalp block group than in Control group, though the difference between the mean data in the two groups is about 3 . This difference does not seem significant from a clinical standpoint, since it seems more related to logistic issues (e.g., availability of bed in the Pediatric Neurosurgery Unit, presence of a parent), rather than clinical problems contraindicating the discharge from PICU. Indeed, the overall hospital length of stay was similar between the two groups. CONCLUSION: Scalp nerve block was effective for immediate postoperative pain control in patients younger than 2 years who underwent cranioplasty for craniosynostosis. The best pain control compared to conventional therapy allowed to limit the need for rescue analgesics in PICU and an earlier recovery time. ClinicalTrials.gov Identification: NCT04133467.

HER2 Positivity Predicts Unresponsiveness to EGFR-Targeted Treatment in Metastatic Colorectal Cancer.

BACKGROUND: HER2 amplification is detected in 3% of patients with colorectal cancer (CRC), making tumors in the metastatic setting vulnerable to double pharmacological HER2 blockade. Preclinical findings show that it also might impair response to anti-epidermal growth factor receptor (EGFR) treatment. SUBJECTS AND METHODS: Patients with KRAS exon 2 wild-type metastatic CRC underwent molecular screening of HER2 positivity by HERACLES criteria (immunohistochemistry 3+ or 2+ in ≥50% of cells, confirmed by fluorescence in situ hybridization). A sample of consecutive HER2-negative patients was selected as control. A regression modeling strategy was applied to identify predictors explaining the bulk of HER2 positivity and the association with response to previous anti-EGFR treatment. RESULTS: From August 2012 to April 2018, a total of 100 HER2-positive metastatic CRC tumors were detected out of 1,485 KRAS exon 2 wild-type screened patients (6.7%). HER2-positive patients show more frequently lung metastases (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.15-3.61; p = .014) and higher tumor burden (OR, 1.48; 95% CI, 1.10-2.01; p = .011), and tumors were more likely to be left sided (OR, 0.50; 95% CI, 0.22-1.11; p = .088). HER2-positive patients who received treatment with anti-EGFR agents (n = 79) showed poorer outcome (objective response rate, 31.2% vs. 46.9%, p = .031; progression-free survival, 5.7 months vs. 7 months, p = .087). CONCLUSION: Testing for HER2 should be offered to all patients with metastatic CRC because the occurrence of this biomarker is unlikely to be predicted based on main clinicopathological features. Patients with HER2-amplified metastatic CRC are less likely to respond to anti-EGFR therapy. IMPLICATIONS FOR PRACTICE: Patients with HER2-amplified/overexpressed metastatic colorectal cancer (mCRC) harbor a driver actionable molecular alteration that has been shown in preclinical models to hamper efficacy of the anti-epidermal growth factor receptor (EGFR) targeted therapies. The present study confirmed that this molecular feature was associated with worse objective tumor response and shorter progression-free survival in response to previous anti-EGFR therapies. Moreover, it was found that the occurrence of this biomarker is unlikely to be predicted based on main clinicopathological features. Therefore, HER2 status assessment should be included in the molecular diagnostic workup of all mCRC for speedy referral to clinical trials encompassing HER2-targeted double blockade independently of previous anti-EGFR treatment.

Clinical Outcomes and Prognostic Factors for Spontaneous Intracerebral Hemorrhage in Pediatric ICU: A 12-Year Experience.

BACKGROUND: In the pediatric population, spontaneous intracerebral hemorrhage (sICH) is as common as ischemic stroke and accounts for significant mortality and morbidity. Differently from the ischemic stroke, there are few guidelines for directing management of sICH. This article aims to analyze both clinical outcomes and prognostic factors in order to produce tools for the design of prospective randomized studies addressed to implement treatment of pediatric sICH. METHODS: Twelve-year retrospective review of a single-center consecutivesICH pediatric cases admitted to the pediatric intensive care unit (PICU). Selected end points were survival, PICU stay, and dichotomized Glasgow Outcome Score (GOS), with recovery and moderate disability (GOS 4-5) classified as favorable outcome and vegetative state or severe disability (GOS 2-3) classified as unfavorable. RESULTS: Data of 107 children younger than 14 years admitted to our PICU due to sICH were analyzed. Overall PICU mortality was 24.2%. On multivariate analysis, the single factor markedly influencing survival was the presence of midline shift (P = .002). In PICU survivors, there were 42 GOS 2-3 and 39 GOS 4-5. A low Glasgow Coma Scale (GCS) on PICU admission was predictive of severe neurological impairment in survivors (P = .003). Intraventricular hemorrhage and infratentorial origin did not influence outcome in this series. CONCLUSION: The severity of presentation of sICH expressed by the midline shift and the GCS at PICU admission are significant prognostic factors for survival and neurological outcome. Some prognostic factors of the adult population have not been confirmed.

Management of Anaesthesia.

Surgical treatment of the craniovertebral junction (CVJ) requires excellent management by the anaesthetist. Patients undergoing this type of surgery have a wide range of concomitant diseases. Therefore, before proceeding to CVJ surgery, it is recommended to analyse the clinical aspects of the patient that could complicate the outcome of the surgical procedure.In this paper we aim to establish what constitutes the best surgical and anaesthesia management of these patients. We consider airway management, trying to identify the gold standard for the patient. We also consider the most appropriate intraoperative approach to guarantee the best management of the patient.

Validation of the Glycemic Stress Index in Pediatric Neurosurgical Intensive Care.

BACKGROUND: Studies have suggested that both the degree and the duration of hyperglycemia are independent risk factors for adverse outcome both in pediatric anesthesia and in critically ill children. In a recent paper, we combined intraoperative glycemic variations and length of surgery creating a metabolic glucose-related stress index called "Glycemic Stress Index" (GSI). AIM: To validate GSI for predicting PICU stay in a population of children undergoing different major neurosurgical procedures. METHODS: A total of 352 patients with craniotomy were enrolled. Basic clinical data and PICU length of stay were recorded real time. Intraoperative blood loss has been determined considering the estimated red cell volume loss ratio. GSI was calculated and subjected to ROC analysis having as targets PICU length of stay >100 or >200 h. RESULTS: The overall mean PICU stay was 35 h. Correlation analysis confirmed a low but highly significant direct correlation between GSI and PICU length of stay. ROC analysis showed an area under the ROC curve (AUC) of 0.74 (p = 0.03) for GSI to predict PICU stay >200 h and an AUC of 0.67 (p = 0.01) to predict PICU stay >100 h. Best predictive cutoff values were 4.5 and 3.9, for PICU stay >200 and >100 h, respectively. Overall accuracy for the test is higher in predicting PICU stay >200 h. CONCLUSIONS: GSI significantly predicts prolonged PICU stay after major neurosurgery in a mixed population of children affected by different neurosurgical conditions.

Species identification of bivalve molluscs by pyrosequencing.

BACKGROUND: The increase in seafood consumption and the presence of different species of bivalves on the global markets has given rise to several commercial frauds based on species substitution. To prevent and detect wilful or unintentional frauds, reliable and rapid techniques are required to identify seafood species in different products. In the present work, a pyrosequencing-based technology has been used for the molecular identification of bivalve species. RESULTS: Processed and unprocessed samples of 15 species belonging to the bivalve families Pectinidae, Mytilidae, Donacidae, Ostreidae, Pharide and Veneridae were analysed and correctly identified by the developed pyrosequencing-based method according to the homology between query sequences of the 16S ribosomal RNA (16S rRNA) and cytochrome c oxidase I (COI) genes and their correspondent reference libraries. This technique exhibits great potential in automated and high-throughput processing systems, allowing the simultaneous analysis of 96 samples in shorter execution and turnaround times. CONCLUSIONS: The correct identification of all the species shows how useful this technique may prove to differentiate species from different products, providing an alternative, simple, rapid and economical tool to detect seafood substitution frauds. © 2016 Society of Chemical Industry.

Anaesthesiological and intensive care management in craniovertebral junction surgery.

The main factors of modern perioperative care of the craniovertebral junction surgery include a comprehensive approach to the patients, including a thorough cardiorespiratory, neurophysiological, and metabolic assessment, intraoperative monitoring of spinal cord function, safe airway management, and judicious use of fluids and blood transfusions. Admission in PICU shortly after the CVJ surgery is mandatory to ensure haemodynamic and respiratory stability and to recognize postoperative complications. Anticipating complications in order to achieve an early treatment and adverse event prophylaxis can contribute to reduced morbidity and mortality and increased patients' safety. Multidisciplinary management of perioperative patient care and careful pain control is mandatory in order to improve the outcomes.

Delta-5 and delta-6 desaturases: crucial enzymes in polyunsaturated fatty acid-related pathways with pleiotropic influences in health and disease.

Polyunsaturated fatty acids (PUFA) play pleiotropic and crucial roles in biological systems. Both blood and tissue levels of PUFA are influenced not only by diet, but to a large extent also by genetic heritability. Delta-5 (D5D) and delta-6 desaturases (D6D), encoded respectively by FADS1 and FADS2 genes, are the rate-limiting enzymes for PUFA conversion and are recognized as main determinants of PUFA levels. Alterations of D5D/D6D activity have been associated with several diseases, from metabolic derangements to neuropsychiatric illnesses, from type 2 diabetes to cardiovascular disease, from inflammation to tumorigenesis. Similar results have been found by investigations on FADS1/FADS2 genotypes. Recent genome-wide association studies showed that FADS1/FADS2 genetic locus, beyond being the main determinant of PUFA, was strongly associated with plasma lipids and glucose metabolism. Other analyses suggested potential link between FADS1/FADS2 polymorphisms and cognitive development, immunological illnesses, and cardiovascular disease. Lessons from both animal models and rare disorders in humans further emphasized the key role of desaturases in health and disease. Remarkably, some of the above mentioned associations appear to be influenced by the environmental context/PUFA dietary intake, in particular the relative prevalence of ω-3 and ω-6 PUFA. In this narrative review we provide a summary of the evidences linking FADS1/FADS2 gene variants and D5D/D6D activities with various traits of human physiopathology. Moreover, we focus also on the potentially useful therapeutic application of D5D/D6D activity modulation, as suggested by anti-inflammatory and tumor-suppressing effects of D6D inhibition in mice models.

Incidence of pain after craniotomy in children.

BACKGROUND: There is very few information regarding pain after craniotomy in children. OBJECTIVES: This multicentre observational study assessed the incidence of pain after major craniotomy in children. METHODS: After IRB approval, 213 infants and children who were <10 years old and undergoing major craniotomy were consecutively enrolled in nine Italian hospitals. Pain intensity, analgesic therapy, and adverse effects were evaluated on the first 2 days after surgery. Moderate to severe pain was defined as a median FLACC or NRS score ≥ 4 points. Severe pain was defined as a median FLACC or NRS score ≥ 7 points. RESULTS: Data of 206 children were included in the analysis. The overall postoperative median FLACC/NRS scores were 1 (IQR 0 to 2). Twenty-one children (16%) presented moderate to severe pain in the recovery room and 14 (6%) during the first and second day after surgery. Twenty-six children (19%) had severe pain in the recovery room and 4 (2%) during the first and second day after surgery. Rectal codeine was the most common weak opiod used. Remifentanil and morphine were the strong opioids widely used in PICU and in general wards, respectively. Longer procedures were associated with moderate to severe pain (OR 1.30; CI 1.07-1.57) or severe pain (OR 1.41; 1.09-1.84; P < 0.05). There were no significant associations between complications, pain intensity, and analgesic therapy. CONCLUSION: Children receiving multimodal analgesia experience little or no pain after major craniotomy. Longer surgical procedures correlate with an increased risk of having postoperative pain.

Incidence and clinical progression of asymptomatic peripherally inserted central catheter-related thrombosis in solid neoplasm patients: ultrasound insights from a prospective cohort study.

Background: Managing central venous catheters in patients with neoplasms is challenging, and peripherally inserted central catheter PORT (PICC-PORT) has emerged as a promising option for safety and efficacy. However, understanding the clinical progression of catheter-related thrombosis (CRT) in cancer patients with central venous catheters remains limited, especially in certain neoplasm types associated with a higher risk of venous thrombosis. Objectives: This study aims to assess the effectiveness of ultrasound-guided management in detecting and treating asymptomatic CRT in cancer patients with PICC. Methods: In this prospective cohort study of 120 patients with solid neoplasms receiving chemotherapy, we investigated the incidence of isolated upper-extremity superficial vein thrombosis, upper-extremity deep vein thrombosis, and fibrin sheath formation through ultrasound follow-up at 30 and 90 days after catheter insertion. We analyzed risk factors associated with CRT and compared incidence rates between PICC-PORT and traditional PICC. Results: Among the cohort, 69 patients (57.5%) had high-risk thromboembolic neoplasm, and 31 cases (25.8%) of CRT were observed, mostly within 30 days, with only 7 cases (22.6%) showing symptoms. Traditional PICC use (odds ratio, 5.86; 95% CI, 1.14-30) and high-risk thromboembolic neoplasm (odds ratio, 4.46; 95% CI, 1.26-15.81) were identified as independent risk factors for CRT. Conclusion: The majority of CRT present asymptomatically within the first 30 days of venous catheter insertion in patients with solid neoplasms. Ultrasound follow-up is valuable for detecting asymptomatic CRT. The risk of CRT was lower with PICC-PORT than with PICC. Additionally, the risk of CRT was found to be higher in patients with high-risk thromboembolic neoplasms. It is crucial for larger studies to confirm the utility of treating asymptomatic thromboses and isolated superficial thrombosis.

Clinical Evaluation of Oral Midazolam Containing Cyclodextrin in Pediatric Magnetic Resonance: A Retrospective Cohort Study.

BACKGROUND: Reducing a child's level of anxiety before magnetic resonance imaging (MRI) procedures allows for better behavioral outcomes. The aim of this retrospective study was to evaluate anxiolytic efficacy of Midazolam/γ-cyclodextrin oral formulation. METHODS: We retrospectively reviewed 100 medical charts of children who, between 1 February and 31 July 2022, underwent MRI under general anesthesia with or without premedication with midazolam/γ-cyclodextrin. Primary outcome was comparison of behavior to facemask positioning, while secondary endpoints were degree of drugs acceptance, anxiolytic effect evaluation, child's behavior on separation, and sevoflurane need. RESULTS: Facemask positioning was accepted by 58% of the midazolam/γ-cyclodextrin group compared to 22% of children in the control group. The rate of acceptance was >90%. At the moment of separation from parent, none of the premedicated children needed to be restrained compared to 18% in the control group. A lower percentage of sevoflurane was needed for eye-closure at induction of anesthesia and for anesthesia maintenance. At emergence from anesthesia, 46% of children in the premedicated group compared to 66% of children in the control group showed transient agitation. CONCLUSIONS: Midazolam/γ-cyclodextrin showed a good profile of acceptance, satisfactory anxiolytic properties, and reduced need for anesthetics when administered to children before MRI under general anesthesia.

Ongoing Clinical Trials and Future Research Scenarios of Circulating Tumor DNA for the Treatment of Metastatic Colorectal Cancer.

Liquid biopsy using circulating tumor DNA (ctDNA) has emerged as a minimally invasive, timely approach to provide molecular diagnosis and monitor tumor evolution in patients with cancer. Since the molecular landscape of metastatic colorectal cancer (mCRC) is substantially heterogeneous and dynamic over space and time, ctDNA holds significant advantages as a biomarker for this disease. Numerous studies have demonstrated that ctDNA broadly recapitulates the molecular profile of the primary tumor and metastases, and have mainly focused on the genotyping of RAS and BRAF, that is propaedeutic for anti-EGFR treatment selection. However, ctDNA soon broadened its scope towards the assessment of early tumor response, as well as the identification of drug resistance biomarkers to drive potential molecular actionability. In this review article, we provide an overview of the current state-of-the-art of this methodology and its applications, focusing on ongoing clinical trials that employ ctDNA to prospectively guide treatment in patients with mCRC.

Clinicopathological characterisation of MTAP alterations in gastrointestinal cancers.

BACKGROUND: Methylthioadenosine phosphorylase (MTAP) is an essential metabolic enzyme in the purine and methionine salvage pathway. In cancer, MTAP gene copy number loss (MTAP loss) confers a selective dependency on the related protein arginine methyltransferase 5. The impact of MTAP alterations in gastrointestinal (GI) cancers remains unknown although hypothetically druggable. Here, we aim to investigate the prevalence, clinicopathological features and prognosis of MTAP loss GI cancers. METHODS: Cases with MTAP alterations were retrieved from The Cancer Genome Atlas (TCGA) and a real-world cohort of GI cancers profiled by next-generation sequencing. If MTAP alterations other than loss were found, immunohistochemistry was performed. Finally, we set a case-control study to assess MTAP loss prognostic impact. RESULTS: Findings across the TCGA dataset (N=1363 patients) and our cohort (N=508) were consistent. Gene loss was the most common MTAP alteration (9.4%), mostly co-occurring with CDKN2A/B loss (97.7%). Biliopancreatic and gastro-oesophageal cancers had the highest prevalence of MTAP loss (20.5% and 12.7%, respectively), being mostly microsatellite stable (99.2%). In colorectal cancer, MTAP loss was rare (1.1%), while most MTAP alterations were mutations (5/7, 71.4%); among the latter, only MTAP-CDKN2B truncation led to protein loss, thus potentially actionable. MTAP loss did not confer worse prognosis. CONCLUSIONS: MTAP alterations are found in 5%-10% of GI cancers, most frequently biliopancreatic and gastro-oesophageal. MTAP loss is the most common alteration, identified almost exclusively in MSS, CDKN2A/B loss, upper-GI cancers. Other MTAP alterations were found in colorectal cancer, but unlikely to cause protein loss and drug susceptibility.

DOAC in the treatment of cancer-associated venous thromboembolism: a retrospective cohort study beyond the guidelines.

BACKGROUND: The emerging use of direct oral anticoagulants (DOAC) in the management of cancer-associated venous thromboembolism (CAT) is significantly improving therapeutic adherence and quality of life. Despite this, many conditions can restrict the therapeutic index of these drugs. For all these reasons the latest guidelines recommend the use of heparins in the treatment of CAT as the preferred treatment in some clinical settings. OBJECTIVES: We evaluated the efficacy and the safety of DOAC, in terms of recurrent venous thromboembolism (VTE) and major bleeding (MB), as a composite primary outcome. Mortality and clinically relevant non-major bleeding (CRNMB) were evaluated as secondary outcomes. METHODS: We performed a retrospective study on 209 patients to compare the effects of DOAC versus heparins for the treatment of CAT. 127 patients with a high bleeding risk neoplasia were enrolled. RESULTS: A primary-outcome event occurred in 11.3% of patients treated with heparins and in 10.5% treated with DOAC (Relative Risk 0.92; 95% CI 0.42-2.01, p = 0.84). Recurrent VTE occurred in 6.1% in the heparins group and in 8.4% in the DOAC group (RR 1.37; 95% CI 0.51-3.64, p = 0.52). MB occurred in 5.2% in the heparins group and in 2.1% in the DOAC group (RR 0.40; 95% CI 0.08-1.93, p = 0.25). CONCLUSIONS: DOAC seem to be as effective and safe as heparins in the treatment of CAT. Most bleeding events occurred in patients with high-risk bleeding neoplasms regardless of the type of anticoagulant. Considering the characteristics and satisfaction of patients using DOAC in this setting, this approach should be considered as a first choice.

Corrigendum: Case report: MAP2K1 K57N mutation is associated with primary resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer.

[This corrects the article DOI: 10.3389/fonc.2022.1030232.].

Circulating Tumor DNA to Drive Treatment in Metastatic Colorectal Cancer.

In the evolving molecular treatment landscape of metastatic colorectal cancer (mCRC), the identification of druggable alterations is pivotal to achieve the best therapeutic opportunity for each patient. Because the number of actionable targets is expanding, there is the need to timely detect their presence or emergence to guide the choice of different available treatment options. Liquid biopsy, through the analysis of circulating tumor DNA (ctDNA), has proven safe and effective as a complementary method to address cancer evolution while overcoming the limitations of tissue biopsy. Even though data are accumulating regarding the potential for ctDNA-guided treatments applied to targeted agents, still major gaps in knowledge exist as for their application to different areas of the continuum of care. In this review, we recapitulate how ctDNA information could be exploited to drive different targeted treatment strategies in mCRC patients, by refining molecular selection before treatment by addressing tumor heterogeneity beyond tumor tissue biopsy; longitudinally monitoring early-tumor response and resistance mechanisms to targeted agents, potentially leading to tailored, molecular-driven, therapeutic options; guiding the molecular triage towards rechallenge strategies with anti-EGFR agents, suggesting the best time for retreatment; and providing opportunities for an "enhanced rechallenge" through additional treatments or combos aimed at overcoming acquired resistance. Besides, we discuss future perspectives concerning the potential role of ctDNA to fine-tune investigational strategies such as immuno-oncology.

The evolving panorama of HER2-targeted treatments in metastatic urothelial cancer: A systematic review and future perspectives.

PURPOSE: HER2 alterations are potential candidates for targeted treatments in metastatic urothelial/bladder cancer (mUC). ERBB2 gene amplification and mutations are found in around 6% and 4% of mUC, respectively. METHODS: This is a systematic review of clinical trials evaluating HER2-targeting (amplification and mutations) in mUC. We assigned each study to one of the following strategies: HER2-targeting with single agents, anti-HER2 agents in combination with cytotoxic chemotherapy, dual HER2 blockade, HER2-targeted antibody-drug conjugates (ADCs), and other novel therapeutic approaches. RESULTS: 36 clinical trials (17 with results and 19 ongoing) were included. As for ERBB2 amplification, anti-HER2 single agents (5 studies) and combinations with chemotherapy (4 studies) failed to provide any benefit, whereas dual HER2 blockade through monoclonal antibodies proved active in one trial in pretreated patients. Two studies assessed single-agent targeting for ERBB2 mutations with negative results. Most promising data come from 2 studies with ADCs in ERBB2 amplified tumors (disitamab-vedotin and trastuzumab-duocarmazine), while 2 other studies with TDM-1 and ADCT-502 was discontinued due to toxicity. In this category, trastuzumab-deruxtecan and other ADCs are still under investigation for either ERBB2-amplified or mutated mUC. Novel approaches include ADCs with immunotherapy (1 study with results), CAR-T cells, and HER2-sensitising vaccines. CONCLUSIONS: ERBB2 amplification could become a novel target in mUC, although the magnitude of clinical benefit remains to be clarified. To this regard, novel ADCs are the most promising strategy. ERBB2 mutations are still at very early stage of clinical study.