Congenital lung malformations: a nationwide survey on management aspects by the Italian Society of Pediatric Surgery.

INTRODUCTION: Over the years, congenital lung malformations (CLM) management remains a controversial topic in pediatric thoracic surgery. The Italian Society of Pediatric Surgery performed a national survey to study the current management variability among centers, trying to define national guidelines and a standardized approach of children with congenital lung malformations. METHODS: Following a National Society approval, an electronic survey including 35 items on post-natal management was designed, focusing on surgical, anesthesiology, radiology and pneumology aspects. The survey was conducted contacting all pediatric surgical units performing thoracic surgery. RESULTS: 39 pediatric surgery units (97.5%) participated in the study. 13 centers (33.3%) were classified as high-volume (Group A), while 26 centers (66.7%) were low volume (Group B). Variances in diagnostic imaging protocols were observed, with Group A performing fewer CT scans compared to Group B (p = 0.012). Surgical indications favored operative approaches for asymptomatic CLM and pulmonary sequestrations in both groups, while a wait-and-see approach was common for congenital lobar emphysema. Surgical timing for asymptomatic CLM differed significantly, with most high-volume centers operating on patients younger than 12 months (p = 0.02). Thoracoscopy was the preferred approach for asymptomatic CLM in most of centers, while postoperative long-term follow-up was not performed in most of the centers. CONCLUSION: Thoracoscopic approach seems uniform in asymptomatic CLM patients and variable in symptomatic children. Lack of uniformity in surgical timing and preoperative imaging assessment has been identified as key areas to establish a common national pattern of care for CLM.

Short-term outcomes of thoracoscopic versus open lobectomy for congenital lung malformations.

PURPOSE: Thoracoscopic and open approaches for the management of congenital lung malformations (CLM) has been debated. The aim of this study is to compare 30-day outcomes for non-emergent lobectomies in children. METHODS: The National Surgical Quality Improvement Program-Pediatric database was queried for patients undergoing CLM resection from 2013 to 2020. Outcomes were compared by operative technique in an intention-to-treat model and then propensity matched. RESULTS: 2157 patients met inclusion criteria and underwent non-emergent pulmonary lobectomy for CLM. The intended operative approach was thoracoscopic in 57.7% of patients. Patients in the open group compared to the thoracoscopic were more likely to be born premature, have chronic lung disease, require preoperative oxygen support, and be ventilator dependent. After propensity matching, there was no statistically significant difference in 30-day mortality, unplanned readmission, and other complications between the thoracoscopic and open groups. Thoracoscopic approach was associated with a shorter length of stay. The proportion of cases approached via thoracoscopy increased over time from 48.8% in 2013 to 69.9% in 2020. CONCLUSIONS: This large multicenter retrospective matched analysis demonstrates thoracoscopic lobectomy in children has similar favorable 30-day outcomes and shorter length of stay for the non-emergent management of CLM, compared to open thoracotomy. LEVEL OF EVIDENCE: Level III.

Thoracoscopic anatomic pulmonary segmentectomy for the treatment of congenital lung malformation in children.

BACKGROUND: Lung-sparing surgery has been used to treat congenital lung malformation in children, and segmentectomy has been advocated as a lung-preservation strategy. However, thoracoscopic pulmonary segmentectomy has gained limited popularity considering the complications, the potential for residual lesions, and the technical difficulties associated with this procedure. Therefore, this study aimed to investigate the safety and feasibility of pediatric thoracoscopic anatomic pulmonary segmentectomy for the treatment of congenital lung malformations. METHODS: We conducted a retrospective review of the medical records of 568 patients who were treated at West China Hospital, Sichuan University, from January 2014 to January 2020. The patients were divided into segmentectomy and lobectomy groups according to the surgical procedures they underwent. Clinical and follow-up outcomes were compared between the two groups. RESULTS: The segmentectomy and lobectomy groups included 206 and 361 cases, respectively. The mean intraoperative blood loss was significantly higher in the segmentectomy group (6.9 mL vs. 4.5 mL; p = 0.03). The mean surgical time was also significantly longer in the segmentectomy group, (55.6 min vs. 41.5 min; p = 0.018). However, the incidence of complications did not differ significantly between the two groups (2.9% vs. 1.1%, p = 0.21). Patients in both groups did not require reoperation or show residual lesions during hospitalization and follow-up. CONCLUSIONS: Thoracoscopic anatomic pulmonary segmentectomy is a safe and feasible definitive lung-sparing treatment for specific cases of congenital lung malformation, and has a complication rate comparable to that of thoracoscopic lobectomy.

Cellular Senescence in Liver Cancer: How Dying Cells Become "Zombie" Enemies.

Liver cancer represents the fourth leading cause of cancer-associated death worldwide. The heterogeneity of its tumor microenvironment (TME) is a major contributing factor of metastasis, relapse, and drug resistance. Regrettably, late diagnosis makes most liver cancer patients ineligible for surgery, and the frequent failure of non-surgical therapeutic options orientates clinical research to the investigation of new drugs. In this context, cellular senescence has been recently shown to play a pivotal role in the progression of chronic inflammatory liver diseases, ultimately leading to cancer. Moreover, the stem-like state triggered by senescence has been associated with the emergence of drug-resistant, aggressive tumor clones. In recent years, an increasing number of studies have emerged to investigate senescence-associated hepatocarcinogenesis and its derived therapies, leading to promising results. In this review, we intend to provide an overview of the recent evidence that unveils the role of cellular senescence in the most frequent forms of primary and metastatic liver cancer, focusing on the involvement of this mechanism in therapy resistance.

Confocal laser imaging in neurosurgery: A comprehensive review of sodium fluorescein-based CONVIVO preclinical and clinical applications.

Given the established direct correlation that exists among extent of resection and postoperative survival in brain tumors, obtaining complete resections is of primary importance. Apart from the various technological advancements that have been introduced in current clinical practice, histopathological study still remains the gold-standard for definitive diagnosis. Frozen section analysis still represents the most rapid and used intraoperative histopathological method that allows for an intraoperative differential diagnosis. Nevertheless, such technique owes some intrinsic limitations that limit its overall potential in obtaining real-time diagnosis during surgery. In this context, confocal laser technology has been suggested as a promising method to have near real-time intraoperative histological images in neurosurgery, thanks to the results of various studies performed in other non-neurosurgical fields. Still far to be routinely implemented in current neurosurgical practice, pertinent literature is growing quickly, and various reports have recently demonstrated the utility of this technology in both preclinical and clinical settings in identifying brain tumors, microvasculature, and tumor margins, when coupled to the intravenous administration of sodium fluorescein. Specifically in neurosurgery, among different available devices, the ZEISS CONVIVO system probably boasts the most recent and largest number of experimental studies assessing its usefulness, which has been confirmed for identifying brain tumors, offering a diagnosis and distinguishing between healthy and pathologic tissue, and studying brain vessels. The main objective of this systematic review is to present a state-of-the-art summary on sodium fluorescein-based preclinical and clinical applications of the ZEISS CONVIVO in neurosurgery.

Ligand-Tuned Multi-Color Luminescence of Single Aluminum (III) Ion Atomic Centers and Their Selective Sensitivity to Different Metal Ions.

Achieving multi-color luminescence with a single atomic center in transition metal complexes is a challenge. In this work, luminescent materials with tunable emission properties were realized by complexation between aluminum (III) ions with the ligands 3-hydroxyflavone (3-HF) and 5,7-dichloro-8-hydroxyquinoline (DCHQ). Aluminum (III) complexes with a single ligand emitted blue from 3-HF and green from DCHQ. High quantum yields (QYs) of 29.42% and 37.00% were also obtained, respectively. DFT calculations revealed details of the photophysical properties of the complexes. Correspondingly, cyan light emission was obtained if these two complexes were mixed together, from which the emission wavelength was located at 470 nm and the QY was 20.52%, under 290 nm excitation. More importantly, the cyan light emitted by the mixtures had selective sensitivity to different metal ions, resulting in either quenching the fluorescence (in the case of Fe3+) or enhancing the fluorescence (in the case of In3+). The fluorescence enhancement effect of In3+ on metal complexes has not been previously reported, neither for transition metal nor lanthanide ions. The linear quenching behavior of Fe3+ functions in the 50-700 µM concentration range, and the linear enhancement behavior of In3+ is demonstrated in the 300-800 mM concentration range.

Deciphering the mutational signature of congenital limb malformations.

Congenital limb malformations (CLMs) affect 1 in 500 live births. However, the value of exome sequencing (ES) for CLM is lacking. The purpose of this study was to decipher the mutational signature of CLM on an exome level. We enrolled a cohort of 66 unrelated probands (including 47 families) with CLM requiring surgical correction. ES was performed for all patients and available parental samples. A definite molecular diagnosis was achieved in 21 out of 66 (32%) patients. We identified 19 pathogenic or likely pathogenic single-nucleotide variants and three copy number variants, of which 11 variants were novel. We identified four variants of uncertain significance. Additionally, we identified RPL9 and UBA2 as novel candidate genes for CLM. By comparing the detailed phenotypic features, we expand the phenotypic spectrum of diastrophic dysplasia and chromosome 6q terminal deletion syndrome. We also found that the diagnostic rate was significantly higher in patients with a family history of CLM (p = 0.012) or more than one limb affected (p = 0.034). Our study expands our understanding of the mutational and phenotypic spectrum of CLM and provides novel insights into the genetic basis of these syndromes.

Divergent FUS phosphorylation in primate and mouse cells following double-strand DNA damage.

Fused in sarcoma (FUS) is a RNA/DNA protein involved in multiple nuclear and cytoplasmic functions including transcription, splicing, mRNA trafficking, and stress granule formation. To accomplish these many functions, FUS must shuttle between cellular compartments in a highly regulated manner. When shuttling is disrupted, FUS abnormally accumulates into cytoplasmic inclusions that can be toxic. Disrupted shuttling of FUS into the nucleus is a hallmark of ~10% of frontotemporal lobar degeneration (FTLD) cases, the neuropathology that underlies frontotemporal dementia (FTD). Multiple pathways are known to disrupt nuclear/cytoplasmic shuttling of FUS. In earlier work, we discovered that double-strand DNA breaks (DSBs) trigger DNA-dependent protein kinase (DNA-PK) to phosphorylate FUS (p-FUS) at N-terminal residues leading to the cytoplasmic accumulation of FUS. Therefore, DNA damage may contribute to the development of FTLD pathology with FUS inclusions. In the present study, we examined how DSBs effect FUS phosphorylation in various primate and mouse cellular models. All cell lines derived from human and non-human primates exhibit N-terminal FUS phosphorylation following calicheamicin γ1 (CLM) induced DSBs. In contrast, we were unable to detect FUS phosphorylation in mouse-derived primary neurons or immortalized cell lines regardless of CLM treatment, duration, or concentration. Despite DNA damage induced by CLM treatment, we find that mouse cells do not phosphorylate FUS, likely due to reduced levels and activity of DNA-PK compared to human cells. Taken together, our work reveals that mouse-derived cellular models regulate FUS in an anomalous manner compared to primate cells. This raises the possibility that mouse models may not fully recapitulate the pathogenic cascades that lead to FTLD with FUS pathology.

Perioperative Circulating Tumor DNA in Colorectal Liver Metastases: Concordance with Metastatic Tissue and Predictive Value for Tumor Burden and Prognosis.

BACKGROUND: The surgical resection of colorectal cancer with liver metastases (CLM) has proven to be the most important modality for long-term survival, while effective biomarkers for outcome prediction or postoperative surveillance are still lacking. Currently, circulating biomarkers obtained from a liquid biopsy are widely used to assess the treatment response, disease recurrence and progression. In this study, we analyzed the value of the liquid biopsy, which includes circulating tumor DNA (ctDNA) and cell-free DNA (cfDNA), in patients with CLM. METHODS: Capture-based targeted deep sequencing was performed on matched pre-surgery, post-surgery and liver metastatic tissues of 20 CRC patients who underwent the resection of liver metastases between May and September 2017 using a panel consisting of 41 genes. Mutation landscapes obtained from pre-surgery plasma samples and metastatic tissue samples were compared. RESULTS: Collectively, we identified 47 mutations from 17 pre-surgery plasma samples (85%), and the remaining 3 patients had no mutation detected from the panel. We revealed a high by-variant concordance rate of 82.14% between pre-surgery plasma samples and liver metastatic tissue samples. We further analyzed the correlation between ctDNA, cfDNA, CEA and tumor burden and revealed a positive correlation between ctDNA and tumor burden (R=0.69, p=0.002). As of the date for data cutoff, 8/20 patients experienced relapse. Our study also demonstrated that pre-surgery ctDNA (p<0.001), cfDNA (p=0.001) and CEA (p=0.012) levels had predictive value for relapse. Patients with low pre-surgery ctDNA (p<0.001), cfDNA (p=0.001) or CEA (p=0.012) levels were more likely to experience prolonged progression-free survival. CONCLUSION: Our data demonstrate that the genomic profile obtained from ctDNA is comparable with the genomic profile obtained from metastatic liver tumors. Furthermore, our study also show that pre-surgery ctDNA levels are positively correlated with tumor burden. In addition, pre-surgery ctDNA, cfDNA and CEA levels have predictive value for relapse.

Hepatobiliary surgeons meet immunologists: the case of colorectal liver metastases patients.

The burgeoning field of cancer immunology demands a change in the paradigm of cancer patient management. The understanding of the course of a given malignant disease should also include the host immune system as one of the key factors in determining the patient's prognosis. Surgical and medical oncologists need to understand the basic and advanced applications of immunotherapies, which are rapidly evolving, and are nowadays an integral part of the armamentarium for the treatment of cancer patients. In the present work, we review the current knowledge concerning the immune landscape of colorectal cancer (CRC) patients with liver metastases, as recently discovered.

Interactions of multiple gene alterations in colorectal liver metastases.

The advancements in next generation sequencing have expanded the information available in clinical practice. Alterations of TP53, APC, RAS, PIK3CA, and SMAD4 are present in more than 10% of patients with colorectal liver metastases (CLM). Of these genes, TP53, RAS and SMAD4 were associated with worse survival in patients undergoing CLM resection. Testing multiple gene alterations provides a more precise prognosis for patients undergoing CLM resection and may be useful for better clinical decision making.

Laparoscopic Hepatectomy for Colorectal Liver Metastases: The Current State of the Art.

Hepatectomy together with systemic chemotherapy is the treatment of choice for patients with liver-limited colorectal metastases. Although the open approach to hepatectomy remains a standard option, there is increasing recognition of the potential advantages of laparoscopic hepatectomy. Laparoscopic approaches have become standardized and are the subject of two international consensus conferences. Major laparoscopic hepatectomy is currently being evaluated in international multi-center trials. The available data to date would indicate that there is oncological equivalence between open and laparoscopic approaches but that the latter is associated with less post-operative pain, shorter hospital stay and an earlier recovery of full function. Surgeons embarking on this approach must be experienced both in the techniques of advanced liver surgery and in laparoscopic surgery.

Early vs late resection of asymptomatic congenital lung malformations.

PURPOSE: To examine postsurgical outcomes of a consecutive series of children treated with elective operations for congenital lung malformations (CLM). METHODS: A retrospective review was performed on a prospectively collected dataset of all fetuses evaluated for a CLM between July 2001 and June 2016. Prenatal findings, operative treatment and postnatal outcomes were collected. Children having elective operations were divided in two groups based on age at time of surgery. RESULTS: Of 220 fetuses, 143 had operations and follow-up at our center. Six had open fetal lobectomy, 17 had EXIT-to-resection, 16 infants had urgent resection for symptoms and 110 with asymptomatic lesions had elective resection. Of these 110, the median fetal maximum CVR was 0.8 [range 0.1-2.2], and median age at operation was 4 (1.5-60) months (58% had resection at ≤4 months). Overall complication rate, including air-leak and pleural effusion, was 15%. When comparing those having resection at ≤4 months to those >4 months, there were no significant differences in complication rates or length of stay. Operative time was shorter for patients with early resection (154 ±â€¯59 vs 181 ±â€¯89, p = 0.05). No infant having resection at ≤4 months was readmitted. Overall, children survived with good recovery. CONCLUSION: Early elective resection of congenital lung malformations prior to 4 months of age is feasible and not associated with increased operative risk. TYPE OF STUDY: Restropective study. LEVEL OF EVIDENCE: Level III.

Proteogenomic characterization and comprehensive integrative genomic analysis of human colorectal cancer liver metastasis.

BACKGROUND: Proteogenomic characterization and integrative and comparative genomic analysis provide a functional context to annotate genomic abnormalities with prognostic value. METHODS: Here, we analyzed the proteomes and performed whole exome and transcriptome sequencing and single nucleotide polymorphism array profiling for 2 sets of triplet samples comprised of normal colorectal tissue, primary CRC tissue, and synchronous matched liver metastatic tissue. RESULTS: We identified 112 CNV-mRNA-protein correlated molecules, including up-regulated COL1A2 and BGN associated with prognosis, and four strongest hot spots (chromosomes X, 7, 16 and 1) driving global mRNA abundance variation in CRC liver metastasis. Two sites (DMRTB1R202H and PARP4V458I) were revealed to frequent mutate only in the liver metastatic cohort and displayed dysregulated protein abundance. Moreover, we confirmed that the mutated peptide number has potential prognosis value and somatic variants displayed increased protein abundance, including high MYH9 and CCT6A expression, with clinical significance. CONCLUSIONS: Our proteogenomic characterization and integrative and comparative genomic analysis provides a new paradigm for understanding human colon and rectal cancer liver metastasis. TRIAL REGISTRATION: ClinicalTrials, NCT02917707. Registered 28 September 2016, https://clinicaltrials.gov/ct2/show/NCT02917707 .

Survival after resection of colorectal liver metastases in octogenarians and sexagenarians compared to their respective age-matched national population.

BACKGROUND: The aim of the current study was to investigate survival after resection of colorectal liver metastases (CLM) in octogenarians. The survival of octogenarian patients was compared to the survival of the national population of octogenarians and the survival of sexagenarians, the latter representing the average-age patient undergoing resection of CLM. METHODS: Octogenarian and sexagenarian were defined as person 80-89 and 60-69 years of age, respectively. Survival analyses of patients who underwent resection of CLM between 2002 and 2014 were performed. Data from Statistics Norway were used to estimate the survival of the age-matched national population of octogenarians (ageM-Octo) and the age-matched national population of sexagenarians (ageM-Sexa). RESULTS: During the study period, 59 octogenarians underwent resection of CLM. The majority of patients underwent a minor liver resection (n=50). In octogenarians, the 5-year survival was 32.5% and 66.3% [difference, 33.8 percentage points (pp)] in patients and ageM-Octo, respectively. The 10-year survival was 14.1% and 31.2% (difference, 17.1 pp) in patients and ageM-Octo, respectively. In sexagenarians, the 5-year survival was 50.9% and 96.2% (difference, 45.3 pp) in patients and ageM-Sexa, respectively. The 10-year survival was 35.7% and 90.3% (difference, 54.6 pp) in patients and ageM-Sexa, respectively. The 5-year cancer-specific survival and 5-year recurrence-free survival (RFS) after resection of CLM in octogenarians were 43.1% and 32.9%, respectively. CONCLUSIONS: After resection of CLM, the survival was poorer in octogenarians than in sexagenarians. However, the difference between the survival curves of patients and their age-matched population was smaller in octogenarians. In practice, this finding may indicate a greater benefit of resection in the elderly than the survival rates alone would suggest.

18F-FDG PET as novel imaging biomarker for disease progression after ablation therapy in colorectal liver metastases.

PURPOSE: Recurrent disease following thermal ablation therapy is a frequently reported problem. Preoperative identification of patients with high risk of recurrent disease might enable individualized treatment based on patients' risk profile. The aim of the present work was to investigate the role of metabolic parameters derived from the pre-ablation 18F-FDG PET/CT as imaging biomarkers for recurrent disease in patients with colorectal liver metastases (CLM). METHODS: Included in this retrospective study were all consecutive patients with CLM treated with percutaneous or open thermal ablation therapy who had a pre-treatment baseline 18F-FDG PET/CT available. Multivariable cox regression for survival analysis was performed using different models for the metabolic parameters (SULpeak, SULmean, SULmax, partial volume corrected SULmean (cSULmean), and total lesion glycolysis (TLG)) corrected for tumour and procedure characteristics. The study endpoints were defined as local tumour progression free survival (LTP-FS), new intrahepatic recurrence free survival (NHR-FS) and extrahepatic recurrence free survival (EHR-FS). Clinical and imaging follow-up data was used as the reference standard. RESULTS: Fifty-four patients with 90 lesions were selected. Univariable cox regression analysis resulted in eight models. Multivariable analysis revealed that after adjusting for lesion size and the approach of the procedure, none of the metabolic parameters were associated with LTP-FS or EHR-FS. Percutaneous approach was significantly associated with a shorter LTP-FS. It was demonstrated that lower values of SULpeak, SULmax, SULmean , and cSULmean are associated with a significant better NHR-FS, independent of the lesion size and number and prior chemotherapy. CONCLUSION: We found no association between the metabolic parameters on pre-ablation 18F-FDG PET/CT and the LTP-FS. However, low values of the metabolic parameters were significantly associated with improved NHR-FS. The clinical implication of these findings might be the identification of high-risk patients who might benefit most from adjuvant or combined treatment strategies.

Advances in fetal surgery.

Historically, the gold standard for the treatment of congenital malformations has been planned delivery at tertiary care center with attempted post-natal repair or amelioration of the lesion. Over the last few decades however, rapid advances in imaging and instrumentation technology combined with superior knowledge of fetal pathophysiology has led to the development of novel intrauterine interventions for most common fetal anomalies. Great success has already been seen the treatment of previous devastating anomalies such as myelomeningocele (MMC), congenital cystic malformations of the lung, twin-twin transfusion, and sacrococcygeal teratomas. Although still limited, these innovative techniques have unique potential to improve outcomes in the most devastating fetal anomalies.

Factors affecting surgical margin recurrence after hepatectomy for colorectal liver metastases.

BACKGROUND: Hepatic recurrence after resection of colorectal liver metastasis (CLM) occurs in 50% of patients during follow-up, with 2.8% to 13.9% presenting with surgical margin recurrence (SMR). The aim of this study is to analyze factors that related to SMR in patients with CLM undergoing hepatectomy. METHODS: Demographics, clinical and survival data of patients who underwent hepatectomy were identified from a prospectively maintained, institutional review board (IRB)-approved database between 2000 and 2012. Statistical analysis was performed using univariate Kaplan Meier and Cox proportional hazard model. RESULTS: There were 85 female and 121 male patients who underwent liver resection for CLM. An R0 resection was performed in 157 (76%) patients and R1 resection in 49. SMR was detected in 32 patients (15.5%) followed up for a median of 29 months (range, 3-121 months). A half of these patients had undergone R1 (n=16) and another half R0 resection (n=16). Tumor size, preoperative carcinoembryonic antigen (CEA) level and margin status were associated with SMR on univariate analysis. On multivariate analysis, a positive surgical margin was the only independent predictor of SMR. The receipt of adjuvant chemotherapy did not affect margin recurrence. SMR was an independent risk factor associated with worse disease-free (DFS) and overall survival (OS). CONCLUSIONS: This study shows that SMR, which can be detected in up to 15.5% of patients after liver resection for CLM, adversely affects DFS and OS. The fact that a positive surgical margin was the only predictive factor for SMR in these patients underscores the importance of achieving negative margins during hepatectomy.