Corrigendum: A structural connectivity atlas of limbic brainstem nuclei.

[This corrects the article DOI: 10.3389/fnimg.2022.1009399.].

Impact of primary tumor resection in the management of metastatic well-differentiated neuroendocrine tumors of the small bowel and pancreas.

Patients with gastroenteropancreatic (GEP) neuroendocrine tumors (NET) often present with advanced disease. Primary tumor resection (PTR) in the setting of unresectable metastatic disease is controversial. Most studies evaluating the impact of PTR on overall survival (OS) have been performed using large population-based databases, with limited treatment related data. This study aims to determine whether PTR improves OS and progression-free survival (PFS) in patients with metastatic well-differentiated GEP-NET. This is a retrospective single-institution study of patients with metastatic well-differentiated GEP-NET between 1978 and 2021. The primary outcome was OS. The secondary outcome was PFS. Chi-squared tests and Cox regression were used to perform univariate and multivariate analyses (MVA). OS and PFS were estimated using the Kaplan-Meier method and log-rank test. Between 1978 and 2021, 505 patients presented with metastatic NET, 151 of whom had well-differentiated GEP-NET. PTR was performed in 31 PNET and 77 SBNET patients. PTR was associated with improved median OS for PNET (136 vs. 61 months, p = .003) and SBNET (not reached vs. 79 months, p<.001). On MVA, only higher grade (HR 3.70, 95%CI 1.49-9.17) and PTR (HR 0.21, 95%CI 0.08-0.53) influenced OS. PTR resulted in longer median PFS for patients with SBNET (46 vs. 28 months, p = .03) and a trend toward longer median PFS for patients with PNET (20 vs. 13 months, p = .07). In patients with metastatic well-differentiated GEP-NET, PTR is associated with improved OS and may be associated with improved PFS and should be considered in a multidisciplinary setting. Future prospective studies are needed to validate these findings.

CSNK2A1-mediated MAX phosphorylation upregulates HMGB1 and IL-6 expression in cholangiocarcinoma progression.

BACKGROUND: We established a novel diethylnitrosamine (DEN) -induced mouse model that reflected the progression of cholangiocarcinoma (CCA) from atypical cystic hyperplasia. METHODS: BALB/c mice were administered DEN by oral gavage. Cells isolated from livers were analyzed for expression of CSNK2A1, MAX and MAX-interacting proteins. Human CCA cell lines (MzChA-1, HuCCT1), normal human cholangiocyte (H69), human hepatic stellate cells (LX-2), macrophages (RAW 264.7), and primary hepatic cells were used for cellular and molecular biology assays. RESULTS: Expression of MAX, CSNK2A1, C-MYC, ß-catenin, HMGB1, and IL-6 was upregulated in hepatic cells from CCA liver tissue. The half-life of MAX is higher in CCA cells, and this favors their proliferation. Overexpression of MAX increased growth, migration, and invasion of MzChA-1, whereas silencing of MAX had the opposite effect. MAX positively regulated IL-6 and HMGB1 through paracrine signaling in HepG2, LX2, and RAW cells and autocrine signaling in MzChA-1 cells. CSNK2A1-mediated MAX phosphorylation shifts MAX-MAX homodimer to C-MYC-MAX and ß-catenin-MAX heterodimers and increases the HMGB1 and IL-6 promoter activities. Increase of MAX phosphorylation promotes cell proliferation, migration, invasion, and cholangiocarcinogenesis. The casein kinase 2 inhibitor CX-4945 induces cell cycle arrest and inhibits cell proliferation, migration, invasion, and carcinogenesis in MzChA-1 cells through the downregulation of CSNK2A1, MAX, and MAX-interaction proteins. CONCLUSION: C-MYC-MAX and ß-catenin-MAX binding to E-box site or ß-catenin-MAX bound to TCFs/LEF1 enhanced HMGB1 or IL-6 promoter activities, respectively. IL-6 and HMGB1 secreted by hepatocytes, HSCs, and KCs exert paracrine effects on cholangiocytes to promote cell growth, migration, and invasion and lead to the progression of cholangiocarcinogenesis. CX-4945 provides perspectives on therapeutic strategies to attenuate progression from atypical cystic hyperplasia to cholangiocarcinogenesis.

Contemporary Cancer Program Practice Profile Report Compliance Rates for Gastric Cancer: A National Cancer Database Analysis.

BACKGROUND: The Commission on Cancer (CoC) established quality measures to be reported in National Cancer Database (NCDB) Quality Reporting Tools. Compliance is provided to accredited cancer programs as Cancer Program Practice Profile Reports (CP3R). At the time of this study, the quality metric for gastric cancer (GC) was removal and pathologic examination of 15 regional lymph nodes for resected GC (G15RLN). OBJECTIVE: This study evaluates national trends in quality metric compliance for GC based on CoC CP3R. METHODS: The National Cancer Database (NCDB) was queried from 2004-2017 to identify patients with stage I-III GC who met criteria for inclusion. National trends in compliance were compared. Overall survival (OS) was compared stage for stage. RESULTS: Overall, 42 997 patients with GC qualified. In 2017, 64.5% of patients met compliance with G15RLN compared to 31.4% in 2004. When comparing academic and non-academic institutions, compliance was met 67.0% vs 60.0% of the time in 2017 (P < .01) and 36% vs 30.6% of the time in 2004 (P < .01). On multivariate logistic regression, patients receiving care at academic institutions (OR 1.5, 95% CI 1.4-1.5) and who underwent surgery at institutions in the >75th percentile for case volume (OR 1.5, 95% CI 1.4-1.6) had higher odds of compliance. When stratified by stage, median OS was better across all stages when compliance was met. CONCLUSION: Compliance rates with GC quality measures have improved over time. Compliance with the G15RLN metric is associated with improved OS, stage for stage. Continued efforts to improve compliance rates across all institutions are critical.

Trends in segmentectomy for the treatment of stage 1A non-small cell lung cancers: Does the robot have an impact?

OBJECTIVES: Lobectomy may unnecessarily resect healthy lung parenchyma in Stage 1A non-small cell lung cancers (NSCLC). Segmentectomies may provide a lung-sparing option. VATS segmentectomies can be technically challenging; robotics may have features that provide advantages in performing segmentectomies. We describe the association of the robot on national trends in segmentectomies. METHODS: The National Cancer Database (2010-2017) was queried for patients with Stage 1A NSCLC who underwent lobectomies and segmentectomies. The proportion of segmentectomies vs. lobectomies and the proportion of robotic vs. VATS segmentectomies was calculated annually. RESULTS: The proportion of segmentectomies increased compared to lobectomies for all surgical approaches but remained constant for minimally-invasive approaches. The proportion of robotic segmentectomies increased over the years compared to VATS segmentectomies. Descriptive statistics are reported as numbers and proportions. Trends in the proportions of lobectomies and segmentectomies were compared using Chi-squared test for categorical variables and unpaired t-test for independent means. A p-value of <0.05 was considered statistically significant. Statistical analysis was performed using SPSS Statistics Software version 24 (IBM Corp, Armonk, NY). CONCLUSIONS: We demonstrate an increasing trend and proportion of robotic segmentectomies being performed in comparison to VATS segmentectomies. The robotic platform may facilitate the performance of more segmentectomies for early-stage NSCLC.

Hyperthermic intraperitoneal chemotherapy for gastric cancer: a narrative review.

BACKGROUND AND OBJECTIVE: Gastric cancer (GC) is the 5th most common malignancy globally, and although there have been modest gains in improving survival rates, it remains a leading cause of death. A component contributing to the poor survival rates includes advanced disease stage at presentation. Approximately 30-40% of GC patients present with metastases at diagnosis, with poorer outcomes when peritoneal metastases are present. However, recent studies have demonstrated potential utility of hyperthermic intraperitoneal chemotherapy (HIPEC) for GC with peritoneal carcinomatosis (GCPC) and for prevention of peritoneal carcinomatosis in high-risk patients. HIPEC for GC is highly debated. It is currently not recommended as part of standard of care for GC. The objective of this study is to discuss the various factors influencing the success of HIPEC, current intraperitoneal (IP) chemotherapy treatment regimens, timing of HIPEC administration, major randomized controlled trials (RCTs) and non-RCTs (NRCTs), and meta-analyses in GC patients. METHODS: A review of the Library of Congress, the Cochrane Review, Google Scholar, PubMed, and ClinicalTrials.gov was performed. All articles and trials with available data in English with full text were considered. Necessary keywords used to search included "gastric cancer" and/or "HIPEC". Included articles were independently reviewed by authors. KEY CONTENT AND FINDINGS: Optimal HIPEC administration timing is unclear, but many utilize it in a neoadjuvant or prophylactic setting. Signet ring pathology and epithelial mesenchymal transition (EMT) cell histologic subtypes may have more aggressive pathology, limiting HIPEC success rates. Patients who receive complete cytoreduction and have low peritoneal carcinomatosis index (PCI) burden have been shown to have improved median overall survival (OS) after HIPEC. The data suggests in GCPC, HIPEC can modestly improve recurrence-free and OS. The data regarding benefits of prophylactic HIPEC in advanced GC (AGC) remains mixed. CONCLUSIONS: HIPEC for GC is controversial. Much of the literature is exploratory in nature or difficult to compare, as many outcomes are novel/not cross validated against substantial preceding data, with highly variable patient populations and study designs. However, in certain clinical scenarios in high volume centers, some patients with non-metastatic or low burden disease who undergo prophylactic or intraoperative HIPEC may benefit with improved overall and recurrence free survival (RFS).

A structural connectivity atlas of limbic brainstem nuclei.

Background: Understanding the structural connectivity of key brainstem nuclei with limbic cortical regions is essential to the development of therapeutic neuromodulation for depression, chronic pain, addiction, anxiety and movement disorders. Several brainstem nuclei have been identified as the primary central nervous system (CNS) source of important monoaminergic ascending fibers including the noradrenergic locus coeruleus, serotonergic dorsal raphe nucleus, and dopaminergic ventral tegmental area. However, due to practical challenges to their study, there is limited data regarding their in vivo anatomic connectivity in humans. Objective: To evaluate the structural connectivity of the following brainstem nuclei with limbic cortical areas: locus coeruleus, ventral tegmental area, periaqueductal grey, dorsal raphe nucleus, and nucleus tractus solitarius. Additionally, to develop a group average atlas of these limbic brainstem structures to facilitate future analyses. Methods: Each nucleus was manually masked from 197 Human Connectome Project (HCP) structural MRI images using FSL software. Probabilistic tractography was performed using FSL's FMRIB Diffusion Toolbox. Connectivity with limbic cortical regions was calculated and compared between brainstem nuclei. Results were aggregated to produce a freely available MNI structural atlas of limbic brainstem structures. Results: A general trend was observed for a high probability of connectivity to the amygdala, hippocampus and DLPFC with relatively lower connectivity to the orbitofrontal cortex, NAc, hippocampus and insula. The locus coeruleus and nucleus tractus solitarius demonstrated significantly greater connectivity to the DLPFC than amygdala while the periaqueductal grey, dorsal raphe nucleus, and ventral tegmental area did not demonstrate a significant difference between these two structures. Conclusion: Monoaminergic and other modulatory nuclei in the brainstem project widely to cortical limbic regions. We describe the structural connectivity across the several key brainstem nuclei theorized to influence emotion, reward, and cognitive functions. An increased understanding of the anatomic basis of the brainstem's role in emotion and other reward-related processing will support targeted neuromodulatary therapies aimed at alleviating the symptoms of neuropsychiatric disorders.

Clinical trends in surgical, minimally invasive and transcatheter aortic valve replacement†.

OBJECTIVES: Transcatheter aortic valve replacement (TAVR) and minimally invasive aortic valve replacement (MIAVR) have emerged as alternatives to surgical aortic valve replacement (SAVR) via traditional sternotomy. However, their effect on clinical practice remains unclear. The study's objective is to describe clinical trends between TAVR, MIAVR and SAVR in patients with severe aortic stenosis (AS). METHODS: This retrospective observational study analyzed trends in isolated severe aortic valve replacement (AVR) among three high volume TAVR, MIAVR and SAVR centres in the United States. The cohort included 2571 patients from 2011 through 2014 undergoing SAVR ( n = 842), MIAVR ( n = 699) and TAVR ( n = 1030) further stratified into transapical (TA-TAVR) and trans-femoral (TF-TAVR). RESULTS: Total AVR volume increased +107% with increases in TF-TAVR (+595%) and MIAVR (+57%). However, SAVR (-15%) and TA-TAVR (-49%) decreased from 2013 to 2014. In the final year, risk stratification by age ≥ 80, redo AVR, patients receiving dialysis and STS score >8% revealed increases in TF-TAVR and MIAVR, while SAVR decreased for all groups. CONCLUSIONS: TF-TAVR and MIAVR increased while SAVR and TA-TAVR trended down in the latter periods, which underscore a paradigm shift in the treatment of severe AS and the importance of surgeon adoption of TF-TAVR and MIAVR techniques. As the demand for minimally invasive modalities increases, further studies comparing MIAVR versus TF-TAVR in low and intermediate risk patients are warranted.