Citations

Abstract BACKGROUND: It is well known that for patients with solitary metastatic disease in the brain, aggressive surgical treatment can prolong survival. However, there is a paucity of literature focusing on simultaneous resection of multiple metastatic brain tumors. METHODS: We analyzed 13 patients and 26 tumors between 2005–2019 who had simultaneous resection of at least 2 metastatic brain tumors via either one or two craniotomies. We independently analyzed those patients with simultaneous resection of metastatic disease in both the supra- and infratentorial compartments. RESULTS: Overall, 26 tumors were resected in a simultaneous fashion. There were 7 females (53.8%) and 6 males (46.2%) total. 5/13 (38.5%) patients had previously known brain metastases in which all 5 had previous adjuvant radiation. All 13 patients had 2 metastatic lesions resected during one operation. Gross total resection rate reached 88.5% with a median post-operative stay of 3 days. Complications presented in only 3 out of 13 cases (grade 2 and 3 according to CTCAE). Primary sites of metastatic disease were lung, breast, skin and renal. 12/13 (92.3%) had two distinct craniotomies and 23/26 (88.5%) tumors had gross total resection of both lesions. There were 11 frontal (42.3%), 7 parietal (26.9%), 2 temporal (7.7%), 1 occipital (3.8%) and 5 cerebellar (19.2%) tumors. There were three patients with both supra- and intratentorial tumors with simultaneous resection. All three patients had two craniotomies and two separate incisions. 1 of the 3 had pre-operative SRS. Overall, average local progression since surgery to at least one resected tumor bed was 88.3 days. CONCLUSIONS: Our results suggest that patients with multiple metastatic brain lesions have comparable outcomes and similar rates of surgical risk to those with solitary brain lesions. In patients with simultaneous supra- and infratentorial brain metastatic disease and indications for decompression, safe resection is feasible.

Abstract PURPOSE: Preoperative stereotactic radiosurgery (SRS) for symptomatic brain metastases has arisen as a therapeutic option for patients with brain lesions, potentially reducing radionecrosis risk, leptomeningeal disease risk, as well as delays in systemic therapy after craniotomy. The purpose of our work is to analyze the current evidence regarding 1-year local control (LC) and RN rates in the preoperative and postoperative settings. METHODS AND MATERIALS: Population, Intervention, Control, Outcomes, Study Design/Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology guidelines were used to select articles in which patients had “large” brain metastases (>4 cm3 or >2 cm in diameter) solely treated with preoperative or postoperative SRS and 1-year LC and/or rates of RN reported. Radiosurgery was stratified by timing: preoperatively or postoperatively. Random effects meta-analyses using timing of SRS relative to surgery as covariates were conducted. Meta-regression and Wald-type tests were used to determine the effect of increasing tumor size on the summary estimate, where the null hypothesis was rejected for p < 0.05. RESULTS: Fifteen studies were included (of 314 screened), published between 2012 and 2018 with 854 brain metastases. Preoperative SRS was delivered in 229 lesions. The 1-year LC random effects estimate was 79.1% (95% confidence interval [CI]: 55.9–95.0%; I 2 = 80%) for preoperative SRS and 80.5% (95% CI: 66.3–91.5%; I 2 = 93%) for postoperative SRS (p=0.9). Radionecrosis incidence random effects estimate was 2.1% (95% CI: 0.1–8.6%; I 2 = 36%) for preoperative SRS and 6.3% (95% CI: 1.1–15.4%; I 2 = 90%) for postoperative SRS (p=0.52). CONCLUSIONS: Rates of 1-year LC and RN incidence are similar after preoperative SRS as compared to postoperative SRS for large brain metastases. Results from ongoing prospective clinical trials studying preoperative SRS are important to further investigate these two techniques.

Abstract Background:All carcinomas contain a variable proportion of benign stromal and immune cells, limiting the sensitivity in the identification of somatic genetic alterations. The average tumor purity of squamous cell carcinomas (SCC) of the lung is only around 50%. Low tumor content in tumor samples represents a challenge in studying intratumoral genomic heterogeneity in cancer research. Here, we applied flow-sorting to enrich for tumor cell nuclei to investigate the clonal relationship of primary SCC and matched metastases. Methods:Tumor tissues from 16 patients with primary SCC of the lung and matched metastases were used. We implemented a flow-sorting based approach to enrich for tumor nuclei as followed: after extraction of nuclei from snap-frozen or FFPE tissue, they were flow-sorted by DNA content (ploidy) and cytokeratin expression of the adherent cytoplasm, using a pan-cytokeratin (pCK) antibody. Isolated diploid and aneuploid pCK-positive tumor cell populations were subjected to whole exome sequencing (WES). DNA from diploid pCK-negative populations was used as germline control. Mutational profile and copy number aberrations (CNA) were determined to infer the clonal relationship and evolution between the primary tumors and their metastases. Results:Our flow-sorting based approach was able to enrich tumor content from 20%-50% to more than 80%-90% and to distinguish between aneuploid and diploid tumor cell populations from bulk tumor tissues. It enabled the identification of somatic mutations and CNA in both, aneuploid and diploid tumor cell populations, including potential subclonal driver mutations in ARID1A and KDM6A at low allelic frequencies. Shared and private mutations were observed in matched longitudinal tumor samples of individual patients and in synchronous distant metastases. Ploidy did not change significantly between primary tumors and relapse or distant metastases. Conclusion:We present a flow-sorting based method to enrich for tumor cell nuclei to facilitate genomic analysis, which also enabled separate analysis of aneuploid and diploid tumor populations. Our results show that the enrichment approach can be used to decode the clonal evolutionary relationship between primary tumors and their matched metastases, even in samples with low tumor cell content. Citation Format: Arthur Krause, Maria R. De Filippo, Thomas Lorber, Tanja Dietsche, Valeria Perrina, Christian Ruiz, Michael T. Barrett, Salvatore Piscuoglio, Charlotte K. Ng, Lukas Bubendorf. Enriching tumor purity using a unique flow-sorting approach to elucidate clonal evolution in matched samples of squamous cell carcinoma of the lung [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4699.

Background Previous studies suggest that medical students may have higher rates of irritable bowel syndrome as compared to the general population. We hypothesized lifestyle characteristics may be associated to irritable bowel syndrome. Methods A cross-sectional survey was conducted in 2015 among students in their fourth, fifth, sixth and seven years of a medical school in Peru. Volunteer participants responded to questions pertaining to demographics, surveys including the Rome III criteria and the Self-reported Stress questionnaire. Regression models were performed to establish variables independently associated with irritable bowel syndrome. Results Out of 452 students, 346 responded the survey (response rate: 76.5%; female rate: 47%; median age: 22 years). The irritable bowel syndrome prevalence in respondents was 9.5% (95% confidence interval: 6.7%–13.1%). On univariate analysis, being a senior medical student (odds ratio: 2.8; 95% confidence interval: 1.3–5.9; P < 0.01), mental illness (odds ratio: 3.3; 95% confidence interval: 1.6–6.8; P = 0.002), psychiatric medication use (odds ratio: 2.8; 95% confidence interval: 1.4–5.9; P = 0.005), sedentary lifestyle (odds ratio: 4.4; 95% confidence interval: 1.8–11; P = 0.001) and stress (odds ratio: 4.4; 95% confidence interval: 2.1–9.3; P < 0.001) were associated to irritable bowel syndrome. On a multivariate analysis, a sedentary lifestyle (odds ratio: 3.2; 95% confidence interval: 1.25–8.20; P = 0.01) and stress (odds ratio: 3.0; 95% confidence interval: 1.35–6.67; P < 0.01) were independently associated with irritable bowel syndrome. Conclusion The prevalence of irritable bowel syndrome in medical students from Peru is slightly lower compared to the global prevalence of irritable bowel syndrome. Stress and a sedentary lifestyle were independent risk factors associated with irritable bowel syndrome. Our study suggests that lifestyle modifications and stress coping techniques could have an impact to reduce the rates of irritable bowel syndrome in medical students.

Abstract Rationale Endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive method used to diagnose suspected mediastinal lymph nodes or masses. However, the accuracy of the diagnosis in patients with suspected lymphoma is unclear. Objectives To evaluate the diagnostic yield of EBUS-TBNA in patients with suspected lymphoma. Methods A literature search including EMBASE, MEDLINE, Cochrane Library, and Google Scholar was performed by two reviewers. Included articles were evaluated using the QUADAS-2 tool and meta-analysis with a binary method model to compare the sensitivity, specificity, and summary receiver operating characteristic curve in patients with suspected lymphoma. Results Fourteen studies (425 participants) were pooled in the analysis. EBUS-TBNA reported an overall sensitivity of 66.2% (confidence interval [CI], 55–75.8%; I 2 = 76.2%) and specificity of 99.3% (CI, 98.2–99.7%; I 2 = 40%). For a new diagnosis of lymphoma, 13 studies including 243 participants reported sensitivity of 67.1% (CI, 54.2–77.9%; I 2 = 66.8%) and specificity of 99.6% (CI, 99.1–99.8%; I 2 = 0%). For recurrence of lymphoma, 11 studies including 166 participants reported sensitivity of 77.8% (CI, 68.1–85.2%; I 2 = 20.2%) and specificity of 99.5% (CI, 98.9–99.8%; I 2 = 0%). In the recurrence group, we found the use of rapid onsite examination, sample size, and flow cytometry increased the sensitivity of EBUS-TBNA, albeit a potential source of heterogeneity. Conclusions EBUS-TBNA has fair sensitivity for identifying a new diagnosis of lymphoma and fair to good sensitivity for identifying recurrence. Trial Registry PROSPERO CRD42018102773 https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=102773.

Objective: The aim of the study was to determine the rate, predictors, and impact of complete pathologic response (cPR) to pretransplant locoregional therapy (LRT) in a large, multicenter cohort of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT). Background: LRT is used to mitigate waitlist dropout for patients with HCC awaiting LT. Degree of tumor necrosis found on explant has been associated with recurrence and overall survival, but has not been evaluated in a large, multicenter study. Methods: Comparisons were made among patients receiving pre-LT LRT with (n = 802) and without (n = 2637) cPR from the United States Multicenter HCC Transplant Consortium (UMHTC), and multivariable predictors of cPR were identified using logistic regression. Results: Of 3439 patients, 802 (23%) had cPR on explant. Compared with patients without cPR, cPR patients were younger; had lower Model for End-stage Liver Disease (MELD) scores, AFP levels, and neutrophil–lymphocyte ratios (NLR); were more likely to have tumors within Milan criteria and fewer LRT treatments; and had significantly lower 1-, 3-, and 5-year incidence of post-LT recurrence (1.3%, 3.5%, and 5.2% vs 6.2%, 13.5%, and 16.4%; P < 0.001) and superior overall survival (92%, 84%, and 75% vs 90%, 78%, and 68%; P < 0.001). Multivariable predictors of cPR included age, sex, liver disease diagnosis, MELD, AFP, NLR, radiographic Milan status, and number of LRT treatments (C-statistic 0.67). Conclusions: For LT recipients with HCC receiving pretransplant LRT, achieving cPR portends significantly lower posttransplant recurrence and superior survival. Factors predicting cPR are identified, which may help prioritize patients and guide LRT strategies to optimize posttransplant cancer outcomes.

Head and neck cancer is the sixth leading cancer by incidence worldwide. Unfortunately, drug resistance and relapse are the principal limitations of clinical oncology for many patients, and the failure of conventional treatments is an extremely demoralizing experience. It is therefore crucial to find new therapeutic targets and drugs to enhance the cytotoxic effects of conventional treatments without potentiating or offsetting the adverse effects. Melatonin has oncostatic effects, although the mechanisms involved and doses required remain unclear. The purpose of this study is to determine the precise underlying mitochondrial mechanisms of melatonin, which increase the cytotoxicity of oncological treatments, and also to propose new melatonin treatments in order to alleviate and reverse radio- and chemoresistant processes. We analyzed the effects of melatonin on head and neck squamous cell carcinoma (HNSCC) cell lines (Cal-27 and SCC-9), which were treated with 0.1, 0.5, 1, and 1.5 mM melatonin combined with 8 Gy irradiation or 10 μM cisplatin. Clonogenic and MTT assays, as well as autophagy and apoptosis, involving flow cytometry and western blot, were performed in order to determine the cytotoxic effects of the treatments. Mitochondrial function was evaluated by measuring mitochondrial respiration, mtDNA content (RT-PCR), and mitochondrial mass (NAO). ROS production, antioxidant enzyme activity, and GSH/GSSG levels were analyzed using a fluorometric method. We show that high concentrations of melatonin potentiate the cytotoxic effects of radiotherapy and CDDP in HNSCC, which are associated with increased mitochondrial function in these cells. In HNSCC, melatonin induces intracellular ROS, whose accumulation plays an upstream role in mitochondria-mediated apoptosis and autophagy. Our findings indicate that melatonin, at high concentrations, combined with cisplatin and radiotherapy to improve its effectiveness, is a potential adjuvant agent.

AbstractBackgroundReliable and valid tools to screen for malnutrition in the intensive care unit (ICU) remain elusive. The sarcopenia index (SI) [(serum creatinine/serum cystatin C) × 100], could be an inexpensive, objective tool to predict malnutrition. We evaluated the SI as a screening tool for malnutrition in the ICU and compared it with the modified‐NUTRIC score.Materials and MethodsThis was a historical cohort study of ICU patients with stable kidney function admitted to Mayo Clinic ICUs between 2008 and 2015. Malnutrition was defined by the Subjective Global Assessment. Diagnostic performance was evaluated with the area under the receiver operating characteristic curve (AUC) and multivariable logistic regression.ResultsOf the 398 included patients, 181 (45%) had malnutrition, with 34 (9%) scored as severely malnourished. The SI was significantly lower in malnourished patients than in well‐nourished patients (64 ± 27 vs 72 ± 25; P = 0.002), and reductions in SI corresponded to increased malnutrition severity (P = 0.001). As a screening tool, the SI was an indicator of malnutrition risk (AUC 0.61) and performed slightly better than the more complex modified‐NUTRIC score (AUC = 0.57). SI cutoffs of 101 and 43 had >90% sensitivity and >90% specificity, respectively, for the prediction of malnutrition. Patients with a low SI (≤43) had a significantly higher risk of mortality (HR = 2.61, 95% CI 1.06–6.48, P = 0.038).ConclusionThe frequency of malnutrition was high in this critically ill population, and it was associated with a poor prognosis. The SI could be used to assess nutrition risk in ICU patients.

Hedgehog (HH) signaling participates in hepatobiliary repair after injury and is activated in patients with cholangiopathies. Cholangiopathies are associated with bile duct (BD) hyperplasia, including expansion of peribiliary glands, the niche for biliary progenitor cells. The inflammation‐associated cytokine interleukin (IL)‐33 is also up‐regulated in cholangiopathies, including cholangiocarcinoma. We hypothesized that HH signaling synergizes with IL‐33 in acute inflammation‐induced BD hyperplasia. We measured extrahepatic BD (EHBD) thickness and cell proliferation with and without an IL‐33 challenge in wild‐type mice, mice overexpressing Sonic HH ( pCMV‐Shh ), and mice with loss of the HH pathway effector glioma‐associated oncogene 1 ( Gli1lacZ/lacZ ). LacZ reporter mice were used to map the expression of HH effector genes in mouse EHBDs. An EHBD organoid (BDO) system was developed to study biliary progenitor cells in vitro . EHBDs from the HH overexpressing pCMV‐Shh mice showed increased epithelial cell proliferation and hyperplasia when challenged with IL‐33. In Gli1lacZ/lacZ mice, we observed a decreased proliferative response to IL‐33 and decreased expression of Il6 . The HH ligands Shh and Indian HH ( Ihh ) were expressed in epithelial cells, whereas the transcriptional effectors Gli1 , Gli2 , and Gli3 and the HH receptor Patched1 ( Ptch1 ) were expressed in stromal cells, as assessed by in situ hybridization and lacZ reporter mice. Although BDO cells lacked canonical HH signaling, they expressed the IL‐33 receptor suppression of tumorigenicity 2. Accordingly, IL‐33 treatment directly induced BDO cell proliferation in a nuclear factor κB‐dependent manner. Conclusion: HH ligand overexpression enhances EHBD epithelial cell proliferation induced by IL‐33. This proproliferative synergism of HH and IL‐33 involves crosstalk between HH ligand‐producing epithelial cells and HH‐responding stromal cells.