Search

Background/aim Heparanase (HPSE) is relevant to therapy resistance in many malignancies yet is largely unstudied in Hodgkin's lymphoma. Here, we investigated links between HPSE, cancer stem cell (CSC) features and radioresistance in KM-H2 and L428 Hodgkin's lymphoma cells. Materials and methods Firstly, HPSE expression in unsorted and sorted CSCs was assessed. Post-irradiation, HPSE and CSC-related gene expression changes were then quantified. Clonogenic ability was investigated with and without artificial changes in HPSE expression pre and post irradiation. Results HPSE was highly expressed in L428 but barely present in KM-H2 cells. HPSE was overexpressed in sorted L428 CSCs. Irradiation induced HPSE and expression of CSC markers. High HPSE-expressing L428 cells showed higher clonogenic ability than low HPSE-expressing KM-H2 cells after irradiation. Down-regulation of HPSE in L428 cells reduced their clonogenic capability post-radiation, whilst overexpression of HPSE in KM-H2 cells increased colony formation. Conclusion HPSE expression is associated with CSC features and contributes to radioresistance in Hodgkin's lymphoma cells.

Background Although CT-based body composition (BC) metrics may inform disease risk and outcomes, obtaining these metrics has been too resource intensive for large-scale use. Thus, population-wide distributions of BC remain uncertain. Purpose To demonstrate the validity of fully automated, deep learning BC analysis from abdominal CT examinations, to define demographically adjusted BC reference curves, and to illustrate the advantage of use of these curves compared with standard methods, along with their biologic significance in predicting survival. Materials and Methods After external validation and equivalency testing with manual segmentation, a fully automated deep learning BC analysis pipeline was applied to a cross-sectional population cohort that included any outpatient without a cardiovascular disease or cancer who underwent abdominal CT examination at one of three hospitals in 2012. Demographically adjusted population reference curves were generated for each BC area. The

Endometrial carcinoma is the most common gynecological cancer in Europe. Musashi-1 is known to be a key regulator of endometrial cancer stem cells and a negative prognostic marker. In the present study, we aimed to understand growth and gene expression patterns in endometrial carcinoma after Musashi-1 knockdown in vitro and in vivo. Changes in therapeutic resistance were also assessed.First, we performed analyses to understand Musashi-1 expression patterns using The Cancer Genome Atlas database. We then proceeded to assess effects of small interfering RNA-based Musashi-1 targeting in two endometrial carcinoma cell lines, Ishikawa and KLE. After quantifying baseline changes in cell metabolism, we used MTT tests to assess chemotherapy effects and colony formation assays to understand changes in radioresistance. For mechanistic study, we used quantitative polymerase chain reaction (qPCR) and western blotting of key Musashi-1 target genes and compared results to primary tissue database studies. Finally, xenograft experiments in a mouse model helped understand in vivo effects of Musashi-1 knockdown.Musashi-1 is aberrantly expressed in primary tumor tissues. In vitro, silencing of Musashi-1 resulted in a strong decline in cell proliferation and radioresistance, while chemoresistance remained unchanged. Loss of Musashi-1 led to downregulation of telomerase, DNA-dependent protein kinase, the Notch pathway and overexpression of cyclin-dependent kinase inhibitor p21, the latter of which we identified as a key mediator of Msi-1 knockdown-related anti-proliferative signaling. In vivo, the anti-proliferative effect was confirmed, with Msi-1 knockdown tumors being about 40% reduced in size.Musashi-1 knockdown resulted in a strong decrease in endometrial cancer proliferation and a loss of radioresistance, suggesting therapeutic potential.

Background Mortality risk prediction in patients undergoing pneumonectomy for non‐small cell lung cancer (NSCLC) remains imperfect. Here, we aimed to assess whether sarcopenia on routine chest computed tomography (CT) independently predicts worse cancer‐specific (CSS) and overall survival (OS) following pneumonectomy for NSCLC. Methods We included consecutive adults undergoing standard or carinal pneumonectomy for NSCLC at Massachusetts General Hospital and Heidelberg University from 2010 to 2018. We measured muscle cross‐sectional area (CSA) on CT at thoracic vertebral levels T8, T10, and T12 within 90 days prior to surgery. Sarcopenia was defined as T10 muscle CSA less than two standard deviations below the mean in healthy controls. We adjusted time‐to‐event analyses for age, body mass index, Charlson Comorbidity Index, forced expiratory volume in 1 second in % predicted, induction therapy, sex, smoking status, tumor stage, side of pneumonectomy, and institution. Results Three hundred and sixty‐seven patients (67.4% male, median age 62 years, 16.9% early‐stage) underwent predominantly standard pneumonectomy (89.6%) for stage IIIA NSCLC (45.5%) and squamous cell histology (58%). Sarcopenia was present in 104 of 367 patients (28.3%). Ninety‐day all‐cause mortality was 7.1% (26/367). After a median follow‐up of 20.5 months (IQR, 9.2–46.9), 183 of 367 patients (49.9%) had died. One hundred and thirty‐three (72.7%) of these deaths were due to lung cancer. Sarcopenia was associated with shorter CSS (HR 1.7, p = 0.008) and OS (HR 1.7, p = 0.003). Conclusions This transatlantic multicenter study confirms that sarcopenia on preoperative chest CT is an independent risk factor for CSS and OS following pneumonectomy for NSCLC., This transatlantic bi‐institutional study confirms sarcopenia on preoperative chest computed tomography (CT) as an independent binary risk factor for both cancer‐specific and overall survival following pneumonectomy for lung cancer. In the future, muscle mass on chest CT scans obtained as part of guideline‐concordant preoperative evaluation could be harnessed to improve mortality risk prediction in this patient cohort.

Purpose While the stem cell marker Musashi-1 (MSI-1) has been identified as a key player in a wide array of malignancies, few findings exist on its prognostic relevance and relevance for cancer cell death and therapy resistance in breast cancer. Methods First, we determined prognostic relevance of MSI-1 in database analyses regarding multiple survival outcomes. To substantiate findings, MSI-1 was artificially downregulated in MCF-7 breast cancer cells and implications for cancer stem cell markers, cell apoptosis and apoptosis regulator p21, proliferation and radiation response were analyzed via flow cytometry and colony formation. Radiation-induced p21 expression changes were investigated using a dataset containing patient samples obtained before and after irradiation and own in vitro experiments. Results MSI-1 is a negative prognostic marker for disease-free and distant metastasis-free survival in breast cancer and tends to negatively influence overall survival. MSI-1 knockdown downregulated stem cell gene expression and proliferation, but increased p21 levels and apoptosis. Similar to the MSI-1 knockdown effect, p21 expression was strongly increased after irradiation and was expressed at even higher levels in MSI-1 knockdown cells after irradiation. Finally, combined use of MSI-1 silencing and irradiation reduced cancer cell survival. Conclusion MSI-1 is a prognostic marker in breast cancer. MSI-1 silencing downregulates proliferation while increasing apoptosis. The anti-proliferation mediator p21 was upregulated independently after both MSI-1 knockdown and irradiation and even more after both treatments combined, suggesting synergistic potential. Radio-sensitization effects after combining radiation and MSI-1 knockdown underline the potential of MSI-1 as a therapeutic target. Supplementary Information The online version contains supplementary material available at 10.1007/s00432-021-03743-y.

OBJECTIVE. CT-based body composition analysis quantifies skeletal muscle and adipose tissue. However, acquisition parameters and quality can vary between CT images obtained for clinical care, which...

Context.—Lesion localization during intraoperative frozen section of lung resection specimens can be challenging. Imaging could aid lesion localization while enabling 3-dimensional specimen analysis.Objective.—To assess the feasibility of integrating micro–computed tomography (micro-CT) into the perioperative evaluation of fresh surgical lung resection specimens.Design.—Fresh lung specimens from patients with a presumptive diagnosis of lung cancer were imaged with micro-CT prior to routine histopathologic and molecular analysis. Micro-CT images were assessed to determine image quality, lesion size, and distance from lesion to the nearest surgical margin. Micro-CT measurements were compared to pathologic measurements using Bland-Altman analysis.Results.—A total of 22 specimens from 21 patients were analyzed (mean image acquisition time, 13 ± 6 minutes). Histologic quality of imaged specimens was indistinguishable from a control group of nonimaged lung specimens. Artifacts, most commonly from specimen deflation (n = 8), obscured fine detail on micro-CT images of 10 specimens. Micro-CT could successfully localize the target lesion in the other 12 specimens. Distance to the nearest surgical margin was determined in 10 specimens. Agreement of micro-CT with final pathology was good, with a mean difference of −2.8% (limits of agreement −14.5% to 20.0%) for lesion size and −0.5 mm (limits of agreement −4.4 to 3.4 mm) for distance to nearest surgical margin.Conclusions.—Micro-CT of fresh surgical lung specimens is feasible and has the potential to evaluate the size and location of lesions within resection specimens, as well as distance to the nearest surgical margin, all without compromising specimen integrity.

Cancer cachexia and sarcopenia can occur frequently in patients with advanced cancer, and may negatively affect treatment outcomes. This article highlights the importance of assessing sarcopenia and describes the relationship between sarcopenia and patients' quality of life in patients with newly diagnosed, incurable cancer., Background. Patients with advanced cancer often experience muscle wasting (sarcopenia), yet little is known about the characteristics associated with sarcopenia and the relationship between sarcopenia and patients’ quality of life (QOL) and mood. Materials and Methods. As part of a randomized trial, we assessed baseline QOL (Functional Assessment of Cancer Therapy‐General [FACT‐G]) and mood (Hospital Anxiety and Depression Scale [HADS]) in patients within 8 weeks of diagnosis of incurable lung or gastrointestinal cancer, and prior to randomization. Using computed tomography scans collected as part of routine clinical care, we assessed sarcopenia at the level of the third lumbar vertebra with validated sex‐specific cutoffs. We used logistic regression to explore characteristics associated with presence of sarcopenia. To examine associations between sarcopenia, QOL and mood, we used linear regression, adjusted for patients’ age, sex, marital status, education, and cancer type. Results. Of 237 participants (mean age = 64.41 ± 10.93 years), the majority were male (54.0%) and married (70.5%) and had lung cancer (56.5%). Over half had sarcopenia (55.3%). Older age (odds ratio [OR] = 1.05, p = .002) and education beyond high school (OR = 1.95, p = .047) were associated with greater likelihood of having sarcopenia, while female sex (OR = 0.25, p

Pretreatment risk stratification is key for personalized medicine. While many physicians rely on an "eyeball test" to assess whether patients will tolerate major surgery or chemotherapy, "eyeballing" is inherently subjective and difficult to quantify. The concept of morphometric age derived from cross-sectional imaging has been found to correlate well with outcomes such as length of stay, morbidity, and mortality. However, the determination of the morphometric age is time intensive and requires highly trained experts. In this study, we propose a fully automated deep learning system for the segmentation of skeletal muscle cross-sectional area (CSA) on an axial computed tomography image taken at the third lumbar vertebra. We utilized a fully automated deep segmentation model derived from an extended implementation of a fully convolutional network with weight initialization of an ImageNet pre-trained model, followed by post processing to eliminate intramuscular fat for a more accurate analysis. This experiment was conducted by varying window level (WL), window width (WW), and bit resolutions in order to better understand the effects of the parameters on the model performance. Our best model, fine-tuned on 250 training images and ground truth labels, achieves 0.93 ± 0.02 Dice similarity coefficient (DSC) and 3.68 ± 2.29% difference between predicted and ground truth muscle CSA on 150 held-out test cases. Ultimately, the fully automated segmentation system can be embedded into the clinical environment to accelerate the quantification of muscle and expanded to volume analysis of 3D datasets.

Background Sarcopenia represented by low psoas muscle area is associated with increased hospital length of stay (LOS), postoperative complications, and mortality. We studied whether thoracic skeletal muscle area (TSMA) derived from computed tomography (CT) predicts morbidity after pneumonectomy for lung cancer. Methods Consecutive patients who underwent pneumonectomy for lung cancer from 2005 to 2017 were retrospectively analyzed. TSMA was defined as the sum of muscle area at the level of the eighth and the 12th thoracic vertebral bodies on preoperative CT. Patients were stratified into sex-specific TSMA quartiles for univariate time-to-event analyses. The effect of continuous TSMA measurements on operative complications, hospital and intensive care unit (ICU) LOS, discharge disposition, and hospital readmission within 90 days was estimated using multivariable models adjusted for age, sex, body mass index, forced expiratory volume in 1 second, Zubrod score, and pneumonectomy type. Results Standard (n = 102, 78.5%) or high-risk (n = 28, 21.5%; extrapleural: n = 3, 2.3%; carinal: n = 9, 6.9%; completion: n = 16, 12.3%) pneumonectomy was performed in 130 patients (60.8 ± 10.6 years; 43.1% women). Major complications occurred in 33.1% (n = 43 of 130) and readmission in 17.7% (n = 23 of 130) of patients. In multivariable models, patients with high TSMA experienced fewer overall (odds ratio [OR], 0.87; P = .04) and cardiopulmonary (OR, 0.86; P = .04) complications, and fewer readmissions (OR, 0.78; P = .01). Associations with ICU LOS (hazard ratio, 1.08; P = .051) and hospital LOS (hazard ratio, 1.05; P = .18) did not reach significance. Conclusions TSMA predicts adverse outcome after pneumonectomy for lung cancer. This marker, readily derived from standard chest CT, identifies patients at increased risk for postoperative complications and may help select patients appropriate for focused rehabilitation before pneumonectomy.

Background Research increasingly focuses on identifying individuals at greater risk of colorectal cancer (CRC) to enhance colonoscopy screening efficacy. Objective The objective of this article is to determine associations between chronic liver disease and lesions along the colorectal adenoma-carcinoma sequence. Methods This retrospective study encompasses consecutive liver disease patients (LDPs) of all etiologies evaluated for liver transplantation at a single institution and a control group of liver-healthy patients (LHPs) undergoing colonoscopy as part of the German CRC screening program. Rates of polyps, adenomas, high-risk situations (HRS) and CRC were analyzed in univariable and multivariable settings adjusting for age, gender, body mass index and number of colonoscopies. Differences between LHPs and LDPs and between cirrhotic and noncirrhotic hepatopathy were assessed. Results In total, 1046 patients (52.6% male, median age 59.6 years) were included, of whom 38.9% had liver disease. A total of 41.0% of all patients showed polyps, 23.2% adenomas, 10.0% HRS, and 0.5% CRC. LDPs were more likely to develop polyps, adenomas and HRS than LHPs, both in univariable and multivariable analysis. There were no significant differences between cirrhotic and noncirrhotic patients. Conclusion Chronic liver disease of any etiology is associated with colonic lesions of the colorectal adenoma-carcinoma sequence, independent of cirrhosis. LDPs should receive intensified, and earlier, colonoscopy screening.

Objectives To assess the prognostic role of thoracic muscle as quantified on preoperative computed tomography (CT) for the estimation of overall survival (OS) following pneumonectomy. Methods Muscle cross-sectional area (CSA) at the level of the fifth (T5) and eighth (T8) thoracic vertebra was measured on CT scans of consecutive patients with lung cancer prior to pneumonectomy. We stratified patients into high and low muscle groups using the gender-specific median of muscle CSA as separator and estimated associations of muscle CSA and OS using the Kaplan-Meier analysis. Multivariable logistic regression adjusted for body mass index, Charlson comorbidity index (includes age), forced expiratory volume in the first second as a % of predicted, sex, race, smoking status, tumour stage and prior lung cancer treatment was performed. Results A total of 128 patients were included (61.0 ± 10.6 years of age, mean body mass index of 26.9 kg/m2, 55.5% men). The T8 level showed fewer artefacts and strong correlation with the T5 level (Pearson's rho = 0.904). T8 CSA was therefore used for subsequent analyses. Mean T8 CSA was 118.5 cm2 (median 115.3 cm2) in men and 75.2 cm2 (median 74.0 cm2) in women. During a median follow-up of 23.6 months (interquartile range 39.3), 65 patients (50.8%) died, of whom 41 were in the low muscle group. The Kaplan-Meier analysis showed significantly longer OS in the high muscle group (log-rank P = 0.02). Multivariable analysis showed an independent association of muscle CSA and OS (P = 0.02) with a hazard ratio of 0.80 (confidence interval 0.67-0.98) per 10-cm2 increment. Conclusions Thoracic muscle is independently associated with long-term overall survival following pneumonectomy for lung cancer and may contribute to refined survival estimates in this population. Irb protocol Protocol #2017P000650, approved 21 April 2017.

Sarcopenia, the loss of muscle mass, has been identified as a potential risk factor for adverse outcomes in hematopoietic cell transplantation (HCT) recipients. However, much remains unknown about change in body composition following HCT. We retrospectively evaluated computed tomography (CT) imaging from 315 lymphoma patients undergoing HCT at our institution between 2000 and 2014. Cross-sectional areas of lean muscle, subcutaneous adipose tissue, and visceral adipose tissue were measured on CT at the level of the third lumbar vertebral body before HCT, 1-year post-HCT, and 2.5 years post-HCT. The incidence of sarcopenia before HCT was 47% in the autologous HCT (auto-HCT) cohort (n = 218) and 55% in the allogeneic HCT (allo-HCT) cohort (n = 97). Older age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.01 to 1.04; P .001) and male sex (OR, 4.59; 95% CI, 1.42 to 4.93; P .001) were associated with sarcopenia before HCT. Increasing body mass index (OR, .78; 95% CI, .73 to .84; P .001) was protective against sarcopenia before HCT. A significant decline in total lean body mass (β = 1.96; 95% CI, .79 to 3.13; P = .001) and increased sarcopenia incidence (OR, 1.72; 95% CI, 1.13 to 2.62, P = .012) was observed over time for patients in the allo-HCT cohort when compared with the trend in the auto-HCT cohort. Both auto-HCT and allo-HCT recipients experienced an increase in total body fat mass over time (β = 3.75; 95% CI, 2.77 to 4.73; P .001). In multivariate analysis of patients undergoing allo-HCT, the presence of sarcopenia on baseline imaging before HCT was associated with a lower risk of acute graft-versus-host disease (OR, .30; 95% CI, .09 to .98; P = .047). In conclusion, we found that total body fat mass increases after both auto-HCT and allo-HCT. Following allo-HCT, total lean body mass significantly decreases corresponding to increased incidence of sarcopenia. Future studies are needed to further characterize changes in body composition in HCT recipients and investigate its impact on HCT outcomes.

Background Computed tomography (CT)-based fat and muscle measures are associated with outcome in large populations. We tested if muscle and fat characteristics are associated with long-term outcomes after TAVR. Methods We included 403 clinical CTs performed prior to TAVR at our center between 2008 and 2016, measuring area (cm2) and density (Hounsfield units, HU) of both psoas muscles (PM), subcutaneous adipose (SAT), and visceral adipose tissue (VAT). Area measures were indexed to height, log-transformed and both area and density were standardized for analysis. We assessed the association of each measure with all-cause mortality (adjusted for age, sex, body mass index (BMI), and the Society of Thoracic Surgeons (STS) risk score. Results Of the 403 individuals (83 ± 8 years; 52% female), 167 (41.4%) died during a median follow-up of 458 days (interquartile range IQR 297–840). Fat measures were feasible and rapid. Fat area was available in 242 (60%) patients with an adequate field of view. Individuals with the lowest PM area, SAT area or VAT area exhibited the highest hazard of mortality. In addition, greater SAT density was associated with a higher mortality hazard (adjusted HR per standard deviation increase in density = 1.35, 95%CI 1.10–1.67, P = 0.005). Conclusion Rapid CT-based tissue characterization is feasible in patients referred for TAVR. Decreased PM area and increased SAT density are associated with long-term mortality after TAVR, even after accounting for age, sex, BMI, and STS score. Further studies are necessary to interrogate sex-specific relationships between CT tissue metrics and mortality and whether CT measures are incremental to well-established frailty metrics.