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Inactivation of SMARCA4 (BRG1), a subunit of SWI/SNF complex, has been reported in malignancies from various sites, including the thorax, uterus, ovary, and gastrointestinal tract, and is usually associated with aggressive clinical course. These tumors have been reported primarily in elderly patients and on histology demonstrate high-grade morphology, often with rhabdoid differentiation. SMARCA4 loss is exceedingly rare in primary gastric cancers. Here, we present a unique example of SMARCA4 deficient gastric carcinoma in a 28-year-old male patient with molecular confirmation which showed a poorly differentiated histology and focal squamous differentiation. Despite multidisciplinary management, including FOLFOX chemotherapy, immunotherapy (nivolumab), and surgical resection, the patient succumbed to his disease within 2 years of diagnosis. This case report highlights the aggressive nature of SMARCA4-deficient carcinomas, which are often resistant to conventional chemotherapy, and underscores the importance of early diagnosis and exploring alternative therapeutic approaches for such malignancies., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Cancer patients infected with COVID-19 were shown in a multitude of studies to have poor outcomes on the basis of older age and weak immune systems from cancer as well as chemotherapy. In this study, the CT examinations of 22 confirmed COVID-19 cancer patients were analyzed., Methodology: A retrospective analysis was conducted on 28 cancer patients, of which 22 patients were COVID positive. The CT scan changes before and after treatment and the extent of structural damage to the lungs after COVID-19 infection was analyzed. Structural damage to a lung was indicated by a change in density measured in Hounsfield units (HUs) and by lung volume reduction. A 3D radiometric analysis was also performed and lung and lesion histograms were compared., Results: A total of 22 cancer patients were diagnosed with COVID-19 infection. A repeat CT scan were performed in 15 patients after they recovered from infection. Most of the study patients were diagnosed with leukemia. A secondary clinical analysis was performed to show the associations of COVID treatment on the study subjects, lab data, and outcome on mortality. It was found that post COVID there was a decrease of >50% in lung volume and a higher density in the form of HUs due to scar tissue formation post infection., Conclusion: It was concluded that COVID-19 infection may have further detrimental effects on the lungs of cancer patients, thereby, decreasing their lung volume and increasing their lung density due to scar formation.

We report results of our prospective pilot trial evaluating safety/feasibility of peritransplantation ruxolitinib for myelofibrosis treatment. Primary objectives were to determine safety and maximum tolerated dose (MTD) of ruxolitinib. Ruxolitinib was administered at 2 dose levels (DLs) of 5 and 10 mg twice daily, with fludarabine/melphalan conditioning regimen and tacrolimus/sirolimus graft-versus-host disease (GVHD) prophylaxis. We enrolled 6 and 12 patients at DL1 and DL2, respectively. Median age at transplantation was 65 years (range, 25-73). Per Dynamic International Prognostic Scoring System, 4 patients were high and 14 intermediate risk. Peripheral blood stem cells were graft source from matched sibling (n = 5) or unrelated (n = 13) donor. At each DL, 1 patient developed dose-limiting toxicities (DLTs): grade 3 cardiac and gastrointestinal with grade 4 pulmonary DLTs in DL1, and grade 3 kidney injury in DL2. All patients achieved engraftment. Grade 2 to 4 and 3 to 4 acute GVHD cumulative incidence was 17% (95% confidence interval [CI], 6-47) and 11% (95% CI, 3-41), respectively. Cumulative incidence of 1-year chronic GVHD was 42% (95% CI, 24-74). With 22.6-month (range, 6.2-25.8) median follow-up in surviving patients, 1-year overall and progression-free survival were 77% (95% CI, 50-91) and 71% (95% CI, 44-87), respectively. Causes of death (n = 4) were cardiac arrest, GVHD, respiratory failure, and refractory GVHD of liver. Our results show peritransplantation ruxolitinib is safe and well tolerated at MTD of 10 mg twice daily and associated with dose-dependent pharmacokinetic and cytokine profile. Early efficacy data are highly promising in high-risk older patients with myelofibrosis. This trial was registered at www.clinicaltrials.gov as #NCT02917096., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose: There is a major shortage of reliable early detection methods for pancreatic cancer in high-risk groups. The focus of this preliminary study was to use Time Intensity-Density Curve (TIDC) and Marley Equation analyses, in conjunction with 3D volumetric and perfusion imaging to demonstrate their potential as imaging biomarkers to assist in the early detection of Pancreatic Ductal Adenocarcinoma (PDAC)., Experimental Designs: A quantitative retrospective and prospective study was done by analyzing multi-phase Computed Tomography (CT) images of 28 patients undergoing treatment at different stages of pancreatic adenocarcinoma using advanced 3D imaging software to identify the perfusion and radio density of tumors., Results: TIDC and the Marley Equation proved useful in quantifying tumor aggressiveness. Perfusion delays in the venous phase can be linked to Vascular Endothelial Growth Factor (VEGF)-related activity which represents the active part of the tumor. 3D volume analysis of the multiphase CT scan of the patient showed clear changes in arterial and venous perfusion indicating the aggressive state of the tumor., Conclusion: TIDC and 3D volumetric analysis can play a significant role in defining the response of the tumor to treatment and identifying early-stage aggressiveness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rahmanuddin, Korn, Cridebring, Borazanci, Brase, Boswell, Jamil, Cai, Sabir, Motarjem, Koay, Mitra, Goel, Ho, Chung and Von Hoff.)

Background: Previously, we characterized subtypes of pancreatic ductal adenocarcinoma (PDAC) on computed-tomography (CT) scans, whereby conspicuous (high delta) PDAC tumors are more likely to have aggressive biology and poorer clinical outcomes compared to inconspicuous (low delta) tumors. Here, we hypothesized that these imaging-based subtypes would exhibit different growth-rates and distinctive metabolic effects in the period prior to PDAC diagnosis., Materials and Methods: Retrospectively, we evaluated 55 patients who developed PDAC as a second primary cancer and underwent serial pre-diagnostic (T0) and diagnostic (T1) CT-scans. We scored the PDAC tumors into high and low delta on T1 and, serially, obtained the biaxial measurements of the pancreatic lesions (T0-T1). We used the Gompertz-function to model the growth-kinetics and estimate the tumor growth-rate constant (α) which was used for tumor binary classification, followed by cross-validation of the classifier accuracy. We used maximum-likelihood estimation to estimate initiation-time from a single cell (10 -6 mm 3 ) to a 10 mm 3 tumor mass. Finally, we serially quantified the subcutaneous-abdominal-fat (SAF), visceral-abdominal-fat (VAF), and muscles volumes (cm 3 ) on CT-scans, and recorded the change in blood glucose (BG) levels. T-test, likelihood-ratio, Cox proportional-hazards, and Kaplan-Meier were used for statistical analysis and p-value <0.05 was considered significant., Results: Compared to high delta tumors, low delta tumors had significantly slower average growth-rate constants (0.024 month -1 vs. 0.088 month -1 , p<0.0001) and longer average initiation-times (14 years vs. 5 years, p<0.0001). α demonstrated high accuracy (area under the curve (AUC)=0.85) in classifying the tumors into high and low delta, with an optimal cut-off of 0.034 month -1 . Leave-one-out-cross-validation showed 80% accuracy in predicting the delta-class (AUC=0.84). High delta tumors exhibited accelerated SAF, VAF, and muscle wasting (p <0.001), and BG disturbance (p<0.01) compared to low delta tumors. Patients with low delta tumors had better PDAC-specific progression-free survival (log-rank, p<0.0001), earlier stage tumors (p=0.005), and higher likelihood to receive resection after PDAC diagnosis (p=0.008), compared to those with high delta tumors., Conclusion: Imaging-based subtypes of PDAC exhibit distinct growth, metabolic, and clinical profiles during the pre-diagnostic period. Our results suggest that heterogeneous disease biology may be an important consideration in early detection strategies for PDAC., Competing Interests: BW revives grant support form Celgene and Eli Lilly, and is consulting for BioLineRx, Celgene, and GRAIL. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer SM declared a past co-authorship with several of the authors, AG and DV, to the handling editor., (Copyright © 2020 Zaid, Elganainy, Dogra, Dai, Widmann, Fernandes, Wang, Pelaez, Ramirez, Singhi, Dasyam, Brand, Park, Rahmanuddin, Rosenthal, Wolpin, Khalaf, Goel, Von Hoff, Tamm, Maitra, Cristini and Koay.)

Three-dimensional imaging is a useful tool to evaluate liver structure and surrounding vessels for preoperative planning. In this study, we compared two methods of visualizing vascular maps on computed tomography including maximum intensity projection (MIP) and 3D volume rendered (VR) imaging. We compiled important imaging components of pre-surgical planning, and developed criteria for comparison. The imaging techniques were compared based on colorization, volume quantification, rotation, vessel delineation, small vessel clarity, and segmental liver isolation. MIP had more overall limitations due to reduced differentiation of superimposed structures, motion artifact, and interference from calcifications. We determined that because 3D quantitative volume rendered imaging can provide more detail and perspective than MIP imaging, it may be more useful in preoperative planning for patients with liver malignancy. Advanced 3D imaging is a useful tool that can have profound clinical implications on cancer detection and surgical planning., Competing Interests: The authors report no declarations of interest., (© 2020 The Authors.)

Purpose: Response assessment with computed tomography after stereotactic body radiation therapy (SBRT) for non-small cell lung cancer (NSCLC) is challenging because myriad anatomic changes can occur after treatment. Diffusion-weighted magnetic resonance imaging (MRI) may provide additional data to guide therapy response. The primary objective was to evaluate the effect of SBRT on the mean apparent diffusion coefficient (ADC)., Methods and Materials: This is a prospective clinical study of patients with NSCLC who received SBRT to the primary lung lesion. Patients underwent MRI scans before and at 1 month after completion of SBRT. MRI consisted of T1- and T2-weighted sequences, along with postcontrast, dynamic-contrast, and diffusion-weighted sequences with construction of ADC maps. Two blinded radiologists generated the ADC. SBRT was given over 5 fractions., Results: A total of 13 patients were enrolled. Twelve patients were eligible for analysis. An average increase of 50% and 46% in mean single-plane ADC was observed after treatment by readers 1 and 2, respectively (P < .01, both reviewers). There was good interobserver agreement of single-plane ADC values between the 2 radiologists (Pearson correlation of 0.85 [baseline] and 0.89 [1-month post-SBRT], P < .001 for both). There was also a significant 18% increase in mean volumetric ADC on the 1-month scan (Wilcoxon P = .02). Two patients developed a local failure after SBRT, 1 at 6 months and the other at 34 months. Using a threshold of volumetric ADC increase of greater than 40%, 2 of 2 patients demonstrated local failure compared with 0 of 10 patients below this limit., Conclusions: A statistically significant increase in ADC was observed 1 month after treatment. An ADC increase of 40% at 1 month was associated with a higher rate of local failure. This pilot study provides impetus for studying ADC as a radiomic biomarker in patients receiving lung SBRT for NSCLC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Anaplastic lymphoma kinase (ALK) gene rearrangements are observed in about 4% to 8% non-small cell lung cancer (NSCLC). ALK+ tumors have been associated with increased pleural and pericardial disease. Our primary objective was to determine the uncommon sites of metastasis of ALK+ NSCLC. Secondary objectives included study of coexisting mutations and factors impacting survival of ALK+ NSCLC., Methods: All patients with metastatic ALK+ NSCLC at the City of Hope Cancer Center in Duarte, California from 2010 to 2017 were selected for retrospective chart review. The demographic variables were collected. The molecular statuses of patients were evaluated through commercially available platforms for next-generation sequencing. Three-dimensional volumetric images were generated for the primary lesion and different sites of metastasis., Results: Sixty two patients with ALK+ NSCLC were identified from 2010 to 2017. The median age was 59 with 36 (58%) female individuals and only 20 (32%) smokers. Twenty four patients had uncommon sites of metastasis which were thyroid, soft tissue, chest and abdominal wall, spleen, peritoneum, omentum, kidney, and ovary. Common characteristics of the primary lesions were right upper lobe location (N=23 [37%]), oval shape (N=22 [35%]), irregular margins (N=26 [42%]), solid lesions (N=27 [44%]), presence of pleural contact or effusion (N=22 [35%]). Twenty four patients had next-generation sequencing testing which showed coexisting mutations such as TP53 (N=8), EGFR (N=5), KRAS (N=3). Patients with uncommon sites of metastasis had a decreased median survival compared with common sites (39 vs. 82 m, P=0.046)., Conclusion: In NSCLC, ALK rearrangements may not be mutually exclusive mutations and can present with unique radiographic patterns. Patients with uncommon sites of metastasis may have worse outcomes.

Pancreas cancer is an aggressive and fatal disease that will become one of the leading causes of cancer mortality by 2030. An all-out effort is underway to better understand the basic biologic mechanisms of this disease ranging from early development to metastatic disease. In order to change the course of this disease, diagnostic radiology imaging may play a vital role in providing a precise, noninvasive method for early diagnosis and assessment of treatment response. Recent progress in combining medical imaging, advanced image analysis and artificial intelligence, termed radiomics, can offer an innovate approach in detecting the earliest changes of tumor development as well as a rapid method for the detection of response. In this chapter, we introduce the principles of radiomics and demonstrate how it can provide additional information into tumor biology, early detection, and response assessments advancing the goals of precision imaging to deliver the right treatment to the right person at the right time.

Background: The contact surface area (CSA) of a tumor with adjacent renal parenchyma may determine the complexity and thus the perioperative outcomes of partial nephrectomy (PN)., Objective: We devised a novel imaging parameter, renal tumor CSA, and correlate it with perioperative outcomes in patients undergoing PN., Design, Setting, and Participants: Of 200 patients undergoing PN for a tumor (January 2010 to August 2011), 162 had renal protocol computed tomography scanning data available. CSA was calculated using image-rendering software (Synapse 3D, Fujifilm), and interobserver variability was determined between three independent observers., Outcome Measurements and Statistical Analysis: CSA was correlated to baseline demographics and perioperative outcomes as a continuous and categorical variable using multivariable logistic regression analysis. The ability of CSA to predict adverse perioperative events was compared with demographic factors and nephrometry scoring systems., Results and Limitations: The mean tumor size was 3.1cm; CSA was 18.3 cm(2). CSA ≥20 cm(2) correlated with adverse tumor characteristics (greater tumor size, volume, and complexity) and perioperative outcomes (more parenchymal volume loss, blood loss, and complications) compared with CSA <20 cm(2). On multivariable logistic regression, CSA independently predicted operative time, complications, hospital stay, and renal functional outcomes. This predictive ability of CSA was superior to the other parameters evaluated., Conclusions: CSA is a novel imaging parameter that quantifies the CSA of renal tumor with adjacent parenchyma. Our preliminary data indicate that CSA correlates with PN outcomes. If validated externally in a larger cohort, CSA could be incorporated into future versions of nephrometry scoring systems., Patient Summary: In this study we outline the method of calculating the contact surface area (CSA) of renal tumors with the surrounding normal kidney using image-rendering software. We found that CSA correlates with a number of important surgical outcomes including operative time, loss of renal function, and complications., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: To determine if oxidative and nitrative stress and/or apoptosis contribute to increased coagulation when combining radiofrequency (RF) ablation with liposomal doxorubicin., Materials and Methods: Animal care committee approval was obtained. R3230 mammary adenocarcinomas in Fischer rats were treated with either RF ablation (n = 43), 1 mg of intravenously injected liposomal doxorubicin (n = 26), or combined therapy (n = 30) and were compared with control subjects (n = 11). A subset of animals receiving combination therapy (n = 24) were treated in the presence or absence of N-acetylcysteine (NAC) administered 24 hours and 1 hour before RF ablation. Tumors were analyzed 2 minutes to 72 hours after treatment to determine the temporal range of response by using immunohistochemical staining of the apoptosis marker cleaved caspase-3, phosphorylated gammaH2AX, and HSP70 and of markers of oxidative and nitrative stress (8-hydroxydeoxyguanosine [8-OHdG], 4-hydroxynonenal [4-HNE]-modified proteins, and nitrotyrosine [NT]). Statistical analyses, including t tests and analysis of variance for comparisons where appropriate, were performed., Results: By 4 hours after RF ablation alone, a 0.48-mm +/- 0.13 (standard deviation) peripheral band with 57.0% +/- 7.3 cleaved caspase-3 positive cells was noted at the ablation margin, whereas a 0.73-mm +/- 0.18 band with 77.7% +/- 6.3 positivity was seen for combination therapy (P < .03 for both comparisons). Combination therapy caused increased and earlier staining for 4-HNE-modified proteins, 8-OHdG, NT, and gammaH2AX with colocalization to cleaved caspase-3 staining. A rim of increased HSP70 was identified peripheral to the area of cleaved caspase-3. Parameters of oxidative and nitrative stress were significantly inhibited by NAC 1 hour following RF ablation, resulting in decreased cleaved caspase-3 positivity (0.28-mm +/- 0.09 band of 25.9% +/- 7.4 positivity vs 0.59-mm +/- 0.11 band of 62.9% +/- 6.0 positivity, P < .001 for both comparisons)., Conclusion: Combining RF ablation with liposomal doxorubicin increases cell injury and apoptosis in the zone of increased coagulation by using a mechanism that involves oxidative and nitrative stress that leads to accelerated apoptosis., (RSNA, 2010)

Purpose: To determine if apparent diffusion coefficient (ADC) histogram analysis can stratify progression-free survival in patients with recurrent glioblastoma multiforme (GBM) prior to bevacizumab treatment., Materials and Methods: The study was approved by the institutional review board and was HIPAA compliant; informed consent was obtained. Bevacizumab-treated and control patients (41 per cohort) diagnosed with recurrent GBM were analyzed by using whole enhancing tumor ADC histograms with a two normal distribution mixture fitting curve on baseline (pretreatment) magnetic resonance (MR) images to generate ADC classifiers, including the overall mean ADC as well as the mean ADC from the lower curve (ADC(L)). Overall and 6-month progression-free survival (as defined by the Macdonald criteria) was determined by using Cox proportional hazard ratios and the Kaplan-Meier method with log-rank test., Results: For bevacizumab-treated patients, the hazard ratio for progression by 6 months in patients with less than versus greater than mean ADC(L) was 4.1 (95% confidence interval: 1.6, 10.4), and there was a 2.75-fold reduction in the median time to progression. For the control patients, there was no significant difference in median time to progression for the patients with low versus high ADC(L) (hazard ratio, 1.8; 95% confidence interval: 0.9, 3.7). For bevacizumab-treated patients, pretreatment ADC more accurately stratified 6-month progression-free survival than did change in enhancing tumor volume at first follow-up (73% vs 58% accuracy, P = .034)., Conclusion: Pretreatment ADC histogram analysis can stratify progression-free survival in bevacizumab-treated patients with recurrent GBM., ((c) RSNA, 2009.)

Objective: The objective of our study was to determine whether perfusion CT can be used to detect early changes in therapeutic response to antiangiogenic therapy in an animal tumor model., Materials and Methods: Twenty-five rats implanted with R3230 mammary adenocarcinoma (diameter, 1.2-2.0 cm) randomly received 7.5 or 30 mg/kg of an antiangiogenic agent, sorafenib, by daily gavage for 4 (n = 4), 9 (n = 9), or 14 (n = 5) days. Seven untreated animals served as a control group. Perfusion MDCT was performed at days 0, 4, 9, and 14 with 0.4 mL of ioversol (350 mg/mL) and included four 5-mm slices covering the entire tumor volume. Changes in tumor growth were determined by volumetric analysis of CT data. Serial changes in tumor volume and blood flow were assessed and correlated with pathology findings., Results: All control tumors grew larger (from 2.0 +/- 0.7 cm(3) at day 0 to 5.9 +/- 1.0 cm(3) at day 14), whereas all treated tumors shrank (from 2.5 +/- 1.1 to 2.1 +/- 1.0 cm(3)), with a statistically significant rate of growth or shrinkage in both groups (p < 0.05). Although perfusion in the control tumors changed little from day 0 to day 14 (day 0, 18.1 +/- 9.2 mL/min/100 g; day 4, 15.8 +/- 5.6; day 9, 21.7 +/- 12.2; day 14, 27.7 +/- 34), in the sorafenib group, the mean blood flow was significantly lower at day 4 (5.2 +/- 3.2 mL/min/100 g, 77% decrease), day 9 (6.4 +/- 4.0 mL/min/100 g, 66% decrease), and day 14 (6.3 +/- 5.2 mL/min/100 g, 83% decrease) compared with day 0 (23.8 +/- 11.6 mL/min/100 g) (p < 0.05). Poor correlation was seen between changes in blood flow and tumor volume for days 0-9 (r(2) = 0.34), 4-9 (r(2) = 0.0004), and 9-14 (r(2) = 0.16). However, when comparing day 4 images with days 9 and 14 images, seven of 14 (50%) sorafenib-treated tumors had focal areas of new perfusion that correlated with areas of histopathologic viability despite the fact that these tumors were shrinking in size from day 4 onward (day 4, 2.18 +/- 0.8 cm(3); day 9, 1.98 +/- 0.8 cm(3))., Conclusion: Perfusion MDCT can detect focal blood flow changes even when the tumor is shrinking, possibly indicating early reversal of tumor responsiveness to antiangiogenic therapy. Given that changes in tumor volume after antiangiogenic therapy do not necessarily correlate with true treatment response, physiologic imaging of tumor perfusion may be necessary.

Neph1-deficient mice develop nephrotic syndrome at birth, indicating the importance of this protein in the development of a normal glomerular filtration barrier. While the precise subcellular localization of Neph1 remains unknown, its relationship with other components of the glomerular filtration barrier is of great interest in this field. In this paper, we localize the expression of Neph1 to the glomerular slit diaphragm by immunogold electron microscopy in rodents and describe its direct interaction with two other components of the slit diaphragm, nephrin and ZO-1. Both native and recombinant Neph1 associate with each other as dimers and multimers and interact with nephrin via their extracellular segments. Disruption of the Neph1-nephrin interaction in vivo by injecting combinations of individual subnephritogenic doses of anti-Neph1 and anti-nephrin results in complement- and leukocyte-independent proteinuria with preserved foot processes. This disruption modestly reduces Neph1 and nephrin protein expression in podocytes and dramatically reduces ZO-1 protein expression via the interaction of ZO-1 PDZ domains with the cytoplasmic tail of Neph1, independent of changes in mRNA expression of all three genes. The interaction between nephrin and Neph1 is specific and not shared by either protein with P-cadherin, another integral slit diaphragm protein. The interaction between nephrin and Neph1 therefore appears to be an important determinant of glomerular permeability.