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Introduction Endobronchial ultrasound (EBUS)-guided transbronchial needle aspirate (TBNA) is a widely used method of minimally invasive lymph node sampling. The benefit of processing samples by cytologic methods versus “core biopsy” is unclear. It is unknown if safety or diagnostic yield varies by needle gauge. Materials and Methods Between June 2018 and July 2019, 40 patients (56 lesions) undergoing EBUS TBNA lymph node evaluation were enrolled in this single center prospective trial. Patients were chosen by permuted block randomization to undergo EBUS TBNA starting with 22-gauge or 19-gauge needles. Separate samples were sent for processing by cytologic methods and histopathology. Surgical pathologists and cytopathologists were blinded to needle size. The primary endpoint was diagnostic yield. Secondary endpoints compared specimen adequacy by rapid on-site evaluation (ROSE), sample adequacy for molecular testing, sample quality, and safety. Results Diagnostic yield for histopathologic examination was 87.5% and 83.9% for 19g and 22g respectively (P-value 0.625). There was no significant difference in diagnostic yield by cytologic examination based on needle size. There was no significant difference in slide quality. Molecular adequacy for core-biopsy was 77% and 80% for 22-gauge and 19-gauge needles, respectively. Molecular adequacy for cytology cell block was 77% and 80% for 22-gauge and 19-gauge needles, respectively. There were no significant procedural complications. Conclusion Both the 22-gauge and 19-gauge EBUS TBNA needles provided a similar diagnostic yield and clinical utility for ancillary testing. Processing techniques by cytologic methods or “core biopsy” showed no significant impact in diagnostic yield or utility of molecular testing.

Background: Inflammatory breast cancer (IBC) is characterized by a young age at diagnosis, high metastatic potential, and poor overall survival. To better understand the etiology of this aggressive disease, we performed a retrospective study to evaluate genomic alterations and tumor microenvironment in IBC patients. Methods: Targeted next generation sequencing (NGS) was performed using blood cell-free DNA (cfDNA) (n=32), paired DNA from tumor tissues (n=29) and DNA from whole blood or normal tissue (n=20). We also characterized the tumor infiltrating lymphocytes (TILs) in tumor tissue biopsies by studying several markers (CD4, CD8, FoxP3, CD20, PD-1 and PD-L1) through immunohistochemistry (IHC) staining. Results: Our results shown a high incidence of germline variants in patients with IBC that could be associated with an increased risk of developing the disease. Germline variants were found more frequently in patients with TN (38.9%) than non-TN IBC (28.6%). IHC staining revealed that in 7 of 24 (29%) patients, tumor biopsies were positive for PD-L1 and PD-1 expression on TILs. Patients with PD-L1&PD-1 positive biopsies had a lower OS (31 months) than patients with PD-L1&PD-1 negative (38 months) tumors, though the difference was not statistically significant. PD-L1&PD-1 positive tumors had significantly more CD8+ (cytotoxic T-cells), CD20+ (B-cells) and FoxP3+ (Tregs) cells than PD-L1&PD-1 negative ones. Furthermore, most IBC patients showed to have deficiencies in the homologous recombination repair (HRR) pathway (BRCA1, BRCA2, PALB2, RAD51C, ATM, BARD1) making them sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. All tumor biopsies showed positive staining for p-FAK1(Tyr 397). Conclusion: A subset of IBC patients (29%) expressed both PD-L1 and PD-1 on tumor immune cells infiltrates, providing rationale for testing PD-1/PD-L1 blocking therapies. IBC patients could have benefits from PD-1/PD-L1 blocking therapies alone or in combination with PARP or FAK (Tyr397) kinase inhibitors, both having the capacity of altering the tumor microenvironment. Citation Format: Maria F. Arisi, Yulan Gong, Rajeswari Nagarathinam, Lorenzo Gerratana, Jianming Pei, Kathy Q. Cai, Jennifer Winn, Zachary Hasse, Elias Obeid, Julio Noriega, Christopher Sebastiano, Eric Ross, R. Katherine Alpaugh, Massimo Cristofanilli, Sandra V Fernandez. Genetic variants and tumor microenvironment in inflammatory breast cancer: Clues for targeted therapies [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-24-02.

Targeted therapy is an important part of the treatment of lung adenocarcinoma. Tests for EGFR mutation, ALK, ROS1, RET and NTRK gene fusions are needed to make a treatment decision. These gene fusions are traditionally detected by fluorescence in situ hybridisation (FISH) or immunohistochemistry. In this study, we investigated whether gene fusions in pulmonary adenocarcinoma could be accurately detected by RNA next-generation sequencing (RNA-NGS) and whether cytology cell blocks could be used effectively for this test.Archived cytological specimens of lung adenocarcinoma submitted for RNA sequencing between 2019 and 2022 at Fox Chase Cancer Center were retrospectively retrieved. Hybrid capture-based targeted RNA next generation sequencing was used, which covers 507 fusion genes, including ALK, ROS1, RET and NTRKs, irrespective of their partner genes. DNA NGS, FISH and chromosomal microarray analysis were used to confirm the results of the RNA-NGS.A total of 129 lung adenocarcinoma cytology specimens were submitted for molecular testing. Eight of 129 (6.2%) cases were excluded from RNA sequencing as their cell blocks contained inadequate numbers of tumour cells. One case (0.8%) failed to yield adequate RNA. The overall success rate was 93% (120/129). Ten of 120 (8.3%) cytology cases were positive for gene fusions, including 7 ALK, 2 ROS1 fusion genes, and 1 RET fusion gene. Twenty-two cell block cases were also tested for ALK fusion genes using FISH. However, 11 of 22 (50%) failed the testing due to inadequate material.Cytology cell blocks can be used as the main source of material for molecular testing for lung cancer. Detection of gene fusions by RNA-based NGS on cell blocks is convenient and reliable in daily practice.

Background Inflammatory breast cancer (IBC) is a rare but aggressive carcinoma characterized by severe erythema and edema of the breast, with many patients presenting in advanced metastatic disease. The “inflammatory” nature is not due to classic immune-mediated inflammation, but instead results from tumor-mediated blockage of dermal lymphatic ducts. Previous work has shown that expression of PD-L1 on tumor cells can suppress T cell activation in triple-negative (TN) non-IBC breast cancer. In the present work, we investigated immune parameters in peripheral blood of metastatic IBC patients to determine whether cellular components of the immune system are altered, thereby contributing to pathogenesis of the disease. These immune parameters were also compared to PD-1 and PD-L1 expression in IBC tumor biopsies. Methods Flow cytometry-based immune phenotyping was performed using fresh peripheral blood from 14 stage IV IBC patients and compared to 11 healthy age-similar control women. Immunohistochemistry for CD20, CD3, PD-1, and PD-L1 was performed on tumor biopsies of these metastatic IBC patients. Results IBC patients with Stage IV disease had lymphopenia with significant reductions in circulating T, B, and NK cells. Reductions were observed in all subsets of CD4+ T cells, whereas reductions in CD8+ T cells were more concentrated in memory subsets. Immature cytokine-producing CD56bright NK cells expressed higher levels of FcγRIIIa and cytolytic granule components, suggesting accelerated maturation to cytolytic CD56dim cells. Immunohistochemical analysis of tumor biopsies demonstrated moderate to high expression of PD-1 in 18.2% of patients and of PD-L1 in 36.4% of patients. Interestingly, a positive correlation was observed between co-expression levels of PD-L1 and PD-1 in tumor biopsies, and higher expression of PD-L1 in tumor biopsies correlated with higher expression of cytolytic granule components in blood CD4+ T cells and CD56dim NK cells, and higher numbers of CD8+ effector memory T cells in peripheral blood. PD-1 expression in tumor also correlated with increased infiltration of CD20+ B cells in the tumor. Conclusions Our results suggest that while lymphocyte populations are severely compromised in stage IV IBC patients, an immune response toward the tumor had occurred in some patients, providing biological rationale to evaluate PD-1/PD-L1 immunotherapies for IBC.

While Ras/mitogen-activated protein kinase (MAPK) signaling is activated in most human cancers, attempts to target this pathway using kinase active site inhibitors have not typically led to durable, clinical benefit. To address this shortcoming, we sought to test the feasibility of an alternative targeting strategy, focused on the ERK2 substrate binding domains, D and DBP. We found that disabling the ERK2-DBP domain in mice caused baseline erythrocytosis. Consequently, we investigated the role of the ERK2-D and -DBP domains in disease, using a JAK2-dependent model of polycythemia vera (PV). Importantly, inactivation of the ERK2-DBP domain promoted the progression of disease from PV to myelofibrosis (MF), suggesting that the ERK2-DBP domain normally opposes progression. ERK2-DBP inactivation also prevented oncogenic JAK2 kinase (JAK2V617F) from promoting oncogene-induced senescence (OIS) in vitro. The ERK2-DBP mutation attenuated JAK2-mediated OIS by preventing the physical interaction of ERK2 with the transcription factor, Egr1. Because inactivation of the ERK2-DBP created a functional ERK2 kinase limited to binding substrates through its D-domain, these data suggested that the D-domain substrates were responsible for promoting oncogene-induced progenitor growth and tumor progression, and that pharmacologic targeting of the ERK2-D domain might attenuate cancer cell growth. Indeed, pharmacologic agents targeting the ERK2-D domain were effective in attenuating the growth of JAK2-dependent myeloproliferative neoplasm cell lines. Taken together, these data indicate that the ERK-D and -DBP domains can play distinct roles in the progression of neoplasms and that the D-domain has the potential to be potent therapeutic target in Ras/MAPK dependent cancers.

Background and Objective: Robotic bronchoscopy has demonstrated high navigational success in small peripheral lung nodules but the diagnostic yield is discrepantly lower. Needle based confocal laser endomicroscopy (nCLE) enables real-time microscopic imaging at the needle tip. We aim to assess feasibility, safety and needle repositioning based on real-time nCLE-guidance during robotic bronchoscopy in small peripheral lung nodules. Methods: Patients with suspected peripheral lung cancer underwent fluoroscopy and radial EBUS assisted robotic bronchoscopy. After radial EBUS nodule identification, nCLE-imaging of the target area was performed. nCLE-malignancy and airway/lung parenchyma criteria were used to identify the optimal sampling location. In case airway was visualized, repositioning of the biopsy needle was performed. After nCLE tool-in-nodule confirmation, needle passes and biopsies were performed at the same location. Measurements and Main Results: Twenty patients were included (final diagnosis n = 17 (lung) cancer) with a median lung nodule size of 14.5 mm (range 8–28 mm). No complications occurred. In 19/20 patients, good quality nCLE-videos were obtained. In 9 patients (45%), real-time nCLE-imaging revealed inadequate positioning of the needle and repositioning was performed. After repositioning, nCLE-imaging provided tool-in-nodule-confirmation in 19/20 patients. Subsequent ROSE demonstrated representative material in 9/20 patients (45%) and overall diagnostic yield was 80% (16/20). Of the three patients with malignant nCLE-imaging but inadequate pathology, two were diagnosed with malignancy during follow-up. Conclusion: Robotic bronchoscopic nCLE-imaging is feasible and safe. nCLE-imaging in small, difficult-to-access lung nodules provided additional real-time feedback on the correct needle positioning with the potential to optimize the sampling location and diagnostic yield.

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death. Advancements in navigational bronchoscopy have shown encouraging results but the diagnostic yield of small lung nodules by bronchoscopic techniques is still below that of transthoracic needle aspiration. The development of robotic bronchoscopy has demonstrated a significantly improved navigational success but the diagnostic yield is regularly limited by near-miss of the target nodule. Needle-based confocal laser endomicroscopy is a novel imaging technique that allows for the real-time visualization of individual cells and structures with microscopic resolution at the tip of the needle. We present the first reported case of confocal laser endomicroscopy guided robotic bronchoscopy for the real-time diagnosis of a small, partially cystic lung nodule.

To better understand the etiology of inflammatory breast cancer (IBC) and identify potential therapies, we studied genomic alterations in IBC patients. Targeted, next-generation sequencing (NGS) was performed on cell-free DNA (cfDNA) (n = 33) and paired DNA from tumor tissues (n = 29) from 32 IBC patients. We confirmed complementarity between cfDNA and tumor tissue genetic profiles. We found a high incidence of germline variants in IBC patients that could be associated with an increased risk of developing the disease. Furthermore, 31% of IBC patients showed deficiencies in the homologous recombination repair (HRR) pathway (BRCA1, BRCA2, PALB2, RAD51C, ATM, BARD1) making them sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. We also characterized the tumor-infiltrating lymphocytes (TILs) in tumor tissue biopsies by studying several markers (CD4, CD8, FoxP3, CD20, PD-1, and PD-L1) through immunohistochemistry (IHC) staining. In 7 of 24 (29%) patients, tumor biopsies were positive for PD-L1 and PD-1 expression on TILs, making them sensitive to PD-1/PD-L1 blocking therapies. Our results provide a rationale for considering PARP inhibitors and PD-1/PDL1 blocking immunotherapy in qualifying IBC patients.

Background & Aims In the West, early gastric cancer is increasingly managed with endoscopic resection (ER). This is, however, based on the assumption that the low prevalence and risk of lymph node metastases observed in Asian patients is applicable to patients in the United States. We sought to evaluate the frequency of and factors associated with metastasis of early gastric cancers to lymph nodes, and whether the Japanese ER criteria are applicable to patients in the US. Methods We performed a retrospective study of 176 patients (mean age 68.5 years; 59.1% male; 58.5% white) who underwent surgical resection with lymph node dissection of T1 and Tis gastric adenocarcinomas, staged by pathologists, at 7 tertiary care centers in the US from January 1, 1999, through December 31, 2016. The frequency of lymph node metastases and associated risk factors were determined. Results The mean size of gastric adenocarcinomas was 23.0 ± 16.6 mm—most were located in the lower-third of the stomach (67.0%), invading the submucosa (55.1%), and moderately differentiated (31.3%). Lymphovascular invasion was observed in 18.2% of lesions. Overall, 20.5% of patients had lymph node metastases. Submucosal invasion (odds ratio, 3.9; 95% CI, 1.4–10.7) and lymphovascular invasion (odds ratio, 4.6; 95% CI, 1.8–12.0) were independently associated with increased risk of metastasis to lymph nodes. The frequency of lymph node metastases among patients fulfilling standard and expanded Japanese criteria for ER were 0 and 7.5%, respectively. Conclusions The frequency of lymph node metastases among patients with early gastric cancer in a US population is higher than that of published Asian series. However, early gastric cancer lesions that meet the Japanese standard criteria for ER are associated with negligible risk of metastasis to lymph nodes, so ER can be recommended for definitive therapy. Expanded criteria cancers appear to have a higher risk of metastasis to lymph nodes, so ER may be considered for select cases.

In the gastro-entero-pancreatic (GEP) tract, neuroendocrine neoplasms (NENs) include well differentiated neuroendocrine tumors (NETs) and high-grade NE carcinomas (NECs), which are thought to make up separate and mutually exclusive tumor entities. Little is known, however, as to whether there may be any pathogenetic link between them. Clustering analysis of a 10-gene panel generated from a previously reported next-generation sequencing analysis on 48 GEP-NENs with clinical annotations was used in the study. Unsupervised cluster analysis showed three histology-independent clusters, namely, C1, C2, and C3, which accounted for 44% of patients but the entire array of mutations. All but two NECs fell into the clusters, yet with different prevalence rates (p

We present a low-grade follicular lymphoma case with highly unusual ancillary study results. The patient is a 50-year-old female with a 4.3 x 3.8 x 2.2 cm left inguinal mass, from which fine needle aspiration and excisional biopsy specimens were obtained. H&E sections showed effacement of the lymph node architecture by closely packed follicles comprised of mainly centrocytes and without tingible body macrophages. Immunohistochemical stains revealed the follicle cells positive for CD20, PAX5, BCL6, CD10 (weak), and BCL2 (weak), while CD3 highlighted small T lymphocytes mainly in the interfollicular areas.

Additional file 1.

Paragangliomas are rare neuroendocrine tumors that can vary in size and metabolic activity. We report a case of giant bilateral malignant retroperitoneal paragangliomas (PGL) in a patient with germline succinate dehydrogenase B (SDHB) mutation. This patient, who presented in an emaciated and debilitated state, was managed with adrenergic blockade followed by radical primary surgery. After being metabolically and radiographically disease free for 4 years, he underwent salvage resection for recurrent retroperitoneal disease and palliative radiation to a site of solidary vertebral metastasis. We review incidence and prognosis of metastatic PGL.

The interaction between ERK2 and its substrates is critically mediated by two domains, the common docking (CD) D-domain and DEF-binding pocket (DBP) domain. Previous studies have suggested that ERK2 is not only necessary to drive hematopoietic and myelo-erythroid development, but it is also important for the pathogenesis of hematological cancers, as revealed by recurrent ERK2 somatic mutations in many types of lymphoma and leukemia. Here we show that the activation of ERK2 in JAK2V617F-driven myeloproliferative neoplasm (MPN) enhance polycythemia vera (PV) progression from erythrocytosis to myelofibrosis when ERK2-DBP binding capacity is disabled. Conversely, targeting the ERK2 D-domain preserves ERK2 catalytic function while reducing outgrowth and proliferation of human and murine MPN cell lines. To determine whether ERK2 binding domains play a role in the pathogenesis of JAK2V617F-driven MPN, we generated an ERK2-Y261A (Erk2 Y261A) mutant knockin mouse model in which the ERK2-DBP domain was inactivated, but ERK2 kinase activity and D-domain function was preserved. We observed splenomegaly in Erk2 Y261A/Y261A, characterized by a 10-fold expansion of CD44+/Ter119+ primitive erythroblasts and Ter119+CD44+/ FSC hi immature erythroid progenitors. We then transplanted Jak2 V617F-expressing ERK2 wildtype (WT), knockout (KO) or DBP hematopoietic progenitors (HSPCs) into irradiated, immunodeficient mice (Rag2 −/−Il2rg −/−) and observed disease resembling human PV, with elevated RBC counts, hematocrit, and hemoglobin levels. ERK2-DBP mutant recipients exhibited mild but sustained erythrocytosis with a prevalence of circulating GFP+ monocytes and neutrophils. At 12-weeks post-transplantation, ERK2-DBP mutant recipients had significant splenic burden and decreased bone marrow cellularity relative to WT and KO recipients. Reticulin staining confirmed progression towards myelofibrosis with interstitial infiltration in both the BM and the spleen of ERK2 DBP mutant recipients. To understand the molecular basis of ERK-DBP domain in JAK2V617F-driven MPN, we performed in vitro colony forming unit assay to assess the clonogenic potential of JAK2V617F-expressing HSPCs in cytokine supplemented-methylcellulose supporting myeloid or erythroid progenitor development. Ectopic JAK2V617F expression markedly reduced colony formation by both ERK2 wildtype and knockout HSPCs. On the other hand, JAK2V617F expression did not reduce colony formation by ERK2-DBP HSPCs. These differences were not evident in methylcellulose cultures that supported erythroid development, suggesting that disabling ERK-DBP binding capacity primarily affects the myeloid lineage. Furthermore, we found that JAK2V617F increased senescence associated β-galactosidase (SA-βGa) activity in ERK2-WT HSPCs. SA-βGal activity was modestly affected by ERK deficiency but was strongly attenuated by the ERK2-DBP mutation, supporting the notion that ERK2-DBP domain promotes oncogene-induced senescence (OIS). Previously, we identified transcription factor, Early growth response 1 (Egr1) which interacts with ERK2-DBP domain and plays a critical role as a tumor suppressor in myeloid neoplasms. We observed that JAK2V617F expression failed to suppress colony formation and senescence by Egr1-deficient HSPCs. The ability of EGR1 to restore these effects is abrogated by inactivating the DEF motif (EGR1-Y252A). Together, this data demonstrates that the interaction between ERK2-DBP and Egr1 is required for JAK2V617F-mediated colony suppression and senescence induction. Finally, to determine whether ERK-D domain acts to promote progression by targeting substrates distinct from those that bind to the DBP domain, we developed an inhibitor (#76) of the ERK-D domain. Indeed, 76 spared ERK phosphorylation and EGR1 induction but impaired RSK phosphorylation, a critical D-domain substrate involved in cancer progression. Moreover, 76 suppressed colony formation by JAK2V61F-expressing HSPCs akin to the active site MEK/ERK inhibitor, U0126. By altering the 4-ethoxybenylidene moiety of 76, we were able to enhance anti-proliferative effects of the parent compound against human MPN cell lines, SET-2, UKE-1, and Ku812. Our findings identify ERK2-domain specific roles in the pathogenesis of JAK2V617F driven MPN and supports a novel therapeutic approach to targeting JAK2 and MAPK dependent MPN. Disclosures Levine: Celgene: Research Funding; QIAGEN: Membership on an entity's Board of Directors or advisory committees; Auron: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Mission Bio: Membership on an entity's Board of Directors or advisory committees; Zentalis: Membership on an entity's Board of Directors or advisory committees; Ajax: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Lilly: Honoraria; Janssen: Consultancy; Astellas: Consultancy; Gilead: Honoraria; Prelude: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy; Roche: Honoraria, Research Funding; Imago: Membership on an entity's Board of Directors or advisory committees. Wiest: Janssen Pharmaceuticals: Research Funding.

In this work, a surface mechanical attrition treatment (SMAT) process was applied to AZ31B magnesium alloy at room temperature. This method produced a gradient structure on the treated AZ31B, in which the grains of the topmost layer are refined to nanoscale sizes. A combination of nanocrystallites at the surface and coarse-grains in the center are the main features of this structure. This structure results in an excellent combination of both strength and ductility. The highest yield strength for the 30 minutes SMAT AZ31B samples increased to 249 ± 5 MPa and the uniform elongation decreased to 9.3 ± 0.8 pct, whereas the original yield strength was only 147 ± 4 MPa and the uniform elongation was 15.4 ± 1.1 pct. Microstructural observations, stress relaxation tests, and hardness tests were used to verify the results. Additionally, there is a specific volume fraction of gradient structure to achieve the best mechanical performance, which is shown to be in the range of 9.3 to 14 pct for the AZ31B alloy.

Using surface mechanical attrition treatment (SMAT), a gradient structure composed of two gradient structure (GS) layers and a coarse grain (CG) layer was generated from a Cu-5.7 wt pct Ge alloy, significantly improving the yield strength of the sample. Unloading–reloading tests showed an unusual Bauschinger effect in these GS samples. The back stresses caused by the accumulated geometrically necessary dislocations (GNDs) on the GS/CG border increased with increasing strain. As found by electron backscatter diffraction (EBSD), the GNDs are mainly distributed in the gradient structured layer, and the density of the GNDs increase with increasing SMAT time. The effect of the back stress increased with increasing SMAT processing time due to the increase in the strain gradient. The pronounced Bauschinger effect in a GS sample can improve the resistance to forward plastic flow and finally contributes to the high strength of GS samples.

The growth of disseminated tumor cells (DTCs) into metastatic lesions depends on the establishment of a favorable microenvironment in the stroma of the target organs. Here we show that mice treated with anakinra, an antagonist of the IL-1β receptor (IL-1R), or harboring a targeted deletion of IL-1R are significantly less prone to develop bone tumors when inoculated in the arterial circulation with human prostate cancer (PCa) cells expressing IL-1β. Interestingly, human mesenchymal stem cells (hMSCs) exposed in vitro to medium conditioned by IL-1β-expressing cancer cells responded by up regulating S100A4, a marker of cancer-associated fibroblasts (CAFs), and this effect was blocked by anakinra. Analogously, the stroma adjacent to skeletal metastases generated in mice by IL-1β-expressing cancer cells showed a dramatic increase in S100A4, COX-2 and the alteration of thirty tumor-related genes as measured by Nanostring analysis. These effects were not observed in the stroma associated to the rare and much smaller metastases generated by the same cells in IL-1R knockout animals, confirming that tumor-secreted IL-1β generates skeletal CAFs and conditions the surrounding bone microenvironment. In skeletal lesions from patients with metastatic PCa, histological and molecular analyses revealed that IL-1β is highly expressed in cancer cells in which the androgen receptor (AR) is not detected (AR−) whereas this cytokine is uniformly absent in the AR-positive (AR+) metastatic cells. The stroma conditioned by IL-1β-expressing cancer cells served as a supportive niche also for coexisting IL-1β-lacking cancer cells, which are otherwise unable to generate tumors after independently seeding the skeleton of mice. This niche is established very early following tumor seeding and hints to a role of IL-1β in promoting early colonization of PCa at the skeletal level.

In this paper, a series of Cu-Al alloys (2.2, 4.5, and 6.9 wt pct Al) with decreasing stacking fault energy (SFE) were processed by surface mechanical attrition treatment (SMAT) to obtain a gradient structure (GS). The yield strength of SMAT-ed samples is attributed to the volume fraction of GS layer and the ductility is associated with the dynamic recovery during deformation. Kocks-Mecking model was utilized to describe the storage and annihilation of dislocations in these samples. The results show that the minimal K2, which represents dynamic recovering, appears in Cu-4.5 wt%Al alloy with a medium SFE, indicating a suppressed dislocation annihilation and a delayed plastic instability during plastic deformation. Repeated stress relaxation tests were applied to characterize the activation volume and the evolution of mobile dislocation. It turns out that the highest relative mobile dislocation density (ρ m /ρ m0 ) emerges in Cu-4.5 wt%Al sample. This could be ascribed to the sufficient twin boundaries (TBs) which can keep the accumulated dislocations slipping easily and lower the exhaustion of mobile dislocation. The high ρ m /ρ m0 demonstrates that more mobile dislocation is preserved and the dislocation annihilation is effectively prohibited in the sample, in accordance with the low K2 obtained from Kocks–Mecking model, providing a reasonable interpretation for the good ductility.

A tissue floater or extraneous cross-contamination tissue on a microscopic slide is rare; however, it is a potential cause of diagnostic error. Occasionally, on collecting and processing of specimens, cross-contamination of tissue occurs leading to pathologic findings that are inconsistent with endoscopic findings. If the extraneous tissue is neoplastic, it can lead to a false-positive diagnosis. We present a case of discordant pathological and endoscopic diagnosis of invasive squamous carcinoma of the esophagus.

By using surface mechanical attrition treatment (SMAT) at room temperature, a gradient structure (GS) is generated in the surface layer of bulk pure copper samples, which exhibits good uniform elongation and high yield strength simultaneously. Changing SMAT processing time leads to different gradient structures with various component fractions and therefore tune their mechanical properties. The yield strength of the SMAT samples is much higher than the sum of standalone GS layer and coarse-grained (CG) matrix, indicating a synergetic strengthening. Repeated stress relaxation tests were performed to characterize the evolution of mobile dislocations. It was found that the relative mobile dislocation density of SMAT processed sample first drops and then increases with increasing tensile strain. The evolution of mobile dislocations correlates well with strain-hardening evolution. These observations provide insight for the superior combination of high strength and good ductility in SMAT samples. Keywords: Gradient structure, Mechanical properties, Mobile dislocation density, Synergetic strengthening, Pure copper, Surface mechanical attrition treatment

Background: The rarity of neuroendocrine malignancies limits the ability to develop new therapies and thus a better understanding of the underlying biology is critical. Methods: Through a prospective, IRB-approved protocol, patients with neuroendocrine malignancies underwent next-generation sequencing of their tumours to detect somatic mutations (SMs) in 50 cancer-related genes. Clinicopathologic correlation was made among poorly differentiated neuroendocrine carcinomas (NECs/poorly differentiated histology and Ki-67 >20%) and pancreatic neuroendocrine tumours (PanNETs/Ki67 ⩽20%) and non-pancreatic neuroendocrine tumours (NP-NETs/Ki67 ⩽20%). Results: A total of 77 patients were enrolled, with next-generation sequencing results available on 63 patients. Incidence of SMs was 83% (19 out of 23) in poorly differentiated NECs, 45% (5 out of 11) in PanNETs and 14% (4 out of 29) in NP-NETs. TP53 was the most prevalent mutation in poorly differentiated NECs (57%), and KRAS (30%), PIK3CA/PTEN (22%) and BRAF (13%) mutations were also found. Small intestinal neuroendocrine tumours (Ki67

Three nanostructured Cu-Al-Zn alloys were produced via rolling at the liquid nitrogen temperature. The deformed Cu alloys were then annealed at 150–300 °C for 1 h. The two alloys with high solute content and thus with low stacking fault energy exhibit unusual annealing hardening, namely, an increase in hardness and strength and a decrease in tensile elongation after annealing at 150 and 200 °C. From X-ray diffraction (XRD) analysis and microstructural observations by transmission electron microscopy (TEM), it is found that microstrain and dislocation density decrease after annealing at 200 °C because of the recovery of dislocations and the lattice parameter decreases due to solute segregation. Meanwhile, the twin density of the two Cu alloys increases and grain size remains basically unchanged. It is shown that the formation of annealing twins and stacking faults and the segregation of solute atoms may be the main causes of unusual annealing hardening.

Herein, Cu and Cu–Ge alloys with different stacking fault energies (SFEs) are prepared via rolling at room temperature (RTR) and via a combination of high-pressure torsion (HPT) and RTR (HPT + RTR). The x-ray diffraction measurements reveal that the grain size, dislocation density, and twin density vary with the strain and SFEs. The tensile tests indicate that the strength of materials with medium SFEs increases initially and then slightly declines, while the ductility is enhanced by increasing the strain via HPT. In contrast, for low-SFE materials, enhanced strength and improved ductility may be achieved simultaneously through increasing the strain to a high level. The variation of strength with respect to strain is primarily dependent on the solute concentration and SFE. The underlying mechanisms governing the effect of strain and SFE on the microstructures and mechanical properties of the metals are also discussed.

This article aims to investigate the mechanical properties of the gradient structured (GS) Cu–Al–Zn alloys. To prepare the GS samples, three kinds of Cu–Al–Zn alloys with different stacking fault energies (SFEs) were processed by surface mechanical attrition treatment (SMAT) at cryogenic temperature. The results show that the Cu-5.5%Al-4.5%Zn alloy having the lowest SFE processed by SMAT for 5 min exhibits an optimized combination of strength and ductility. For both the initial annealed sample and the SMAT samples processed for the same processing time, uniform elongation (UE) and ultimate tensile strength (UTS) increase with decreasing SFE, whereas the yield strength (YS) is not sensitive to SFE. In the case of the same SFE, as the SMAT processing time increases, the YS and UTS of the GS alloy increase and the UE decrease. The optimized SMAT processing time can sufficiently refine the grains in the GS layer, which can increase the strength and maintain good ductility. Also, sufficient grain refinement promotes the better accumulation of geometrically necessary dislocations (GNDs), thus forming rather effective hetero-deformation induced (HDI) stress strengthening and HDI hardening to enhance strength while maintaining good ductility. The combination of low SFE and optimized SMAT processing time is beneficial to obtain an optimized combination of strength and ductility. Additionally, since the near-surface layer of the GS material is plastically deformed earlier than the sub-surface layer, the accumulation of GNDs at the interface between the two layers also contributes to HDI strengthening and HDI hardening to improve strength and ductility.

In order to better understand the etiology of inflammatory breast cancer (IBC), we performed a retrospective study to evaluate genomic alterations in 32 IBC patients using circulating DNA from blood. In 20 patients, mutation analyses were also conducted on tumor tissue or tumor cells from pleural effusions; in 15 of these patients, blood and tissue or pleural effusions were collected at the same time. Next generation sequencing (NGS) and a panel of 93 breast cancer related genes (Qiagen) were used for these studies. We found that of the 32 total patients, 11 (34.4%) carried at least one putative pathogenic germline variant, and another 8 patients (25%) carried at least one likely pathogenic germline variant. Ten patients (31.3%) carried only germline variants of uncertain significance and in 3 patients (9.4%) germline variants were not detected. Putative germline pathogenic variants were observed in the BRCA2 (2/32), TP53 (2/32), BRCA1 (1/32), PALB2 (1/32), CHEK2 (1/32), ATM (1/32), PMS1 (1/32), MUTYH (1/32), and MSH2 (1/32) genes. In addition, putative germline likely pathogenic variants were observed in the BARD1 (10/32), RB1 (2/32), APC (1/32), FANCC (1/32), AR (1/32), RAD51C (1/32), RAD51D (1/32) and CASP8 (1/32) genes. Most of the patients in our study had a family history of cancer and seventeen of the patients (53.1%) had family history of breast cancer in particular. Of those patients, 7 had a family history of breast cancer at a young age ( Citation Format: Jennifer S. Winn, Zachary Hasse, Jianming Pei, Michael Slifker, Sebastian M. Arisi-Fernandez, Jacqueline N. Talarchek, Elias Obeid, Karthik Devarajan, Hong Wu, Yulan Gong, Massimo Cristofanilli, R.Katherine Alpaugh, Sandra Viviana Fernandez. Germline and somatic variants in patients with inflammatory breast cancer (IBC) detected using cell-free DNA [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-03-11.

We studied genomic alterations in 19 inflammatory breast cancer (IBC) patients with advanced disease using samples of tissue and paired blood serum or plasma (cell-free DNA, cfDNA) by targeted next generation sequencing (NGS). At diagnosis, the disease was triple negative (TN) in eleven patients (57.8%), ER+ Her2- IBC in six patients (31.6%), ER+ Her2+ IBC in one patient (5.3%), and ER- Her2+ IBC in one other patient (5.3%). Pathogenic or likely pathogenic variants were frequently detected in TP53 (47.3%), PMS2 (26.3%), MRE11 (26.3%), RB1 (10.5%), BRCA1 (10.5%), PTEN (10.5%) and AR (10.5%), other affected genes included PMS1, KMT2C, BRCA2, PALB2, MUTYH, MEN1, MSH2, CHEK2, NCOR1, PIK3CA, ESR1 and MAP2K4. In 15 of the 19 patients in which tissue and paired blood were collected at the same time point, 80% of the variants detected in tissue were also detected in the paired cfDNA. Higher concordance between tissue and cfDNA was found for variants with higher allele fraction in tissue (AFtissue &ge, 5%). Furthermore, 86% of the variants detected in cfDNA were also detected in paired tissue. Our study suggests that the genetic profile measured in blood cfDNA is complementary to that of tumor tissue in IBC patients.

The purpose of this paper is to investigate the effect of dynamic recovery on the mechanical properties of copper (Cu) during surface mechanical attrition treatment (SMAT) at both room temperature (RT) and cryogenic temperature (CT). Copper sheets were processed by SMAT at RT and at CT for 5, 15, and 30 min, respectively. The Cu samples after SMAT at RT for 30 min exhibited better ductility but lower strength than the samples after SMAT at CT for 30 min due to dynamic recovery. X-ray diffraction analysis indicated that decreasing temperature during SMAT led to an increase in the twin and dislocation densities. In addition, a thicker gradient structure layer with finer grains was obtained in the SMAT-processed Cu samples at CT than at RT. The results indicated that SMAT at CT can effectively suppress the occurring of dynamic recovery and produce ultrahigh strength pure copper without seriously sacrificing its ductility.

This paper reports the influence of gradient structure volume fraction on the tensile mechanical behaviors of pure copper processed by surface mechanical attrition treatment at cryogenic temperature. Superior combinations of tensile strength and ductility are observed in a certain volume fraction, in which strain hardening uprising after yielding is also observed. The gradient structure produces a synergetic strengthening and extra work hardening. These findings suggest the existence of an optimum volume fraction of gradient structure for the best mechanical properties.

Cu–2.5 at.% Al–2.5 at.% Zn, Cu–4.5 at.% Al–22.8 at.% Zn and Cu–12.1 at.% Al–4.1 at.% Zn alloys with stacking fault energies (SFEs) of 40, 10, and 7 mJ/m2, respectively, were processed by combination of room temperature rolling (RR) and liquid nitrogen temperature rolling (LNR). The effect of SFE on microstructure refinement and mechanical properties of these materials were investigated. Microstructural observations indicate that a decrease in SFE leads to a decrease in crystallite size and to increase in microstrain, dislocation and twin densities for the RR and LNR samples. The results show that under the same deformation conditions, lower SFE promotes the formation of nanostructures and deformation twins. An analysis shows that the experimental results are consistent with a theoretical model which predicted the minimum grain size produced by milling.