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Accumulating evidence shows that high expression of casein kinase 2 (CK2) and phosphorylated acetyl CoA carboxylase (pACC) in patients with squamous cell carcinoma of the head and neck (SCCHN) correlates with decreased survival rates. Computational analysis has shown that ACC is a potential substrate for CK2, and its inhibition can suppress ACC phosphorylation in vitro. CX-4945, also known as silmitasertib, is an orally administered, highly specific, ATP-competitive inhibitor of CK2 and is under clinical investigation as a treatment for malignancies. We hypothesize that inhibition of CK2 by CX-4945 can reduce CK2-downstream phosphorylation of ACC as a therapeutic strategy against SCCHN.Three aggressive SCCHN cell lines (OSC-19, FaDu and HN31) were cultured to investigate the anticancer mechanism of the CK2 inhibitor, CX-4945. Cell cycle analysis, Annexin V/PI staining, and cleavage of PARP were performed to detect apoptosis. Western blot, electron microscopy and analysis of acidic vesicular organelle development were used to detect autophagy. Interference with cellular metabolism by CX-4945 treatment was determined by Seahorse XF24 Extracellular Flux Analyzer and mass spectrometry.Cellular metabolism was impeded by CX-4945 in aggressive SCCHN cells by Seahorse XF24 Extracellular Flux Analyzer and mass spectrometry, and consequently time- and dose-dependent lipid droplet accumulation and non-apoptotic cell death were observed. The lipogenic enzyme ACC was demonstrated to be associated with CK2, and its repressive phosphorylation could be removed by the CK2 inhibitor CX-4945. Overexpression of ACC resulted in impaired cell survival following transient transfection.The findings demonstrate that CK2 inhibition impairs normal cellular energy metabolism and may be an attractive therapy for treating aggressive SCCHN.

Neuroendocrine carcinomas (NECs) are rare, but aggressive malignant tumors of the female genital tract, especially in the uterine the cervix. Beside histologic morphology, positivity of neuroendocrine markers with immunohistochemistry plays an important role in diagnosis of NECs. Insulinoma-associated protein 1 (INSM1) is a novel marker reported to be widely expressed in a variety of neuroendocrine tumors. A previous study also suggested INSM1 has superior performance to conventional neuroendocrine markers in cervical NECs. In our present study, comparison between immunomarkers was performed in female genital tract NECs. Forty-nine patients with gynecologic NECs (4 vagina, 39 cervix, 5 endometrium, 1 ovary) were included from 1993 to 2019 at our center. Immunohistochemistry was performed with INSM1, CD56, synaptophysin (SYN), chromogranin-A (CgA), and thyroid transcription factor 1 (TTF1). The results show INSM1 has superior sensitivity and intensity compared with CD56, SYN, CgA, and TTF1 in cervical small cell NECs, but not in large cell NECs. In contrast to cervical NECs, INSM1 immunohistochemistry shows only focal and weak staining in endometrial NECs. Our result suggested INSM1 is a sensitive marker which can be used as first-line test in histologic suspicious cervical cases, especially small cell NECs. However, negative INSM1 stain does not exclude the possibility of NECs. In endometrial NECs, conventional panel with CD56, SYN, CgA has better diagnostic performance than INSM1 alone.

Background: Fatigue is a complicated syndrome associated with multiple factors. The development of fatigue after incidental radiotherapy (RT) to the adrenal gland has been observed in clinical practice. This study aimed to investigate the effect of adrenal RT on fatigue and related physiological impacts.Methods: Three patients with inevitable RT to the adrenal gland were enrolled. Serum levels of cortisol, aldosterone, and adrenocorticotropic hormone (ACTH) were measured before, during, and after RT. Fatigue was scored according to the validated fatigue severity scale, and dosimetric parameters were collected. BALB/c mice were surgically explored for the identification of the left adrenal gland. Intra-operative RT was delivered with an electron beam. The swimming endurance test was applied for endurance assessment to represent fatigue. Plasma levels of stress hormones and histopathological features were examined.Results: In the enrolled patients, serum baseline cortisol levels declined after RT. Alterations in levels of morning cortisol and aldosterone showed a similar trend to baseline cortisol, whereas ACTH levels increased, indicating possible compensatory feedback from the hypothalamic-pituitary-adrenal axis. In an experimental mouse model, RT to a unilateral adrenal gland decreased baseline cortisol levels and swimming endurance time. In the histopathological assessment, the irradiated adrenal glands showed characteristic RT injury features in the adrenal cortex.Conclusions: The preliminary clinical observation of fatigue development and characteristic hormone alterations indicated that the adrenal glands could be regarded as an organ at risk from RT adverse effects. This observation was supported by functional and histopathological evidence from an experimental animal model.

The clinicopathologic relevance of various gene rearrangements underlying dermatofibrosarcoma protuberans (DFSP) remains insufficiently characterized. In 188 DFSPs, we determined PDGFB, COL1A1, PDGFD, COL6A3, and EMILIN2 rearrangements by fluorescence in situ hybridization (FISH). The clinicopathologic significance of rearrangement types and factors related to recurrence and metastasis were statistically analyzed. In all, classic PDGFB rearrangement, cryptic COL1A1-PDGFB fusion, and PDGFD rearrangement were identified in 172 (91.4%), 8 (4.3%), and 8 (4.3%: 4 COL6A3-PDFGD, 4 EMILIN2-PDGFD) cases, respectively. In an index DFSP harboring the cryptic fusion, the COL1A1-PDGFB transcript was confirmed by both RNA sequencing and reverse transcription-polymerase chain reaction. In comparison with cases harboring classic PDGFB rearrangement, cryptic PDGFB-rearranged DFSPs usually exhibited higher 5'-COL1A1 copy numbers. In a combined reappraisal of published and current cases, COL6A3-PDGFD-positive DFSPs (n=16) predominated in females (n=14, 88%) and torso (n=14, 88%), especially the breast (n=7, 44%); EMILIN2-PDGFD-positive DFSPs (n=6) preferentially demonstrated near exclusively subcutaneous growth (n=5, 83%) and fibrosarcomatous transformation (n=5, 83%). In our cohort, local recurrence was related to fibrosarcomatous variant (P=0.029, odds ratio=3.478) and head and neck location (P=0.046, odds ratio=3.508). Distant metastasis only occurred in the fibrosarcomatous variant (9/73, 12.3%) but not in other cases. In conclusion, 8.6% of DFSPs are negative for PDGFB break-apart FISH, which, especially those with challenging subcutaneous and circumscribed manifestation, require complementary diagnosis by FISH assays targeting COL1A1 and PDGFD. The types of fusion gene rearrangements, head and neck location, and fibrosarcomatous transformation may account for clinicopathologic and prognostic variations in DFSPs and warrant future independent validation.

Reprogramming of cellular energy metabolism, such as lipid metabolism, is a hallmark of squamous cell carcinoma of the head and neck (SCCHN). However, whether protein expression related to fatty acid oxidation (FAO) affects survival in SCCHN remains unclear. We aimed to investigate FAO-related enzyme expression and determine its correlation with clinicopathological variables in SCCHN patients. Immunohistochemical analysis (IHC) of FAO-related protein expression, including carnitine palmitoyltransferase 1 (CPT1), the acyl-CoA dehydrogenase family, and fatty acid synthase (FAS), was performed using tissue microarrays from 102 resected SCCHN tumors. Expressions were categorized according to IHC scores, and the statistical association with clinicopathological factors was determined. Moderate-to-high expression of long-chain acyl-CoA dehydrogenase (LCAD) had a protective role against cancer-related death (adjusted hazard ratio (HR), 0.2, 95% confidence interval (CI), 0.05&ndash, 0.87) after covariate adjustment. Age and clinical stage remained independent predictors of survival (adjusted HR, 1.75, 95% CI, 1.22&ndash, 2.49 for age, adjusted HR, 14.33, 95% CI, 1.89&ndash, 108.60 for stage III/IV disease). Overexpression of medium-chain acyl-CoA dehydrogenase and FAS correlated with advanced tumor stage (T3/T4), however, none of these factors were independent predictors of survival. Several FAO-related enzymes were upregulated and LCAD overexpression had a protective effect on overall survival in advanced SCCHN patients. FAO-related-enzyme expression might have a prognostic impact on survival outcomes in SCCHN.

Summary: Background: Endoscopic ultrasound guided fine needle aspiration has become a standard procedure in diagnosis of pancreatic neoplasms with a high diagnosis yield. However, the clinical application focusing on the elderly population is scanty. Methods: Consecutive procedures for EUS-FNA diagnosis of pancreatic neoplasms at a tertiary referral center from March 2014 to December 2015 were analyzed retrospectively. The procedures were divided into two groups according to their age, the control group consisted of patients ≤60 years old and the elderly groups consisted of patients >60 years old. The primary outcome is the accuracy of the diagnosis in the two groups. The secondary outcome is the safety during the procedure. Results: A total of 28 EUS-FNA procedures were performed. The mean age of the control group was 48.7 years (n = 14) versus 70.2 years (n = 14) for the elderly cohort. Diagnostic accuracy of the EUS-FNA procedure in detecting malignant (true positive) and benign (true negative) lesions were higher in the control group (nonelderly: 85.7% vs. elderly: 50%; P = 0.046). There were two mild acute pancreatitis associated to the EUS-FNA procedures in the control group. Conclusion: Although EUS-FNA is safe and well tolerated in the elderly patients, our study showed a lower EUS-FNA diagnosis accuracy in this group. Focal fibrotic changes in the pancreas associated with the elderly patients resembled that of chronic pancreatitis microscopically. Keywords: EUS-FNA, pancreatic neoplasms, elderly, endoscopy, diagnosis

Background In personalized medicine, companion diagnostic tests provide additional information to help select a treatment option likely to be optimal for a patient. Although such tests include several techniques for detecting low levels of mutant genes in wild-type backgrounds with fairly high sensitivity, most tests are not specific, and may exhibit high false positive rates. In this study, we describe a new primer structure, named ‘stuntmer’, to selectively suppress amplification of wild-type templates, and promote amplification of mutant templates. Results A single stuntmer for a defined region of DNA can detect several kinds of mutations, including point mutations, deletions, and insertions. Stuntmer PCRs are also highly sensitive, being able to amplify mutant sequences that may make up as little as 0.1% of the DNA sample. Conclusion In conclusion, our technique, stuntmer PCR, can provide a simple, low-cost, highly sensitive, highly accurate, and highly specific platform for developing companion diagnostic tests.

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Inflammation contributes to cancer development and inflammatory bowel disease is an important risk factor for CRC. The aim of this study is to assess whether a widely used probiotic Enterococcus faecalis can modulate the NLRP3 inflammasome and protect against colitis and colitis-associated CRC. We studied the effect of heat-killed cells of E. faecalis on NLRP3 inflammasome activation in THP-1-derived macrophages. Pretreatment of E. faecalis or NLRP3 siRNA can inhibit NLRP3 inflammasome activation in macrophages in response to fecal content or commensal microbes, P. mirabilis or E. coli, according to the reduction of caspase-1 activation and IL-1&beta, maturation. Mechanistically, E. faecalis attenuates the phagocytosis that is required for the full activation of the NLRP3 inflammasome. In in vivo mouse experiments, E. faecalis can ameliorate the severity of intestinal inflammation and thereby protect mice from dextran sodium sulfate (DSS)-induced colitis and the formation of CRC in wild type mice. On the other hand, E. faecalis cannot prevent DSS-induced colitis in NLRP3 knockout mice. Our findings indicate that application of the inactivated probiotic, E. faecalis, may be a useful and safe strategy for attenuation of NLRP3-mediated colitis and inflammation-associated colon carcinogenesis.

Figure S1. The mutant detection sensitivity of single annealing temperature. The mutant detection sensitivity of single annealing temperature with the cfDNA Reference Standard Set was tested. In exon 19 deletion, the stuntmer was able to detect the mutant templates in only 0.1% of the tested samples. The detection sensitivity of the L858R and T790â M is 1%. (DOCX 81 kb)

To investigate the clinicopathologic characteristics of patients with immunoglobulin G4-related chronic sclerosing sialadenitis (IgG4-RCSS), a recently recognized disease.Case series with chart review and pathology study.Tertiary care hospital.We evaluated chronic sialadenitis specimens obtained over 11 years using pathologic examination and IgG4 immunohistochemistry staining. The specimens were assigned a revised diagnosis of IgG4-RCSS or chronic sialadenitis not otherwise specified, and clinicopathologic data from each group were compared.Of the 84 patients, 21 were diagnosed with IgG4-RCSS and 63 with chronic sialadenitis not otherwise specified. IgG4-RCSS patients were older (68.2 ± 13.9 vs 54.2 ± 15.8 years, P = .001), predominantly male (85.7% vs 61.9%, P = .036), and more likely to present with painless swelling (75% vs 44.3%, P = .001) and bilateral involvement (52.4% vs 6.3%, P.001). Ratio of IgG4-positive plasma cells to IgG-positive plasma cells in IgG4-RCSS tissues was 0.81 ± 0.14. The mean value of serum IgG4 in IgG4-RCSS patients was 918.8 mg/dL.IgG4-RCSS is more common in older male patients and frequently presents with bilateral involvement. Informing head and neck surgeons of the clinical features of IgG4-RCSS and promoting a combined approach of clinical evaluation, imaging, and biopsy can improve the accuracy of preoperative diagnoses.

Background Atypical lipomatous tumor (ALT) is a low-grade, slow-growing, locally aggressive malignant mesenchymal neoplasm. ALT of the extremities and trunk wall is associated with a relatively favorable outcome. However, these tumors can still recur locally and secondary dedifferentiation after recurrence has been reported. There is currently no consensus about the optimal surgical treatment of ALT. Therefore, we aimed to clarify the clinical behavior, appropriate treatment, and outcomes of ALT of the extremities and trunk wall. Methods We retrospectively reviewed the files of 45 patients treated between 2000 and 2014 with the diagnosis of atypical lipomatous tumors of the extremities and trunk wall at our institution. The median follow-up period was 84.5 months (range, 24-183 months). The patient demographics, clinical presentation, surgical methods, margin status, and administration of radiation therapy were recorded. Patients were evaluated for their local recurrence, dedifferentiation, and postoperative complications. Results Wide resection was performed on 11 patients, and marginal resection was performed on 34 patients. Seven patients underwent adjuvant radiotherapy. The overall recurrence rate was 17.8% (8/45), and dedifferentiation rates was 0% (0/8). The mean time to local recurrence was 5.25 years (range, 2.6-10.6 years). No ALT-related deaths occurred during the follow-up period. There were no differences in recurrence-free survival for the different surgical methods (P = 0.337) and radiotherapy (P = 0.228), whereas the R0 resection had better recurrence-free survival (P = 0.031). The postoperative complication rates were higher in wide resection group than in marginal resection group. (45.5% vs 14.7%, P = 0.048). Conclusions Atypical lipomatous tumors of the extremities and trunk wall are associated with a favorable overall survival and do not metastasis. Although they have a tendency to recur, the risk of secondary dedifferentiation is small. Wide resection had similar recurrence rates to marginal resection, but it might lead to more complications. Therefore, marginal resection is considered appropriate for the treatment of ALTs.

Rationale The diagnosis of anaplastic lymphoma kinase (ALK)-negative inflammatory myofibroblastic tumors (IMT) remains challenging because of their morphological resemblance with spindle cell sarcoma with myofibroblastic characteristics. Patient concerns A 69-year-old female patient presented with loco-regional recurrent IMT several times within 8 years after primary treatment and neck lymph node metastasis 3.5 years after last recurrence. Diagnosis The primary, recurrence, and lymph node metastasis lesions were diagnosed as ALK-negative IMTs based on the histopathological features. Interventions Biopsy samples were obtained during repeated surgeries and evaluated for genomic alterations during first and recurrent presentations. The evaluation was done using pathway-driven massive parallel sequencing, and genomic alterations between primary and recurrent tumors were compared. Outcomes Copy number gains and overexpression of mouse double minute 2 homolog (MDM2) and cyclin dependent kinase 4 (CDK4) were observed in the primary lesion, and additional gene amplification of Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2), Succinate Dehydrogenase Complex II subunit C (SDHC), and thyroid stimulating hormone receptor (TSHR) Q720H were found in the recurrent tumors. Metastases to the neck lymph node were observed 3.5 years after recurrence. Lessons Our results indicated genetic evolution in a microscopically benign condition and highlighted the importance of molecular characterization of fibro-inflammatory lesions of uncertain malignant potential.

Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs often occur in middle-aged and older individuals. The main morphologic type of GISTs is the spindle cell type. Immunohistochemistry and genotyping can help to identify GISTs from other subgroups of sarcoma. Materials and Methods: This retrospective study collected 304 patients over a 10-year period (from January 2009 to June 2019) who were diagnosed with GISTs based on the pathological database of our hospital. We retrospectively analyzed the clinical manifestations and treatment strategies. Results: Anemia or gastrointestinal bleeding was the most common symptom (36.5%), followed by gastrointestinal discomfort (32.6%) and incidental findings (21.4%). Ruptured tumors with hollow organ perforation increased the mortality risk. Liver metastasis and peritoneal seeding were the most two common patterns of recurrence. GISTs arising in adults are characterized by the near-universal expression of CD117/KIT antigen. Early surgery with margin-free resection is the best strategy for GISTs without metastasis. Routine lymph node dissection is not recommended. Laparoscopic surgery is feasible and safe for GISTs in the gastrointestinal tract. Endoscopic submucosal dissection to treat GISTs is suitable for small tumors with very low-to-intermediate risk in the stomach. Postoperative treatment with tyrosine kinase inhibitors can prolong recurrence-free survival after surgery. Conclusion: Surgical resection is the preferred treatment for patients without metastasis. Administration of tyrosine kinase inhibitors such as imatinib is recommended for unresectable, metastatic, or recurrent GISTs. Postoperative follow-up by computed tomography to detect early recurrence is recommended.

Tumor-to-tumor metastasis is a very rare phenomenon. The most common donor and recipient of tumor-to-tumor metastasis are carcinomas of lung and renal cell carcinoma, respectively. We report a case of primary lung adenocarcinoma that metastasized into a renal angiomyolipoma 9 years after the resection of primary lung tumor. Comparisons in morphology, immunohistochemical profiles, and genetic mutations indicate that the tumor metastasizing into angiomyolipoma originated from the same clone of previous lung adenocarcinoma. Albeit rare, pathologists should be aware of the possibility of tumor-to-tumor metastasis when confronting a neoplasm exhibiting 2 distinct morphological features.

Aims Heat shock proteins (HSPs) are a group of molecules induced by a variety of environmental and pathophysiologic stresses, including cancer. HSPs are implicated in the regulation of apoptosis and immunity in neoplasm. Transcription factor heat shock factor1 (HSF1) acts as the master regulator to control HSP expression, and therefore is involved in tumorigenesis. The purpose of this study was to evaluate the expression and clinicopathologic relevance of HSPs and HSF1 in clear cell renal cell carcinoma (ccRCC). Methods and results The expression of HSP27, HSP60, HSP70, HSP90 and HSF1 was assessed in 428 cases of ccRCC using immunohistochemistry. High expression of HSP60 and HSP70 was positively correlated with grade and stage. High expression of HSF1 was positively correlated with stage. Univariate and multivariate analyses demonstrated that 216 patients (52%) with tumour expressing 3 or 4 markers in a panel of HSP60, HSP70, HSP90, and HSF1 had a significantly heightened risk for cancer-specific mortality than tumours expressing

Following publication of the original article [1], the author informed us that the legend for Fig. 2 was incorrect.

Gliomatosis peritonei is a very rare phenomenon occurring almost exclusively in association with ovarian immature teratoma. It is characterized by numerous benign, mature glial nodules in the omentum and mesentery. The presence of glial tissue outside abdominal cavity is extremely rare in the setting of ovarian immature teratoma. We present a case of ovarian immature teratoma with both gliomatosis peritonei and pleural glial implant in a 4-year-old girl. Glial emboli were present in the pleural implant, suggesting lymphovascular dissemination might be the cause of extra-abdominal glial implantation.

Pre-mRNA alternative splicing is an important mechanism for the generation of synaptic protein diversity, but few factors governing this process have been identified. From a screen forDrosophilamutants with aberrant synaptic development, we identifiedbeag, a mutant with fewer synaptic boutons and decreased neurotransmitter release.Beagencodes a spliceosomal protein similar to splicing factors in humans andCaenorhabditis elegans. We find that bothbeagmutants and mutants of an interacting genedsmu1have changes in the synaptic levels of specific splice isoforms of Fasciclin II (FasII), theDrosophilaortholog of neural cell adhesion molecule. We show that restoration of one splice isoform of FasII can rescue synaptic morphology inbeagmutants while expression of other isoforms cannot. We further demonstrate that this FasII isoform has unique functions in synaptic development independent of transsynaptic adhesion.beaganddsmu1mutants demonstrate an essential role for these previously uncharacterized splicing factors in the regulation of synapse development and function.

Asymmetric cell division is an important and conserved strategy in the generation of cellular diversity during animal development. Many of our insights into the underlying mechanisms of asymmetric cell division have been gained from Drosophila, including the establishment of polarity, orientation of mitotic spindles and segregation of cell fate determinants. Recent studies are also beginning to reveal the connection between the misregulation of asymmetric cell division and cancer. What we are learning from Drosophila as a model system has implication both for stem cell biology and also cancer research.