Absence Of Lymph Node Metastasis Research Articles

Anatomical Patterns of Nodal Spread in Unilateral Papillary and Medullary Thyroid Cancer.

Background: Skip metastases, node metastases in the lateral neck sparing the ipsilateral central neck, challenge the current concept of central-to-lateral lymphatic spread. This study sought to delineate patterns of central and lateral neck involvement in unilateral papillary thyroid cancer (PTC) and medullary thyroid cancer (MTC). Methods: This was a retrospective correlative analysis of nodal patterns in surgical specimens from patients with unilateral PTC or MTC who had undergone thyroidectomy with at least ipsilateral central neck dissection between November 1994 and January 2024 at a tertiary referral center. Results: Included were 833 patients with unilateral PTC and 640 patients with unilateral MTC. Simultaneous presence or absence of node metastases was noted in ipsilateral central and lateral neck compartments in 76.6-78.1% of patients with PTC (both node positive in 27.0-54.7% and both node negative in 23.4-49.6%) and 77.3-80.0% of patients with MTC (both node positive in 26.6-33.2% and both node negative in 44.1-53.4%). Only one ipsilateral neck compartment was node positive in 21.9-23.4% of patients with PTC and 20.0-22.7% of patients with MTC. The ipsilateral central, but not the ipsilateral lateral compartment, was node positive in 8.8-16.9% with PTC and 8.6-8.8% of patients with MTC, whereas the ipsilateral lateral, but not the ipsilateral central compartment, was node positive in 6.5-13.1% with PTC and 11.3-14.1% with MTC. Ipsilateral lateral neck involvement sparing the ipsilateral central neck was 1.5-2 times more frequent in patients with node positive MTC than patients with node positive PTC (24.2-25.2% vs. 12.9-17.1%). Greater numbers of node metastases in the ipsilateral central neck compartment were associated with more frequent involvement of the ipsilateral lateral, contralateral central, and contralateral lateral neck compartments. Thyroid tumor diameter intensified nodal spread without changing nodal spread patterns. Conclusions: These histopathological findings, which need to be interpreted in light of the respective tumor biology, offer an unprecedented glimpse at the metastatic patterns of unilateral PTC and MTC. Customizing neck dissection to the patterns of nodal spread, considering operative status (initial vs. reoperative surgery) and experience with neck dissection, may require more frequent concomitant dissections of ipsilateral central and ipsilateral lateral neck compartments.

Clinical Significance of the Immunohistochemical Expression of Histone Deacetylases (HDACs)-2, -4, and -5 in Ovarian Adenocarcinomas.

Histone deacetylases (HDACs) are implicated in carcinogenesis, and HDAC inhibitors (HDACis) are explored as a therapeutic tool in several tumors. The aim of this study was to evaluate the clinical significance of HDAC-2, -4, and -5 expression in epithelial ovarian carcinoma (EOC). HDAC-2, -4, and -5 immunohistochemical expression was examined in 92 EOC tissue specimens and was correlated with clinicopathological characteristics. HDAC-2 was the most frequently (94.4%) expressed isoform, being marginally higher in serous tumors compared with other types (p = 0.08). HDAC-5 was the less frequently expressed (28.1%), being positively associated with HDAC-4. HDAC-4 positivity was associated with lower FIGO-stage (p = 0.045) and T-category (p = 0.043) and the absence of lymph node (p = 0.05) or distant metastasis (p = 0.09) in serous carcinomas. HDAC-2 positivity was correlated with the absence of lymph node metastasis in serous tumors (p = 0.045). On the contrary, HDAC-5 nuclear positivity was correlated with lymph node metastasis in the entire cohort (p = 0.048). HDAC-4 positivity was marginally associated with favorable prognosis in serous carcinomas in univariate survival analysis (p = 0.086), but this correlation was not significant in multivariate analysis. These findings suggest a differential expression among HDAC-2, -4, and -5 in ovarian adenocarcinomas in terms of immunolocalization, positivity rate, and associations with clinicopathological parameters, providing evidence for a potential role in the pathobiology of EOC.

Platelet-lymphocyte ratio as a predictor of lymph node metastasis in small bowel cancer.

The purpose of this research was to investigate the potential predictive value of preoperative systemic inflammatory indexes in identifying lymph node metastasis among patients diagnosed with small bowel cancer. A retrospective analysis of clinical data was conducted on small bowel cancer patients who underwent surgical treatment at the gastrointestinal surgery department of our hospital between January 2010 and June 2021. Patients were divided into groups based on the presence or absence of lymph node metastasis as confirmed by postoperative pathological results. The study compared the differences in preoperative inflammatory indexes and clinical data between the two groups using single factor analysis and multifactorial Logistic regression analysis. Furthermore, a nomogram model for predicting lymph node metastasis in colorectal cancer was constructed using R software and internally validated. The study sample consisted of 140 small bowel cancer patients,postoperative pathology confirmed lymph node metastasis in 72 cases. Univariate analysis results indicated associations between preoperative inflammatory indexes and clinical data with lymph node metastasis in small bowel cancer. Multifactorial logistic regression analysis revealed that gender, PLR, number of lymph node dissection, and lymphovascular invasion independently influenced lymph node metastasis in small bowel cancer patients. The developed nomogram model demonstrated a C-index of 0.855 (95% CI 0.792-0.917), with a calibrated prediction curve closely resembling the ideal curve. An elevated PLR is an independent risk factor for LNM in patients with small bowel cancer.

Abstract 5206: High level STING expression in tumor and inflammatory cells is linked to microsatellite instability and favorable tumor parameters in a cohort of 1,900 colorectal cancer patients

Abstract Background: The stimulator of interferon genes (STING) is a transmembrane protein expressed on a variety of cell types including epithelial, inflammatory (lymphocytes and macrophages), and endothelial cells. STING expression has been described at variable levels in various tumor types where it might enhance anti-tumoral effects of the immune system and impact tumor angiogenesis. STING activating targeted therapies are currently evaluated in preclinical studies. However, the clinical significance of STING expression in tumor cells as compared to tumor-associated inflammatory cells is not fully resolved. Methods: To evaluate the potential clinical significance of STING expression in different cell types of colorectal cancer (CRC) tissue (tumor cells, lymphocytes, macrophages and endothelial cells), more than 1,900 patients were analyzed by multiplex fluorescence immunohistochemistry (CKpan, STING, CD45, CD68 and CD31) in a tissue microarray format (TMA) in combination with a deep-learning based algorithm for automated cell detection. Results: STING expression on colorectal cancer cells varied markedly. Of 1,905 evaluable cancers, 601 (31.5%) showed a strong expression in virtually all tumor cells and 428 (22.5%) lacked STING staining while 478 (25.1%) showed a weak, and 398 (20.9%) a moderate staining. High STING expression on tumor cells was associated with microsatellite instability (MSI, p<0.0001), low tumor stage (p=0.0013), absence of nodal metastasis (pN0, p=0.0003) and tumor localization in the right colon (p<0.0001). A multivariate analysis revealed that these associations were solely driven by the tight relationship between STING expression in tumor cells and MSI. Accordingly, subgroups of tumors with and without MSI lacked significant associations between STING expression on tumor cells and pT or pN categories. While the total number of lymphocytes and macrophages were related to MSI, low pT, and pN0, there were significant associations between a high percentage of STING positive macrophages and lymphocytes to low pT stage (p<0.0001 each) and absence of nodal metastases for high percentage of STING positive macrophages (p=0.0033). STING was regularly expressed on endothelial cells of small vessels. Although the intensity appeared to be variable, there was no link to tumor phenotype. Conclusion: In summary, the significant link between high STING expression on tumor cells, lymphocytes and macrophages with a favorable tumor phenotype supports the concept of STING representing an enhancer of anti-tumoral effects of the immune system. Citation Format: Elena Bady, Zhihao Huang, Maximilian Lennartz, Claudia Hube-Magg, Julia Ebner, Frank Jacobsen, Stefan Steurer, Christian Bernreuther, Till S. Cauditz, Andreas H. Marx, Till Krech, Eike Burandt, Guido Sauter, Ronald Simon, Sarah Minner, Jan Hendrik Mueller. High level STING expression in tumor and inflammatory cells is linked to microsatellite instability and favorable tumor parameters in a cohort of 1,900 colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5206.

Prognostic significance of pyroptosis-associated molecules in endometrial cancer: a comprehensive immunohistochemical analysis.

Endometrial cancer, the most prevalent malignancy of the female genital tract, has a concerningly poor prognosis when diagnosed in advanced stages, with limited targeted therapy options available for advanced or recurrent cases. Pyroptosis, a type of nonapoptotic cell death mediated by caspase-1, has shown potential antitumor effects in various tumors. NLRP3, a cytosolic sensor, initiates the canonical pyroptotic pathway, leading to caspase-1 activation, subsequent gasdermin D cleavage, and plasma membrane pore formation. The ESCRT-III machinery, particularly CHMP4B, acts as a key inhibitor of pyroptosis by repairing gasdermin D-induced membrane damage. The current study aimed to evaluate the clinicopathologic relevance of key pyroptosis-associated molecules in endometrial cancer. Immunohistochemistry was used to assess the expression of four pyroptosis-associated molecules (NLRP3, cleaved caspase-1 p20, cleaved gasdermin D, and CHMP4B) in 351 patients with endometrial cancer, and their associations with clinical, pathological, and survival outcomes were analyzed. High NLRP3 expression was significantly associated with age ≤ 50 years and premenopause. Increased cleaved caspase-1 p20 expression was associated with nonendometrioid carcinoma, Federation of Gynaecology and Obstetrics (FIGO) grade 3, and the p53 mutant pattern and was independently associated with poor recurrence-free survival (RFS) and overall survival. Increased cleaved gasdermin D expression was associated with a body mass index of >25 kg/m², FIGO grades 1-2, early FIGO stage (I-II), and absence of lymph node metastasis. High CHMP4B expression was associated with nonendometrioid carcinoma and poor RFS. Cleaved gasdermin D-high/CHMP4B-low endometrial cancer was associated with endometrioid carcinoma, FIGO grades 1-2 and favorable RFS. Our study identified cleaved caspase-1 p20 as an independent predictor of adverse outcomes in endometrial cancer. CHMP4B, an inhibitor of pyroptosis, was associated with an unfavorable RFS, whereas high cleaved gasdermin D/low CHMP4B expression was associated with a favorable RFS. These findings underscore the prognostic significance of pyroptosis and the potential interaction between cleaved gasdermin D and CHMP4B in endometrial cancer.

Diagnostic and prognostic value of serum soluble B7-H3 in nonsmall cell lung cancer.

The aim of this study was to investigate the utility of serum soluble B7-H3 (sB7-H3) as a diagnostic marker for early-stage nonsmall cell lung cancer (NSCLC) and its potential for evaluating the prognosis of patients with advanced-stage NSCLC. In this study, an ELISA was employed to detect the expression levels of sB7-H3 in a cohort of patients diagnosed with NSCLC ( n = 122) and a control group ( n = 42) during the same observation period. Comparative analyses were conducted to ascertain the variations in sB7-H3 concentrations between the NSCLC cohort and the healthy control group, as well as across pathological types and the presence and absence of lymph node metastasis. (1) The concentration of sB7-H3 in patients diagnosed with NSCLC exhibited a statistically significant increase compared to that observed in the healthy control group ( P < 0.05). Elevated expression levels of sB7-H3 demonstrated a significant correlation with pathological type, lymph node metastasis, tumor, node and metastasis stage and programmed cell death ligand (PD-L1) expression ( P < 0.05). (2) The diagnostic utility of sB7-H3 for the diagnosis of NSCLC and the heightened expression of PD-L1 demonstrated high levels of sensitivity and specificity. (3) Elevated levels of sB7-H3 emerged as an independent risk factor impacting the overall survival of patients diagnosed with advanced NSCLC. The findings of this study suggest that sB7-H3 holds promise as a diagnostic tool for early-stage NSCLC. The elevated expression of sB7-H3 appears to serve as a reliable indicator for assessing the prognosis of patients diagnosed with advanced NSCLC.

Transcriptomic analysis of Porphyromonas gingivalis-infected head and neck cancer cells: Identification of PLAU as a candidate prognostic biomarker.

Periodontal disease is a risk factor for head and neck squamous cell carcinoma (HNSCC), and Porphyromonas gingivalis, a major periodontal pathogen, has been identified as a specific and potentially independent microbial factor that increases the risk of cancer mortality. Gene expression in HNSCC due to P. gingivalis infection and how changes in gene expression affect the prognosis of HNSCC patients are not clarified. When P. gingivalis was cultured with HNSCC cells, it efficiently adhered to these cells and enhanced their invasive ability. A transcriptome analysis of P. gingivalis -infected HNSCC cells showed that genes related to migration, including CCL20, CITED2, CTGF, C8orf44-SGK3, DUSP10, EGR3, FUZ, HBEGF, IL1B, IL24, JUN, PLAU, PTGS2, P2RY1, SEMA7A, SGK1 and SIX2, were highly up- or down-regulated. The expression of up-regulated genes was examined using the expression data of HNSCC patients obtained from The Cancer Genome Atlas (TCGA) database, and the expression of 5 genes, including PLAU, was found to be higher in cancer tissue than in solid normal tissue. An analysis of protein-protein interactions revealed that these 5 genes formed a dense network. A Cox regression analysis showed that high PLAU expression levels were associated with a poor prognosis in patients with TCGA-HNSCC. Furthermore, the prognostic impact correlated with tumour size and the presence or absence of lymph node metastasis. Collectively, these results suggest the potential of PLAU as a molecular prognostic marker in HNSCC patients. Further invivo and invitro studies are needed to verify the findings of this study.

Prognostic Value of Immune Cells Subsets Within the Tumor Microenvironment in Patients With Rectal Adenocarcinoma.

One-third of newly diagnosed colorectal cancer cases are rectal cancers. Multimodal treatment regimens including surgery, radiotherapy, and chemotherapy improve local control and survival outcome and decrease tumor relapse for patients with rectal adenocarcinoma (READ). However, stratification of patients to predict their responses is urgently needed to improve therapeutic responses. Immunostainings of CD3+, CD8+, and CD45RO+ immune cell subsets within the tumor microenvironment were evaluated using immunohistochemistry in two hundred seventy-nine READ patients. In this study, we found that examination of the adaptive immune response by quantifying CD3+, CD8+, and CD45RO+ immune cell subsets, provides improved and independent prognostic value for patients with READ. Regardless of conventional clinical and pathologic parameters, the densities of T cell subsets were strongly related to a better prognosis in patients with READ. High density of intratumoral immune cells is associated with absence of nodal metastasis, lymphovascular invasion, and perineural invasion. Moreover, high tumor-infiltrating lymphocyte (TIL) subsets were associated with favorable survival outcome in patients with READ, especially high-risk patients with advanced READ. Immune cell subsets including CD3, CD8, and CD45RO within the tumor microenvironment were independent prognostic factors for patients with READ.

Pks-positive Escherichia coli in tumor tissue and surrounding normal mucosal tissue of colorectal cancer patients.

A significant association exists between the gut microbiome and colorectal carcinogenesis, as well as cancer progression. It has been reported that Escherichia coli (E. coli) containing polyketide synthetase (pks) island contribute to colorectal carcinogenesis by producing colibactin, a polyketide-peptide genotoxin. However, the functions of pks+ E. coli in initiation, proliferation, and metastasis of colorectal cancer (CRC) remain unclear. We investigated the clinical significance of pks+ E. coli to clarify its functions in CRC. This study included 413 patients with CRC. Pks+ E. coli of tumor tissue and normal mucosal tissue were quantified using droplet digital PCR. Pks+ E. coli was more abundant in Stages 0-I tumor tissue than in normal mucosal tissue or in Stages II-IV tumor tissue. High abundance of pks+ E. coli in tumor tissue was significantly associated with shallower tumor depth (hazard ratio [HR] = 5.0, 95% confidence interval [CI] = 2.3-11.3, p < 0.001) and absence of lymph node metastasis (HR = 3.0, 95% CI = 1.8-5.1, p < 0.001) in multivariable logistic analyses. Pks+ E. coli-low and -negative groups were significantly associated with shorter CRC-specific survival (HR = 6.4, 95% CI = 1.7-25.6, p = 0.005) and shorter relapse-free survival (HR = 3.1, 95% CI = 1.3-7.3, p = 0.01) compared to the pks+ E. coli-high group. Pks+ E. coli was abundant in Stages 0-I CRC and associated with CRC prognosis. These results suggest that pks+ E. coli might contribute to carcinogenesis of CRC but might not be associated with tumor progression.

Expression of AHR-regulated and PD-L1-regulated microRNAs in squamous cell lung cancer

Introduction. Despite modern advances in research into the risk of development, immunological control and treatment options for lung cancer (LC), it is the leading cause of death from cancer. Tobacco smoking remains the predominant risk factor for the development of lung cancer, especially one of its aggressive subtypes, squamous cell lung cancer (SCLC). Benzo[a]pyrene, a component of cigarette smoke, promotes the activation of the aryl-hydrocarbon receptor (AhR). AhR regulates the expression of many oncogenes, including PD-L1, the positive status of which is an indication for immunotherapy, one of the main treatment strategies for SCLC. However, to improve the effectiveness of treatment of SCLC, further search for new diagnostic, prognostic and therapeutic markers is necessary. MicroRNAs (miRs), which are highly stable and present in biological fluids, can act as such markers.Objective. Search for microRNAs that could potentially serve as diagnostic markers or therapeutic targets for SCLC. For this purpose, microRNAs were selected whose promoter regions contain AhR binding sites or whose target is PD-L1.Materials and methods. A biocollection of tumor and conditionally normal lung tissue samples (n = 40) was collected at the thoracic department of the Novosibirsk Clinical Oncology Dispensary. The relative levels of selected miRNAs were examined using real-time reverse transcription-PCR (RT-PCR) technique.Results. The levels of miR-342 and miR-181a in SCLC tissues were reduced by 3 times relative to conditionally normal tissue. The expression of miR-181a and miR-155 is associated with tumor size (lower levels in tumors larger than 3 cm) and the presence of metastases in the lymph nodes (3- and 2-fold lower levels in cases with metastases). The level of miR-146a decreased by 3 times in patients with metastatic lesions of lymph nodes. A significant relationship between the levels of miR-93, miR-181a and miR-155 and the expression status of PD-L1 was also found.Conclusions. The expression profile of miR-146a, miR-93, miR-181a and miR-155 differs in SCLC patients depending on PD-L1 status and the presence or absence of lymph node metastases.

Clinical impact of heterogeneously distributed tumor-infiltrating lymphocytes on the prognosis of colorectal cancer.

Tumor-infiltrating lymphocytes (TILs) exist in various malignancies, and have been viewed as a promising biomarker to predict the efficacy and outcome of treatment. However, the marked inter- and intra-tumor heterogeneity of TILs has resulted in some confusion regarding their impact on the prognosis of colorectal cancer (CRC). In this study, 78 CRC patients were enrolled and the CD3+ and CD8+ TILs densities at the tumor center (TC), the invasive margin (IM) and the tumor stroma (TS) were assessed by immunohistochemical staining. Their associations with clinicopathological features and progression free survival (PFS) were analyzed to evaluate the predictive and prognostic values of TILs. TILs were mainly distributed along the invasive margin. High density of TILs in tumor center and invasive margin was associated with smaller tumor size (CD3+TILsIM), reduced tumor invasion (CD3+TILsIM), absence of lymph node metastasis (CD3+TILsIM and CD8+TILsTC), earlier stage (CD3+TILsIM and CD8+TILsIM), and lower tumor grade (CD3+TILsIM and CD8+TILsTC). However, stromal TILs were not associated with any clinicopathological features. Kaplan-Meier survival analysis revealed that high densities of TILs always correlated with prolonged patient survival. The pathological N stage, CD3+ TILsIM and CD8+ TILsTC were found to be independent prognostic indicators. Additionally, early-stage CRC patients who developed recurrence after surgery, showed a higher CD3+/CD8+ TILs ratio in invasive margin. In the present study, it was clarified that CD3+ and CD8+ TILs were heterogeneously distributed in tumor tissues of CRC. The increase in intratumoral and peritumoral TILs had been shown to be strongly predictive of improved clinical outcome. More importantly, the immune signatures enabled to stratify early-stage CRC patients with high risk of recurrence, highlighting the prognostic power of TILs.

High KRT17 expression in tumour budding indicates immunologically 'hot' tumour budding and predicts good survival in patients with colorectal cancer.

Emerging evidence has demonstrated that tumour budding (TB) is negatively associated with T-lymphocyte infiltration in CRC. Despite extensive research, the molecular characteristics of immunologically 'hot' TB remain poorly understood. We quantified the number of TB by haematoxylin-eosin (H&E) sections and the densities of CD3+ and CD8+ T-lymphocytes by immunohistochemistry in a CRC cohort of 351 cases who underwent curative resection. We analysed the differential expression and T-lymphocyte infiltration score of 37 human epithelial keratins in CRC using RNA sequencing from the TCGA dataset. In 278 TB-positive cases, KRT17 expression was evaluated in tumour centre (TC) and TB with a staining score. Patient demographic, clinicopathological features and survival rates were analysed. In a CRC cohort of 351 cases, low-grade TB was associated with high CD3+ and CD8+ T-cell densities in the invasive margin (IM) but not in the TC. Of 37 human epithelial keratins, only KRT17 expression in TB had an apparentassociation with TB-grade and T-lymphocyte infiltration. In 278 TB-positive cases, high KRT17 expression in TB (KRT17TB) was negatively associated with low-grade TB and positively associated with high CD3+ and CD8+ T-cell densities in IM. High KRT17TB predicted early tumour grade, absence of lymph node metastasis and absence of tumour deposits. Additionally, patients with high KRT17TB had good overall survival and disease-free survival. Notably, low KRT17TB can specifically identify those patients with a poor prognosis among colorectal cancer patients with low TB and high T-lymphocyte infiltration. KRT17 can be employed as a new indicator for distinguishing different immunological TBs.

Primary Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma of the Prostate: MRI and FDG-PET Imaging Findings

Background: Primary mucosa-associated lymphoid tissue (MALT) lymphoma of the prostate is a rare condition, and there is no report on magnetic resonance imaging (MRI) and its relationship with fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET). Objectives: The purpose of this article is to present the MRI and FDG-PET imaging findings of primary MALT lymphoma of the prostate and discuss the imaging findings’ importance in the diagnosis and management. Case summaries: A 73-year-old male patient underwent a prostate biopsy for lower urinary tract symptoms and an elevated serum prostate-specific antigen level. Histopathologic and immunohistochemical findings were consistent with MALT lymphoma. As the tumor was confined to the prostate and adjacent tissues and no lymph node metastases were detected on PET-CT, the diagnosis was primary MALT lymphoma of the prostate. The tumor of the transitional zone infiltrated along the obturator internus muscle and into the pubic bone, the levator ani muscle was almost intact on MRI. Conclusion: The absence of lymph node metastasis or gross muscle destruction but a high degree of invasiveness into surrounding tissues is an important imaging finding in the diagnosis of primary MALT lymphoma of the prostate. Keywords: Differential Diagnosis; MRI; Prostate Neoplasms

Expression of acetylated histones H3 and H4 and histone deacetylase enzymes HDAC1, HDAC2 and HDAC6 in simple mammary carcinomas of female dogs.

Histone deacetylation is an important mechanism involved in human breast cancer tumorigenesis and recent veterinary oncology studies also demonstrate a similar relationship in some canine neoplasms. The use of HDAC inhibitors in vitro and in vivo has demonstrated antitumor action on several strains of human and animal cancers. The present study aims to correlate the expression of H3K9Ac, H4K12Ac, HDAC1, HDAC2 and HDAC6 in simple mammary carcinomas in dogs with clinicopathological parameters and overall survival time. To this end, 61 samples of simple breast carcinomas were analyzed by the immunohistochemistry technique with subsequent validation of the antibodies by the Western Blot technique. The expressions obtained via a semi-quantitative way were categorized by assigning scores and classified into high or low expressions according to the given score, except for HDAC6, when the marking percentage was considered and subdivided into high and low expressions using the median value. For statistical analysis, the chi-square test or Fisher exact test were used as univariate analysis and correspondence analysis as a multivariate test, in addition to the Kaplan-Meier survival analysis. In the studied samples, the highest frequencies were determined for the high expression proteins H4K12Ac (88.5%), HDAC2 (65.6%) and HDAC6 (56.7%) and the low expression proteins H3K9Ac (73.8%) and HDAC1 (54.1%). An association between the low expression of HDAC1 and the presence of lymph node metastasis (p = 0.035) was indicated by univariate analysis while the high expression of HDAC1 was associated with favorable prognostic factors, such as the absence of lymph node metastasis and low mitotic index by multivariate analysis. Also, by multivariate analysis, the low expression of HDAC6 was correlated with the low expression of Ki67, smaller tumors, and better prognosis factors as well. Protein expression was not correlated with patients' overall survival time (p > 0.05). The high expressions of HDAC2 and HDAC6 in mammary carcinomas in female dogs may be useful information for research involving therapeutic targets with iHDACs since their inhibition favors hyperacetylation and transcription of tumor suppressor genes.

Evaluation of a miRNA-371a-3p Assay for Predicting Final Histopathology in Patients Undergoing Primary Nerve-sparing Retroperitoneal Lymphadenectomy for Stage IIA/B Seminoma or Nonseminoma

Patients with marker-negative clinical stage IIA/B seminoma or nonseminoma represent a therapeutic challenge, as 20–30% might harbor nonmalignant histologies. MicroRNA 371a-3p (miR371) may represent a biomarker with diagnostic and predictive properties in testicular germ cell tumors (TGCTs). We evaluated the predictive accuracy of this biomarker in identifying the presence or absence of lymph node metastases (LNMs) in clinical stage IIA/B TGCT. In a cohort of 24 consecutive patients with marker-negative clinical stage IIA/B TGCT (n = 15 seminoma, n = 9 nonseminoma) serum miR371 was assessed 1 d before nerve-sparing retroperitoneal lymphadenectomy. Histology revealed metastatic TGCT in 22/24 patients (91.7%), with positive miR371a findings for 20 of these 22 patients with metastases (90.9%). Histology revealed no malignancy in one patient and lymphoma in another, both of whom had negative miR371a findings. One additional patient with pure teratoma and one with a microscopic seminomatous LNM had false-negative miR371a findings. The miR371 assay had sensitivity of 90.9% and specificity of 50%. The positive predictive value was 100.0% and the negative predictive value was 75.0%. According to the data available, miR371a represents a highly reliable, personalized tumor marker for predicting the presence of low-volume retroperitoneal LNMs in marker-negative TGCT. miR371 has potential for inclusion in the diagnostic armamentarium for men with equivocal lymph nodes to facilitate avoidance of unnecessary treatment and the associated toxicity. Patient summaryOur study demonstrates that blood tests for the biomarker miR371 are highly reliable in predicting the presence of lymph node metastases in patients with stage IIA/B testicular cancer. For patients with equivocal findings, use of this test may help in avoiding unnecessary treatment.

Predicting Treatment Response of Esophageal Cancer Treated by Concurrent Chemoradiotherapy Using Pre- and Posttreatment 18F-FDG PET Metabolic Characteristics.

This study hypothesizes that metabolic characteristics of esophageal tumors can be used to predict treatment response, which considers changes in the primary tumor and lymph nodes, for patients receiving neoadjuvant concurrent chemoradiotherapy (CCRT). This study retrospectively included 60 esophageal cancer patients receiving CCRT followed by surgery. All patients received 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) examinations prior to CCRT and in the interval between CCRT and surgery. On the pre-treatment FDG PET/CT images, the maximum standardized uptake value (SUVMaxPre) within the primary tumor was identified. By computerized methods, the CT images of pre- and post-treatment FDG PET/CT were registered. Then, the coordinates of SUVMaxPre were transformed to the post-treatment FDG PET images and delineated a sphere with a diameter of 5 cm to indicate the tumor position. After excluding air, the sphere was partitioned into several metabolic volumes by the optimal dichotomy of high and low metabolic FDG uptakes. Finally, the volume with the shortest distance to the center was adopted and represented by the maximum standardized uptakes (SUVMaxPost). Two additional features, SUVDiff and SUVDiffR, were defined as SUVMaxPost - SUVMaxPre and (SUVMaxPost - SUVMaxPre) / SUVMaxPre. Besides, for defining treatment response, the patients with and without residual tumors were defined as ypT+ and ESOCR based on the histopathology results of surgery. The ESOCR was further classified into pCR to indicate the absence of lymph node metastasis and LNM for remaining. Finally, the area under the receiver operating characteristic curve analysis (AUC) was conducted to assess the features' ability to differentiate two treatment responses. Kruskal-Wallis test was used to evaluate the differences in features between treatment responses. Of the 60 patients, 55 were men (92%), and the mean age was 58. The number of tumors at the esophagus's upper, middle, and lower third were 8, 18, and 34, respectively. Ninety-eight percent of the tumors were squamous cell carcinomas (59/60). The patient numbers of ypT+ and ESOCR were 43 and 17 of which contained 13 pCR and 4 LNM. The SUVDiff and SUVDiffR exhibited a significant ability to identify the ESOCR with AUC = .337 (p = .05) and AUC = .290 (p = .012), respectively. In addition, a statistically significant difference was found among the three groups of ypT+, pCR, and LNM on SUVMaxPre (H = 6.252 and p = .044), SUVDiff (H = 7.948 and p = .019), and SUVDiffR (H = 8.405 and p = .015). In the post-hoc tests corrected by the Bonferroni, the difference between ypT+ and LNM was significant on these features. The metabolic characteristics extracted from pre- and post-treatment FDG PET/CT images could indicate treatment response and disease progression. Further studies are warranted.

Mutation Profile via Next-Generation Sequencing in Patients with Colorectal Adenocarcinoma and Its Clinicopathological Correlation.

Recent studies that reveal the molecular profiles of colorectal carcinomas have demonstrated tumor heterogeneity. Characterization of colorectal carcinoma-specific genomic alterations is essential for developing more successful and targeted treat- ment protocols. Moreover, it is vital in elucidating the pathogenesis and mechanisms of resistance against treatment and predicting prognosis. The study included 73 cases diagnosed with colorectal carcinomas and subjected to molecular analysis by the next-generation sequencing. The association between the clinicopathologic parameters and pathogenic mutations detected in 32 genes was evaluated. Pathogenic mutations were determined in a total of 24 genes. The Cell Division Cycle 27 (CDC27), Kirsten rat sarcoma viral proto-oncogene (KRAS), serine/threonine protein kinase B-raf (BRAF), phosphatase and tensin homolog, breast cancer 2 (BRCA2), and phosphotidylinositol-4,5-biphosphate 3-kinase (PIK3CA) mutations were determined at higher rates, with the adenomatous polypo- sis coli mutation determined at a lower rate than in the literature. There were significant positive correlations between CDC27 and phosphatase and tensin homolog (PTEN), PTEN and BRCA2, and PTEN and adenomatous polyposis coli (APC) concomitant muta- tions, whereas negative correlations were present between BRAF and KRAS. Statistically significant relationships were present between KRAS exon 2 and mucinous morphology, PIK3CA and absence of perineural invasion, BRAF and tumor differentiation/localization, MutS homolog 3 (MSH3) and tumor diameter, and BRCA2 and absence of lymph node metastasis. It is necessary to have a comprehensive database of genomic alterations of colorectal carcinomas to interpret mutations more accurately clinically. There are no studies on the frequency of mutations in colorectal carcinomas in the Turkish population; thus, follow-up and treatment protocols are organized following the European and American databases and guidelines. A comprehensive study of the colorectal carcinoma patients' mutation profile in the Turkish patient cohort by the next-generation sequencing method will help to provide significant therapeutic, prognostic, and predictive data and design more successful treatment and follow-up strategies.

Predictive significance of lymphocyte level and neutrophil-to-lymphocyte ratio values during radiotherapy in cervical cancer treatment.

The objective of this research was to analyze the prognostic significance of the minimum count of lymphocytes (LY) and the corresponding ratio of neutrophil-to-lymphocyte (NLR) in cervical cancer (CC) patients receiving radiotherapy. We retrospectively collected data from 202 CC patients who received concurrent chemoradiotherapy or radiotherapy alone at our hospital. Statistical methods including the Kaplan-Meier method, log-rank test and the Cox proportional hazards model were included to examine survival differences and identify independent factors that may affect overall survival (OS) and progression-free survival (PFS). The research enrolled a total of 202 patients. Patients with higher LY levels and lower NLR values during radiotherapy had significantly better survival prognosis than those with lower LY levels and higher NLR values. Multivariate COX regression analysis revealed that FIGO stage I, pathological types of SqCC, absence of lymph node metastasis, concurrent chemoradiotherapy, higher LY levels during radiotherapy, and lower NLR values before radiotherapy were independently associated with poorer PFS. Similarly, FIGO stage I, absence of lymph node metastasis and lower NLR values during and before radiotherapy were independently linked with poorer OS. Minimum LY value and its corresponding NLR during radiotherapy serve as prognostic factors for CC.

NeoRAS wild-type metastatic colorectal cancer in the SCRUM-Japan GOZILA study.

3506 Background: The ’’Neo RAS’’ phenomenon refers to RAS mutant (MT) metastatic colorectal cancer (mCRC) that becomes RAS wild-type (WT) following treatment. This Neo RAS WT population might represent a novel indication for EGFR inhibitors, which are less effective in RAS MT mCRC. The incidence and clinicopathological characteristics of Neo RAS WT mCRC using plasma cell-free DNA (cfDNA) next generation sequencing has not been defined. Methods: As part of a large-scale nationwide screening platform (SCRUM-Japan GOZILA), 478 patients with an initial diagnosis of RAS MT mCRC by tissue analysis (MEBGEN RASKET-B) who received systemic therapy underwent cfDNA testing (Guardant 360) prior to later lines of treatment. Based on the cfDNA results, we evaluated the clinicopathological characteristics of those with Neo RAS WT and RAS MT. Neo RAS WT was defined as no RAS MT ( KRAS or NRAS) detected in plasma and was assessed in the overall cohort (Cohort A) and in the subgroup with at least one somatic alteration detected in plasma (Cohort B) to exclude those with insufficient tumor DNA shedding. Results: Median age at the time of blood sampling was 62.0 years old, and 257 (51.9%) were men. 160 (32.3%) and 319 (64.4%) had right-sided tumors and multi-organ metastases. The lungs were the most frequent site of metastasis (60.2%), followed by liver (57.4%), lymph nodes (28.9%), and peritoneum (28.5%). The prevalence of Neo RAS WT was 19.0% (91/478) in Cohort A and 9.8% (41/429) in Cohort B. The frequency of Neo RAS WT in tumors originally with KRAS exon 2 MT tended to be lower than in those with other RAS MT (18.1% vs 25.4%, P = 0.21 in Cohort A, 9.0% vs 15.4%, P = 0.14 in Cohort B). There were significant differences in the prevalence of Neo RAS WT between patients with single organ vs multi-organ metastases (P &lt; 0.001 in Cohort A, P = 0.004 in Cohort B), absence vs presence of liver metastasis (P &lt; 0.001 in both Cohort A and B), lymph node metastasis (P = 0.006 in Cohort A), peritoneal metastasis (P = 0.002 in group A), and bone metastasis (P = 0.029 in Cohort A), testing immediately prior to 2nd through to 4th line treatment vs later lines (P = 0.007 in Cohort A), immediate prior use of regorafenib (P = 0.027 in Cohort A) and any history of vascular endothelial growth factor inhibitors (P = 0.003 in Cohort A, P = 0.035 in Cohort B). In the logistic regression multivariate analysis, absence of liver metastasis (odds ratio [OR], 5.83; P &lt; 0.001 in Cohort A, OR, 2.84; P = 0.005 in Cohort B), absence of lymph node metastasis (OR, 2.18; P = 0.034 in Cohort A) and tissue RAS MT other than KRAS exon 2 (OR, 2.35; P = 0.049 in Cohort B) were significantly related to the emergence of Neo RAS WT. Among 6 Neo RAS WT patients tretd with EGFR inhibitors, one had partial response and another one had stable disease for at least 6 months. Conclusions: Liver and lymph node metastasis and RAS MT other than those in KRAS exon 2 are factors associated with the development of Neo RAS WT mCRC. EGFR inhibitors might be effective treatment.

Lymph node metastatic status could predict the prognosis of intracholecystic papillary neoplasm of gallbladder

Intracholecystic papillary neoplasm (ICPN) is a non-invasive epithelial tumor that presents as a grossly identifiable mass arising in the mucosa and protruding into the lumen. ICPN is associated with invasive carcinoma. There are few studies on the clinicopathological features of ICPN, including that with invasive carcinoma. We evaluated the clinicopathological characteristics of 42 ICPNs and 41 conventional gallbladder adenocarcinomas (cGBAs). Subserosa or deeper (≥ss) invasion was significantly lower in ICPN (61.9%) than that in cGBA (90.2%) (P=0.004). Cox regression analysis revealed that lymph node metastasis (hazard ratio [HR] [95% confidence interval (CI)]: 2.610 [1.131, 6.024], P=0.025) and positive margin (HR [95% CI]: 5.143 [2.113, 12.516], P<0.001), but not ≥ss invasion (HR [95% CI]: 1.541 [0.479, 4.959], P=0.469), were independent prognostic factors. In addition, there was a significant interaction between histological type and lymph node metastasis (HR [95% CI]: 0.191 [0.042, 0.983], P=0.033). In cGBA, the presence or absence of lymph node metastasis did not affect prognosis; however, ICPN without lymph node metastasis had better prognosis. Therefore, the histological classification of ICPN and cGBA and the pathological evaluation of lymph node metastasis in ICPN are crucial for determining prognosis.