High Rate Of Distant Metastasis Research Articles

The relationship between differentially expressed thyroid cancer genes and clinical characteristics in metastatic children and adolescents

Objective: To investigate the relationship between genes and clinical characteristics in children and adolescents with metastatic differentiated thyroid cancer (caDTC). Methods: A cross sectional study. A total of 67 caDTC patients with lymph node metastasis or distant metastasis in Peking Union Medical College Hospital from December 2020 to December 2022 were included, according to the inclusion and exclusion criteria. Then the differences in clinicopathologic features and iodine intake were compared among different genomes, and the age subgroups divided by the age of 12 were further analyzed. Results: Among the 67 cases of caDTC, the diagnosed age [M(Q1, Q3)]was 13.2 (9.7, 16.9) years old, with 23 males and 44 females. There were 68.7% (46/67) of patients have distant metastasis (M1 stage). Pathogenic or potentially pathogenic gene variants were detected in 68.7% (46/67) of the patients, with RET or NTRK fusion (RET/NTRK) being the most common [43.3%(29/67)], BRAF V600E mutation followed [19.4%(13/67)].There was only 1 caDTC with NRAS Q61R mutation. The patients were divided into RET/NTRK fusion group (n=29), BRAF mutation group (n=12), other mutation group (n=4), and non-mutation group (n=21) (1 patient was not included in the gene mutation subgroup comparison due to the presence of NRAS Q61R mutation and BRAF V600E mutation). The comparison of gene feature groups showed that compared to the BRAF mutation group, caDTC with RET/NTRK fusion tended to have a lower age at diagnosis [12.6(9.3, 15.9) vs 17.2(15.5, 18.1) years old, P<0.001], the proportion of mutation load≥2 was higher (10.4% vs 8.3%, P=0.027), with statistically significant difference. Among 46 M1 stage patients, 71.7% (33/46) had initial iodine intake, and 30.4% (14/46) developed radioiodine-refractory (RAIR). In age group comparison, the<12 year old group had a higher proportion of male patients (51.9% vs 22.5%, P=0.013) and a lower incidence of BRAF V600E mutations (0 vs 32.5%, P<0.001) compared to the≥12 year old group, and the differences were statistically significant. Conclusions: The incidence of RET/NTRK fusion ranks first in metastatic caDTC, featured with younger age at diagnosis and higher rate of distant metastasis. Although most metastatic lesions initially consume iodine, they are prone to RAIR. Attention should be paid to the potential role of RET/NTRK fusion in the invasion and iodine resistance of young caDTC patients.

Invasive micropapillary type male breast cancer: a case report

Male breast cancer is rarely seen and peaks at the age of 71. Hyperestrogenism, gonadal dysfunction, obesity, and alcohol are among the risk factors for male breast cancer. In hereditary cases, BRCA2 mutation is often observed. The most common symptom is a painless mass that is palpable behind the nipple. Most male breast cancers are ductal carcinomas (81%), papillary carcinomas (13%), and mucinous carcinomas (6%). The invasive micropapillary carcinoma of the breast is important due to its high rate of lymphnode metastasis, recurrence, and distant metastasis. Mortality is 50% higher in men with lymphnode involvement compared to non-involved cases. Furthermore, as the number of affected lymphnodes increases, the prognos is worsens. In this study, we examined a case of invasive micropapillary type male breast cancer with clinical presentation as a palpable mass, lymphnode involvement, and aimed to highlight the radiological considerations that need attention.

Complications Rate and Related Factors After Laparoscopic Sphincter-Preserving Total Mesorectal Excision for Low Rectal Cancer: A Single-Center Study in Vietnam.

Colorectal cancer is a significant health concern. Surgery remains a critical component of the multimodal treatment strategy. The laparoscopic sphincter-preserving total mesorectal excision (TME) is increasingly utilized and effective, offering enhanced quality of life for patients compared to previous traditional methods. This study aims to determine the rate of complications and the related factors associated with complications following laparoscopic sphincter-preserving total mesorectal excision for low rectal cancer. This retrospective study was conducted at the University Medical Center of Ho Chi Minh City from March 2022 to March 2023. It included patients aged 18 years and older diagnosed with low rectal cancer who underwent laparoscopic sphincter-preserving total mesorectal excision. Data on patient demographics, surgical details, and postoperative complications were retrospectively collected and analyzed. Follow-ups were conducted up to six months after surgery. Of the 83 patients included, the postoperative complications rate was 14.5%. The complications observed included surgical wound infections (five cases), anastomotic leaks (five cases, including three recto-vaginal fistulas and two pelvic abscesses), urinary retention (one case), and pneumonia (one case). A significant finding was the higher rate of distant metastases in patients with complications compared to those without (p=0.033). Laparoscopic sphincter-preserving total mesorectal excision for low rectal cancer is safe and effective, with a high success rate and low complication rate during or after surgery. Anastomotic leakage remains the most significant complication. Despite advancements in surgery, modern suturing tools, and preoperative patient optimization, complications are avoidable. Therefore, understanding the related factors and implementing preventive interventions is crucial.

Association between the expression of epithelial-mesenchymal transition (EMT)-related markers and oncologic outcomes of colorectal cancer.

Epithelial-mesenchymal transition (EMT) is a key step in the development of colorectal cancer (CRC) that confers metastatic capabilities to cancer cells. The present study aimed to assess the immunohistochemical (IHC) expression and impact of EMT markers, including E-cadherin, Vimentin, β-catenin, and SMAD4, on the oncologic outcomes of CRC. This was a retrospective review of 118 CRC patients. Tissue slides were retrieved from the slide archive and five tissue microarray construction blocks were constructed. IHC for E-cadherin, Vimentin, β-catenin, and SMAD4 was done. The main outcome was the association between abnormal marker expression and overall survival (OS), and disease-free survival (DFS). Adenocarcinomas accounted for 71.2% of tumors, whereas 25.4% and 3.4% were mucinous and signet ring cell carcinomas. The rates of lymphovascular invasion and perineural invasion were 72.9% and 20.3%, respectively. There was a positive, significant correlation, and association between the four markers. Abnormal expression of E-cadherin was associated with significantly lower OS (p < 0.0001) and similar DFS (p = 0.06). Abnormal Vimentin expression was associated with a significantly higher rate of distant metastasis (p = 0.005) and significantly lower OS and DFS (p < 0.0001). Abnormal expression of β-catenin was associated with significantly lower OS (p < 0.0001) and similar DFS (p = 0.15). Abnormal expression of SMAD4 was associated with significantly lower OS and DFS (p < 0.0001). Abnormal expression of all four markers was associated with a higher disease recurrence, lower OS, and lower DFS. Abnormal expression of each marker was associated with lower OS, whereas abnormal expression of Vimentin and SMAD4 only was associated with lower DFS.

Giant Cell Tumor of Soft Tissue: An Updated Review.

Giant cell tumor of soft tissue (GCTST) is a locally aggressive mesenchymal neoplasm of intermediate malignancy that predominantly occurs in the superficial soft tissue of the extremities. It is histologically similar to a giant cell tumor of bone (GCTB) and shows a mixture of round to oval mononuclear cells and osteoclast-like multinucleated giant cells. Currently, immunohistochemistry plays a very limited role in the diagnosis of GCTST. Primary or secondary malignant GCTST has recently been described and tumors exhibiting high-grade histological features demonstrate higher rates of distant metastasis. GCTST lacks the H3-3A gene mutations that are identified in the vast majority of GCTBs, suggesting a different pathogenesis. Surgery is the standard treatment for localized GCTST. Incomplete surgical resection is usually followed by local recurrence. Radiation therapy may be considered when the close proximity of critical structures prevents microscopically negative surgical margins. The systemic treatment options for advanced or metastatic disease are very limited. This review provides an updated overview of the clinicoradiological features, pathogenesis, histopathology, and treatment for GCTST. In addition, we will discuss the differential diagnosis of this peculiar neoplasm.

Pushing the envelope in breast conserving surgery − is multiple-wire localization (3 or more wires) associated with increased risk of compromised margins and long-term recurrence?

IntroductionIn the last two decades there has been a paradigm shift with breast conserving surgery (BCS) being applied to larger and more extensive breast malignancies. The aim of this study is to examine the success of BCS being performed in patients with extensive breast malignancies requiring at least 3 wires for localization, and to assess possible risk factors for failure. Materials and methodsWe performed a retrospective single center review of 232 patients who underwent BCS between 2010 and 2020 requiring at least 3 wires for localization, thus comprising the multi-wire group (MWG). The cohort included a control group of 232 single-wire BCS patients (SWG) chronologically matched with the MWG. Patients with either invasive malignancy or ductal carcinoma in situ (DCIS) were included in the study. Clinical, radiological, and pathological data was collected. Proportions of positive surgical margins, re-lumpectomies and conversion to mastectomy were calculated. Survival analysis for locoregional and distant recurrence was performed. ResultsWomen in the MWG were younger (mean age 57 vs. 63.1, P < 0.001), had larger tumor size (mean size 5.1 cm vs. 1.3 cm, p < 0.001), a higher prevalence of calcifications on mammograms (72 % vs. 17 %, P < 0.001), a higher proportion of positive lymph nodes (75 % vs. 45 %, P = 0.019), and an elevated incidence of a ductal carcinoma in situ (DCIS) component (72 % vs. 38 %, P < 0.001).Positive surgical margins were higher in the MWG (13 % vs 7 %, P = 0.03), which lead to higher proportions of re-lumpectomies or conversion to mastectomies (7 % vs 4 %, P = 0.17). On multivariate analysis of the entire cohort, patients with positive margins were more likely to have a DCIS component (77 % vs 53 %, P = 0.001), an infiltrating lobular carcinoma (ILC) component (15 % vs 9 %, P = 0.013), and positive ER hormonal status (94 % vs 85 %, p = 0.05). The number of wires was not an independent predictor of positive margins.On long-term analysis, the locoregional disease-free survival was similar between the SWG and MWG (P = 0.1). However, the MWG showed higher rates of distant metastasis (12 % vs 4 %, P = 0.006). ConclusionsBCS requiring 3 or more wires is associated with a slightly higher proportion of positive margins. The increased risk of positive margins appears to be related to the type of tumor (DCIS component, ILC component and ER status) rather than to the number of wires. The number of wires does not significantly impact locoregional disease-free survival.

Arenobufagin induces cell apoptosis by modulating the cell cycle regulator claspin and the JNK pathway in nasopharyngeal carcinoma cells

ABSTRACT Background The high recurrence rate and incidence of distant metastasis of nasopharyngeal carcinoma (NPC) result in poor prognosis. It is necessary to identify natural compounds that can complement combination radiation therapy. Arenobufagin is commonly used for heart diseases and liver cancer, but its effectiveness in NPC is unclear. Study Design and Methods The effect of arenobufagin-induced apoptosis was measured by a cell viability assay, tumorigenic assay, fluorescence assay, and Western blot assay through NPC-039 and NPC-BM cell lines. The protease array, Western blot assay, and transient transfection were used to investigate the underlying mechanism of arenobufagin-induced apoptosis. An NPC xenograft model was established to explore the antitumor activity of arenobufagin in vivo. Results Our findings indicated that arenobufagin exerted cytotoxic effects on NPC cells, inhibiting proliferation through apoptosis activation. Downregulation of claspin was confirmed in arenobufagin-induced apoptosis. Combined treatment with arenobufagin and mitogen-activated protein kinase inhibitors demonstrated that arenobufagin induced NPC apoptosis through the c-Jun N-terminal kinases (JNK) pathway inhibition. Furthermore, arenobufagin suppressed NPC tumor proliferation in vivo. Conclusion Our results revealed the antitumor effect of arenobufagin in vitro and in vivo. Arenobufagin may have clinical utility in treating NPC due to its suppression of claspin and inhibition of the JNK pathway.

Abstract 1591: Hepatocytes compensate for the loss of PHGDH in pancreatic cancer cells during liver metastasis

Abstract Background: Pancreatic cancer (PC), one of the deadliest malignancies, exhibits a high rate of distant metastasis that directly correlates with the mortality rate. Liver serves as one of the most predominant sites of metastasis in PC patients. The nutrient availabilities at the metastatic organ and the metabolic dependencies of the invading tumor cells play pivotal role in shaping the metastatic tumor microenvironment (TME) and establishing metastatic colonies. We observed an elevated expression of PHGDH, the first rate-limiting enzyme of the serine (Ser) biosynthesis pathway, in the hepatocytes (most abundant liver-resident cells) isolated from murine pancreatic liver-metastasis (LM), as compared to normal livers. Hence, we hypothesized that hepatocytes may promote the growth of PC cells by sufficing for their Ser-requirement during LM. Methods: Murine PC line (HY19636 derived from LSL-KrasG12D; p53 L/+, Ptf1a-Cre+ tumors), were used to generate LMs in B6 mice via hemi-splenic route. PHGDH was knocked-out by lentiviral and AAV-mediated delivery of CRISPR-Cas9 gRNAs in vitro and in vivo, respectively. RNA-seq, immunoblot, immunohistochemistry, confocal microscopy, ELISA, flow cytometry, chromatin immunoprecipitation and promoter-reporter analyses were performed to identify the molecular axis, followed by functional validations using genetic and pharmacologic inhibitions in murine and human lines. Frozen homogenates with matched formalin-fixed sections of LMs from PC patients provided a unique correlative platform for the study. Results: A significant portion of the LM tissues (68% in our cohort of 32 PC patients) demonstrated no to very low expression of PHGDH in the cancer cells, rendering them as exogeneous Ser (exSer)-dependent. Notably, loss of PHGDH in the tumor cells induced an elevated PI3K/AKT signaling, downstream of a CXCL5/CXCR2 axis, in the neighboring hepatocytes. This led to FOXO3A’s cytoplasmic sequestration and decline in its occupancy on PHGDH promoter, causing a transcriptional upregulation of PHGDH in these hepatocytes, which enabled them to supply Ser and support the growth of exSer-dependent cancer cells in the liver. Abrogation of each node in the CXCR2-PI3K-FOXO3A axis and hepatocyte-specific deletion of PHGDH, led to a significant decline in the metastatic burden of exSer-dependent cells in the liver with a significant increase in overall mice survival, particularly under Ser-deprived dietary conditions. Conclusion: Our findings demonstrate a novel cancer cell-hepatocytes crosstalk necessary for the growth of PC cells in Ser-depleted conditions. Here, we have identified several actionable signaling nodes in the liver that serve as compensatory metabolic allies for PC cells during liver metastasis, and can be considered as potential therapeutic targets in adjuvant setting. Citation Format: Koelina Ganguly, Keisuke Yamamoto, Joel Encarnacion Rosado, Albert Sohn, Douglas Biancur, Elaine Lin, Elshadai White, Alec C. Kimmelman. Hepatocytes compensate for the loss of PHGDH in pancreatic cancer cells during liver metastasis [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 1591.

Assessment of Ki-67 expression in cases of prostatic carcinoma and its correlation with clinical outcomes.

Treatment decisions after diagnosis of clinically localized prostate cancer are difficult due to variability in tumor behavior. As there is a high prevalence of low-grade prostate cancer with an indolent course, we need improved markers of prostate cancer lethality in order to reduce the overtreatment. In the current study, we assessed Ki-67 expression in cases of prostate carcinoma and correlated its expression with clinical outcomes. It was a single-center retrospective descriptive type of study. A total of 50 cases were included. Diagnosed cases of adenocarcinoma on Transurethral Resection of the Prostate (TURP) chips and Trucut prostatic biopsies (Archival biopsy specimens) for whom five years follow-up was available from record files and/or telephonic interviews were included. The clinical outcomes (rate of distant metastases, disease specific survival, and overall survival) over a period of five years were recorded. In the current study, 78% of the cases of carcinoma prostate were positive for Ki-67 expression. The mean Ki-67 staining index was 15.22% among the cases. The cases with High Ki-67 Staining index had a significantly higher rate of distant metastasis, poor disease-specific survival, and overall survival compared to cases with low Ki-67 staining index. Ki-67 can be used along with the other established prognostic parameters to assess the lethality of prostate cancer.

Risk factor analysis of distant metastases in patients with primary medullary thyroid cancer: a population-based study.

Medullary thyroid carcinoma has a high rate of recurrence and distant metastasis. The aim of this study was to investigate the risk factors for distant metastasis in patients with primary medullary thyroid carcinoma. Patients diagnosed with primary medullary thyroid cancer between 2010 and 2015 were enrolled using the Surveillance, Epidemiology, and End Results (SEER) database. Patient demographics and tumor clinicopathological features were evaluated to identify potential risk factors for distant metastasis in patients with primary medullary thyroid cancer. Univariate and multivariate logistic regression analyses were used to determine independent risk factors for distant metastasis in patients with primary medullary thyroid carcinoma. All statistical analyses were performed using SPSS statistical software (version 27.0). A two-tailed P < 0.05 was considered statistically significant. We collected 685 patients with primary medullary thyroid carcinoma, 40 of whom (5.84%) developed distant metastases. Univariate logistic regression analysis showed that except marital status, age, sex, race, pT stage, N stage, multifocal and capsular infiltration were significantly correlated with distant metastasis of medullary thyroid carcinoma. Multivariate logistic regression analysis showed that patients aged ≤ 18years or > 55years, Black race, higher pT stage and N stage were independent risk factors for distant metastasis of medullary thyroid carcinoma. This study found that ≤ 18years or > 55years, black race, higher pT stage and N stage were significantly associated with distant metastasis of medullary thyroid cancer. This is important for clinicians to identify patients at high risk of distant metastasis in a timely manner.

Case Report: Genetic profiling of small intestine metastasis from poorly differentiated non-small cell lung cancer: report of 2 cases and literature review of the past 5 years

BackgroundPoorly differentiated non-small cell lung cancer (NSCLC) is characteristic of high rate of distant metastasis and late stages at diagnosis. Small intestine metastasis is a rare but severe complication of lung cancer with a high rate of mortality. However, there is currently a lack of genetic profile studies on the small intestine metastasis of lung cancer.Case presentationsWe present 2 cases of male patients in their 60s with primary NSCLC of low differentiation, initially with no distant metastasis detected. Biopsy samples were obtained from the primary pulmonary lesions, and both patients received systematic radiotherapy (RT) and chemotherapy. However, both cases presented with abdominal pain and distension, and immunohistochemistry of small intestine biopsy samples obtained by endoscopy confirmed lung cancer metastasis. Next generation sequencing was used to explore the genetic profiles from the biopsy samples of both the primary pulmonary lesions and small intestine metastases. The correlated genes responsible for the small intestine metastasis from poorly differentiated NSCLC in these 2 patients included TP53, LRP1B, and FGFR2. The reports of small intestine metastasis from poorly differentiated NSCLC with the past 5 years were systematically reviewed and summarized subsequently.ConclusionsPoorly differentiated NSCLC with small intestine metastases, while rare, substantially impacts the prognosis and poses major challenges for diagnosis and treatment. Through comparisons of genetic profiles between patients and in the same patient before and after metastasis, we identified the mutations in genes such as TP53, LRP1B, and FGFR2, which were correlated with the occurrence and progression of poorly differentiated NSCLC, as well as its small intestinal metastasis. This discovery has the potential to guide clinicians in developing personalized treatment plans through the manipulation of targeted and radiation therapies.

Triptolide Reduces MDA-MB-231 Cell Metastasis by Attenuating Epithelial-Mesenchymal Transition through the ROCK/PTEN/Akt Axis.

Triple-negative breast cancer (TNBC) is a highly heterogeneous and invasive subtype of breast cancer. The prognosis of TNBC is poor because of its high distant metastasis rate. Triptolide is a type of diterpene trioxide natural compound with potential anti-tumor activities. This study explored the metastatic inhibitory effect of triptolide on MDA-MB-231 cells and its underlying mechanism. Triptolide suppressed cell proliferation and induced cell apoptosis in a time- and dose-dependent manner. Low doses of triptolide (0-8 nM) reduced the migration and invasion capabilities of MDA-MB-231 cells. Triptolide decreased ROCK1, p-Akt, N-cadherin, vimentin and MMP-9 expressions, but increased PTEN and E-cadherin expressions on protein and mRNA levels. Furthermore, the down-regulation of ROCK1 expression in MDA-MB-231 cells after being treated by triptolide could be rescued by ROCK1 specific inhibitor Y27632. Molecular docking showed that triptolide and Y27632 shared the same active center of ROCK1 protein. This article's findings taken together showed that ROCK1 is the primary target of triptolide, which can cause cell apoptosis and inhibit the epithelial-mesenchymal transition of MDA-MB-231 cells.

The Regulatory Role of Circular RNAs as miRNA Sponges in Cervical Cancer

Abstract: Cervical cancer is ranked as the fourth most frequently diagnosed cancer and the fourth leading cause of cancer-related deaths among females. Cervical cancer is a complex disease influenced by various genetic, epigenetic, and environmental factors. While treatment options such as radiotherapy, chemotherapy, and hormonal therapy exist, the prognosis remains poor due to high rates of distant and lymphatic metastasis. Recent research has shed light on the role of non-coding RNAs (ncRNAs) in cervical cancer development, with circular RNAs (circRNAs) emerging as a potentially significant regulator of cellular processes. Through targeting miRNAs/mRNAs, circRNAs can impact cell growth and invasion in cervical cancer cells, making them a promising biomarker for diagnosis and treatment. This review provides an overview of the functional roles of circRNAs in the context of cervical cancer.

Salvage Abdominoperineal Resection for Locally Recurrent or Persistent Anal Squamous Cell Carcinoma after Definitive Chemoradiation.

Initial treatment for patients with squamous cell carcinoma of the anal canal includes definitive chemoradiation. Salvage abdominoperineal resection (APR) is the treatment of choice for recurrent or persistent disease. Older studies suggest approximately 50% successful salvage of recurrent or persistent disease with APR. Risk factors for failure after salvage APR are incompletely characterized. Using a single institutional database, patients were identified who underwent salvage APR after definitive intensity-modulated radiotherapy-based chemoradiation between 2003 and 2022. Clinical and pathologic variables analyzed included age at APR, sex, race, HIV status, initial cT stage, initial cN stage, radiation dose, recurrent vs persistent disease, recurrent pT stage, recurrent pN stage, the presence of LVSI, PNI or <2mm surgical margins, and the use of either intraoperative radiation or another treatment modality in addition to APR. The log rank test was used to determine differences in time from APR to events (local recurrence, distant metastasis and death) based on clinical and pathologic variables. The Cox Proportional Hazard Model was used to perform multivariable analysis for all factors with a univariate P-value <0.1. Of 628 patients with anal squamous cell carcinoma, 50 (8.0%) were treated with abdominoperineal resection for locally recurrent (n = 29, 58%) or locally persistent (n = 21, 42%) disease. Median [interquartile range] follow up was 40.0 months [15.2-68.0 months] from APR. Median local recurrence-free survival was not reached; 1- and 2-year local recurrence-free survival was 81% (95% CI 72-92%) and 76% (64-89%). On multivariable analysis, pathologic T-stage of the recurrence (3.85 (1.07-13.9); P = .040), the presence of lymphovascular space invasion (9.1 (1.12-73.62); P = .038) and surgical margins <2mm (8.81 (2.11-36.73); P = .003) were all significantly associated with higher rates of local recurrence. Median distant metastasis-free survival was not reached; 1- and 2-year distant metastasis-free survival was 88% (81-98%) and 79% (67-92%). On multivariable analysis, only persistent (versus recurrent) local disease was significantly associated with higher rates of distant metastasis (1.23 (1.05-5.55) P = .043). Median overall survival was not reached; 1- and 2-year overall survival was 90% (81-98%) and 78% (65-90%). On multivariable analysis, only recurrent pT stage (T3/4 vs T1/2) was associated with higher rates of death (5.87 (1.02-33.65); P = .047). APR is a successful salvage modality for anal squamous cell carcinoma with recurrent or persistent disease after chemoradiation results. Patients with pT3/4 disease, lymphovascular space invasion, surgical margins <2 mm may be associated with higher re-recurrence rates and may benefit from more frequent monitoring or treatment escalation.

Angiosarcoma in the breast: a population-based cohort from Sweden.

Breast angiosarcoma is a rare disease mostly observed in breast cancer (BC) patients who have previously received radiotherapy (RT). Little is known about angiosarcoma aetiology, management, and outcome. The study aim was to estimate risk and to characterize breast angiosarcoma in a Swedish population-based cohort. The Swedish Cancer Registry was searched for breast angiosarcoma between 1992 and 2018 in three Swedish healthcare regions (population 5.5 million). Information on previous BC, RT, management, and outcome were retrieved from medical records. Overall, 49 angiosarcomas located in the breast, chest wall, or axilla were identified, 8 primary and 41 secondary to BC treatment. Median age was 51 and 73 years, respectively. The minimum latency period of secondary angiosarcoma after a BC diagnosis was 4 years (range 4-21 years). The cumulative incidence of angiosarcoma after breast RT increased continuously, reaching 1.4‰ after 20 years. Among 44 women with angiosarcoma treated by surgery, 29 developed subsequent local recurrence. Median recurrence-free survival was 3.4 and 1.8 years for primary and secondary angiosarcoma, respectively. The 5-year overall survival probability for the whole cohort was 50 per cent (95 per cent c.i., 21 per cent-100 per cent) for primary breast angiosarcoma and 35 per cent (95 per cent c.i., 23 per cent-54 per cent) for secondary angiosarcoma. Breast angiosarcoma is a rare disease strongly associated with a history of previous BC RT. Overall survival is poor with high rates of local recurrences and distant metastasis.

Diagnosis and treatment in a case of uterine leiomyosarcoma - case report and review of the literature

Introduction: Uterine leiomyosarcoma accounts for approximately 3%–7% of all uterine cancers and it is the most common subtype of uterine sarcoma. They are associated with high potential to both local recurrence and distant metastases, and they contribute to a significant proportion of uterine cancer deaths. Tumor stage is the single most important prognostic factor for uterine sarcomas. Presenting symptoms may be vague and mimic other benign uterine conditions.The aim of the study: This study aims to describe a case of uterine leiomyosarcoma and summarize current knowledge about classification, diagnostics and treatment.Materials and methods: The research method was a case study. This review was based on available data collected in the PubMed database and Google Scholar web search engine, using the key words: uterine leiomyosarcoma, uterine sarcoma, hysterectomy, gynecologic oncology.Conclusion: Surgery is considered the mainstay of treatment for sarcomas limited to the uterus. In patients with carcinosarcomas postoperative radiotherapy increases the local control. High rate of distant metastases suggests potential role of systemic therapy. However, the benefits of postoperative chemotherapy and endocrine therapy in high-risk patients are of no proven value in the adjuvant setting. These methods, in addition to palliative radiotherapy and surgery are used in recurrent and advanced disease.Keywords: uterine leiomyosarcoma, uterine sarcoma, hysterectomy, gynecologic oncology

HIF1A-repressed PUS10 regulates NUDC/Cofilin1 dependent renal cell carcinoma migration by promoting the maturation of miR-194-5p.

Renal cell carcinoma (RCC) is characterized by a high rate of distant metastasis, which leads to poor prognosis in patients with advanced RCC. PUS10 has been recognized as a member of the pseudouridine synthase family, and recently other functions beyond the synthesis of the RNA modification have been uncovered. However, little is known about its role in diseases such as cancer. RT-qPCR, western blot and immunohistochemistry were used to measure the expression of PUS10 in RCC tissues. Transwell assay, wound healing assay, and in vivo metastasis model were conducted to determine the function of PUS10 in RCC progression. MicroRNA sequencing and GEO database were used to screen for the downstream microRNAs of PUS10. RNA immunoprecipitation, dual luciferase reporter assay, immunostaining, and rescue experiments were employed to establish the PUS10/miR-194-5p/nuclear distribution protein C(NUDC)/Cofilin1 axis in RCC migration. Chromatin immunoprecipitation and dual luciferase reporter assay were used to verify its upstream transcriptional regulator. The expression of PUS10 was significantly decreased in RCC tissues, and low expression predicted poor prognosis. In vitro and in vivo experiments showed that PUS10 suppressed RCC migration, which, however, was independent of its classical pseudouridine catalytic function. Mechanically, PUS10 promoted the maturation of miR-194-5p, which sequentially inhibited RCC migration via disrupting NUDC-dependent cytoskeleton. Furthermore, hypoxia and HIF-1A were found involved in the downregulation of PUS10. We unraveled PUS10 restrained RCC migration via the PUS10/miR-194-5p/NUDC/Cofilin1 pathway, which independent of its classical catalytic function. Furthermore, a linkage between the critical tumor microenvironment hallmark with malfunction of the forementioned metastasis inhibition mechanism was presented, as demonstrated by repressed expression of PUS10 due to hypoxia and HIF-1A.

Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers.

Adenoid cystic carcinoma (ACC) is a MYB-driven head and neck malignancy with high rates of local recurrence and distant metastasis and poor long-term survival. New effective targeted therapies and clinically useful biomarkers for patient stratification are needed to improve ACC patient survival. Here, we present an integrated copy number and transcriptomic analysis of ACC to identify novel driver genes and prognostic biomarkers. A total of 598 ACCs were studied. Clinical follow-up was available from 366 patients, the largest cohort analyzed to date. Copy number losses of 1p36 (70/492; 14%) and of the tumor suppressor gene PARK2 (6q26) (85/343; 25%) were prognostic biomarkers; patients with concurrent losses (n = 20) had significantly shorter overall survival (OS) than those with one or no deletions (p < 0.0001). Deletion of 1p36 independently predicted short OS in multivariate analysis (p = 0.02). Two pro-apoptotic genes, TP73 and KIF1B, were identified as putative 1p36 tumor suppressor genes whose reduced expression was associated with poor survival and increased resistance to apoptosis. PARK2 expression was markedly reduced in tumors with 6q deletions, and PARK2 knockdown increased spherogenesis and decreased apoptosis, indicating that PARK2 is a tumor suppressor in ACC. Moreover, analysis of the global gene expression pattern in 30 ACCs revealed a transcriptomic signature associated with short OS, multiple copy number alterations including 1p36 deletions, and reduced expression of TP73. Taken together, the results indicate that TP73 and PARK2 are novel putative tumor suppressor genes and potential prognostic biomarkers in ACC. Our studies provide new important insights into the pathogenesis of ACC. The results have important implications for biomarker-driven stratification of patients in clinical trials. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Clinical characteristics and treatment outcomes of invasive ductal and lobular carcinoma: analyses of 54,832 taiwan cancer registry index cases.

Invasive lobular cancer (ILC) is the second most common histology type of breast cancer followed by invasive ductal carcinoma (IDC). This study aimed to investigate the characteristic, treatment strategies, and clinical outcomes of ILC based on a national population-based cancer registry. This study recruited 2671 ILC and 52,215 IDC patients diagnosed between 2011 and 2017 using the Taiwan Cancer Registry (TCR). Correlations between ILC and IDC subgroups were assessed using 1:4 propensity score matching and compared using the χ2 test. Disease free survival(DFS) and overall survival(OS) were estimated using the Kaplan-Meier method with the log-rank test. The risk of disease relapse and mortality were assessed using Cox proportional hazards model. ILC patients had larger tumor sizes, more positive axillary lymph node involvement, lower tumor grade, and higher cancer stage than IDC patients. After matching, ILC patients had a significantly higher rate of receiving mastectomy (58.93% and 53.85%) and positive surgical margin regardless of surgery type. ILC exhibited a significantly higher rate of distant metastasis than IDC(3.67% and 2.93%), but no difference in local recurrence rate, DFS or OS between the two groups. Higher cancer stage, higher grade, and mastectomy were risk factors for disease relapse and cancer-specific mortality. The hormone receptor-positive and HER2 over-expression subtypes were found to be associated with a reduced risk of disease relapse, while only PR positivity was associated with a decreased risk of mortality. (all P-values < 0.05). ILC patients had a higher mastectomy rate, higher surgical margin rate and distant metastasis rate than IDC patients. There is no significant difference in DFS or OS between ILC and IDC patients. Mastectomy was associated with poor outcomes regardless of ILC or IDC.

The Rac inhibitor HV-107 as a potential therapeutic for metastatic breast cancer

BackgroundThe significant challenge in treating triple-negative breast cancer (TNBC) lies in its high rate of distant metastasis. To address this, inhibiting metastasis formation in TNBC is vital. Rac is a key player in cancer metastasis. Previously, we developed Ehop-016, a Rac inhibitor that successfully reduced tumor growth and metastasis in mice. In this study, we assessed the effectiveness of HV-107, a derivative of Ehop-016, in inhibiting TNBC metastasis at lower doses.MethodsRho GTPases activity assays were performed with the use of GST-PAK beads and Rac, Rho, and Cdc42 GLISA. Cell viability was assessed through trypan blue exclusion and MTT assays. Cell cycle analysis was conducted using flow cytometry. To evaluate invading capabilities, transwell assays and invadopodia formation assays were performed. Metastasis formation studies were conducted using a breast cancer xenograft mouse model.ResultsHV-107 inhibited Rac activity by 50% in MDA-MB-231 and MDA-MB-468 cells at concentrations of 250–2000 nM, leading to a 90% decrease in invasion and invadopodia activity. Concentrations of 500 nM and above caused dose-dependent reductions in cell viability, resulting in up to 20% cell death after 72 h. Concentrations exceeding 1000 nM upregulated PAK1, PAK2, FAK, Pyk2, Cdc42, and Rho signallings, while Pyk2 was downregulated at 100–500 nM. Through in vitro experiments, optimal concentrations of HV-107 ranging from 250 to 500 nM were identified, effectively inhibiting Rac activity and invasion while minimizing off-target effects. In a breast cancer xenograft model, administration of 5 mg/kg HV-107 (administered intraperitoneally, 5 days a week) reduced Rac activity by 20% in tumors and decreased metastasis by 50% in the lungs and liver. No observed toxicity was noted at the tested doses.ConclusionThe findings indicate that HV-107 exhibits promising potential as a therapeutic medication utilizing Rac inhibition mechanisms to address metastasis formation in TNBC.