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Frontiers in Oncology 2022Glioblastomas (GBM) are the most common and aggressive form of primary malignant brain tumor in the adult population, and, despite modern therapies, patients often...
Glioblastomas (GBM) are the most common and aggressive form of primary malignant brain tumor in the adult population, and, despite modern therapies, patients often develop recurrent disease, and the disease remains incurable with median survival below 2 years. Resistance to bevacizumab is driven by hypoxia in the tumor and evofosfamide is a hypoxia-activated prodrug, which we tested in a phase 2, dual center (University of Texas Health Science Center in San Antonio and Dana Farber Cancer Institute) clinical trial after bevacizumab failure. Tumor hypoxic volume was quantified by 18F-misonidazole PET. To identify circulating metabolic biomarkers of tumor hypoxia in patients, we used a high-resolution liquid chromatography-mass spectrometry-based approach to profile blood metabolites and their specific enantiomeric forms using untargeted approaches. Moreover, to evaluate early response to treatment, we characterized changes in circulating metabolite levels during treatment with combined bevacizumab and evofosfamide in recurrent GBM after bevacizumab failure. Gamma aminobutyric acid, and glutamic acid as well as its enantiomeric form D-glutamic acid all inversely correlated with tumor hypoxia. Intermediates of the serine synthesis pathway, which is known to be modulated by hypoxia, also correlated with tumor hypoxia (phosphoserine and serine). Moreover, following treatment, lactic acid was modulated by treatment, likely in response to a hypoxia mediated modulation of oxidative vs glycolytic metabolism. In summary, although our results require further validation in larger patients' cohorts, we have identified candidate metabolic biomarkers that could evaluate the extent of tumor hypoxia and predict the benefit of combined bevacizumab and evofosfamide treatment in GBM following bevacizumab failure.
PubMed: 36226069
DOI: 10.3389/fonc.2022.900082 -
Cell Reports Jul 2020Immunotherapy shifted the paradigm of cancer treatment. The clinical approval of immune checkpoint blockade and adoptive cell transfer led to considerable success in... (Review)
Review
Immunotherapy shifted the paradigm of cancer treatment. The clinical approval of immune checkpoint blockade and adoptive cell transfer led to considerable success in several tumor types. However, for a significant number of patients, these therapies have proven ineffective. Growing evidence shows that the metabolic requirements of immune cells in the tumor microenvironment (TME) greatly influence the success of immunotherapy. It is well established that the TME influences energy consumption and metabolic reprogramming of immune cells, often inducing them to become tolerogenic and inefficient in cancer cell eradication. Increasing nutrient availability using pharmacological modulators of metabolism or antibodies targeting specific immune receptors are strategies that support energetic rewiring of immune cells and boost their anti-tumor capacity. In this review, we describe the metabolic features of the diverse immune cell types in the context of the TME and discuss how these immunomodulatory strategies could synergize with immunotherapy to circumvent its current limitations.
Topics: Endoplasmic Reticulum Stress; Humans; Immunity; Immunotherapy; Models, Biological; Neoplasms; Tumor Microenvironment
PubMed: 32640218
DOI: 10.1016/j.celrep.2020.107848 -
Cancers Nov 2017In order to find low abundant proteins secretome and tumor tissue proteome data have been explored in the last few years for the diagnosis of colorectal cancer (CRC).... (Review)
Review
In order to find low abundant proteins secretome and tumor tissue proteome data have been explored in the last few years for the diagnosis of colorectal cancer (CRC). In this review we aim to summarize the results of studies evaluating markers derived from the secretome and tumor proteome for blood based detection of colorectal cancer. Observing the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines PubMed and Web of Science databases were searched systematically for relevant studies published up to 18 July 2017. After screening for predefined eligibility criteria a total of 47 studies were identified. Information on diagnostic performance indicators, methodological procedures and validation was extracted. Functions of proteins were identified from the UniProt database and the the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was used to assess study quality. Forty seven studies meeting inclusion criteria were identified. Overall, 83 different proteins were identified, with carcinoembryonic Antigen (CEA) being by far the most commonly reported (reported in 24 studies). Evaluation of the markers or marker combinations in blood samples from CRC cases and controls yielded apparently very promising diagnostic performances, with area under the curve >0.9 in several cases, but lack of internal or external validation, overoptimism due to overfitting and spectrum bias due to evaluation in clinical setting rather than screening settings are major concerns. Secretome and tumor proteome-based biomarkers when validated in blood yield promising candidates. However, for discovered protein markers to be clinically applicable as screening tool they have to be specific for early stages and need to be validated externally in larger studies with participants recruited in true screening setting.
PubMed: 29144439
DOI: 10.3390/cancers9110156 -
Oncology Letters Aug 2022Malignant Brenner tumor (MBT) of the ovary is a rare malignant ovarian tumor, whereas uterine corpus endometrioid carcinoma (UEC) constitutes one of the most common...
Coexistence of malignant ovarian Brenner tumor and borderline mucinous cystadenoma, combined with primary uterine corpus endometrioid carcinoma: A case report and literature review.
Malignant Brenner tumor (MBT) of the ovary is a rare malignant ovarian tumor, whereas uterine corpus endometrioid carcinoma (UEC) constitutes one of the most common malignant tumors of the female reproductive system. The present study reported on a case of the coexistence of ovarian MBT and borderline mucinous cystadenoma combined with primary UEC. Therefore, the present case is a synchronous primary cancer of both ovary and endometrium. Although synchronous primary cancers of the endometrium and ovary are relatively uncommon, they are not rare; however, due to the rarity of MBT, this case was considered singular. To the best of our knowledge, this was the first-ever reported case of the coexistence of an ovarian MBT and borderline mucinous cystadenoma combined with primary UEC. Based on a review of the literature associated with the present case, its clinicopathological features, immunohistochemical phenotype, differential diagnosis, molecular changes, prognosis and treatment were summarized and discussed. The aim of the present study was to improve the understanding of this rare synchronous primary cancer of the ovary and endometrium so as to avoid future misdiagnosis.
PubMed: 35782900
DOI: 10.3892/ol.2022.13392 -
Gynecologic Oncology Reports May 2019Malignant Brenner tumor (MBTs) is a rare histological subtype of epithelial ovarian cancer, accounting for <0.05% of all ovarian neoplasms. As such, current evidence on...
Malignant Brenner tumor (MBTs) is a rare histological subtype of epithelial ovarian cancer, accounting for <0.05% of all ovarian neoplasms. As such, current evidence on the treatment of MBTs is predominantly limited to case studies and small case series. To add to existing literature, we performed a retrospective review of 10 cases of MBT diagnosed and treated at a single institution between 1999 and 2018. For the 10 cases included in our cohort, the median age was 64 and the median tumor stage was IIa/IIb. All patients underwent either a primary or interval debulking surgery and achieved an R0 resection per classifications set by the Union for International Cancer Control (UICC). Lymph node dissections were performed on 6 patients and found no evidence of positive nodal disease. 7 patients received platinum-based adjuvant chemotherapy and experienced a median progression-free survival (PFS) of 37 months. Recurrent disease was varied in terms of locoregional versus distant spread, and these patients had largely suboptimal responses to salvage chemotherapy with doxorubicin, gemcitabine, and eribulin. Sites of metastatic disease included the liver, lungs, bone, and brain. While there is no consensus for the optimal treatment of this rare disease, MBTs seem to respond well to adjuvant platinum-taxane treatment after complete surgical resection, consistent with the current management approach of other epithelial ovarian cancers. Recurrent disease is considerably more difficult to manage, and clinicians may consider a wider avenue of treatment options to include hormonal, biologic, and radiation therapies.
PubMed: 30815527
DOI: 10.1016/j.gore.2019.02.003 -
Journal of the Turkish German... Mar 2022The purpose of the present study was to evaluate the clinical and pathological features and oncological outcomes of Brenner tumors (BT).
OBJECTIVE
The purpose of the present study was to evaluate the clinical and pathological features and oncological outcomes of Brenner tumors (BT).
MATERIAL AND METHODS
Evaluation was performed on the data of 46 patients with BTs retrieved from the oncology clinic database and pathology reports between 2005 and 2020.
RESULTS
The median (range) age of the patients was 52 (22-75) years. Median (range) tumor size was 52.5 (5.0-300) mm. The tumor was benign in 37 (80.4%), borderline in one (2.2%), and malignant in the remaining eight (17.4%). Ten (21.7%) of the tumors were detected incidentally. Mixed tumor, BT plus another ovarian pathology, was found in 13 (28.2%). Recurrence developed in 2/8 (25%) with malignant BT (MBT). The stage of these patients was 3C, and both received chemotherapy after surgery.
CONCLUSION
BTs are rare and generally detected incidentally. MBTs are treated in the same way as epithelial tumors. Due to the rarity of these tumors, lymphadenectomy and optimal chemotherapy regimens are controversial issues.
PubMed: 35000896
DOI: 10.4274/jtgga.galenos.2021.2021.0001 -
Frontiers in Oncology 2024Benign Brenner tumor (BBT) is a rare ovarian tumor, and there are few discrete reports about its manifestation in an ultrasound. This study sought to investigate the...
OBJECTIVE
Benign Brenner tumor (BBT) is a rare ovarian tumor, and there are few discrete reports about its manifestation in an ultrasound. This study sought to investigate the two-dimensional (2D) and contrast-enhanced ultrasound (CEUS) features of this entity.
METHODS
This is a retrospective single-center study. The clinical manifestations, laboratory examination, and ultrasound data of 25 female patients with BBT were confirmed by pathology when they underwent 2D and/or CEUS examination at Ningbo First Hospital from January 2012 to June 2023. The ultrasound findings of the patients were analyzed using the terminology of the International Organization for the Analysis of Ovarian Tumor and were read by two senior sonographers who reached an agreement.
RESULTS
Among the all 25 patients, most of them were unilateral, and only one patient was bilateral. Thus, 26 lesions were found: 44.0% (11/25) were in the left and 52.0% (13/25) were in the right. Moreover, 53.84% (14/26) were solid lesions, 15.38% (4/26) were mixed lesions, and 26.92% (7/26) were cystic lesions. Among the solid-type patients, 42.85% (6/14) of the cases were with calcification. Upon laboratory examination, 12.0% (3/25) of the patients had high carbohydrate antigen 125 (CA-125) level, and 19.04% (4/21) of the patients had an elevated carbohydrate antigen724 (CA-724) level in the serum tumor markers. In the hormone test, 14.28% (3/21) were found to have a high postmenopausal estrogen level and 14.28%(3/21) were found to have a high level of follicle-stimulating hormone (FSH). One patient with complex manifestations and three with solid manifestations were examined by CEUS to observe the microcirculation perfusion of the tumor. One with solid and cystic separation was rapidly hyperenhanced and cleared, and the filling subsided faster than the uterus. The postoperative pathological diagnosis was benign Brenner tumor with mucinous cystadenoma. The other three cases were solid adnexal lesions, which showed isoenhancement on CEUS and disappeared slowly, synchronizing with the uterus. The CEUS results were considered as benign tumors and confirmed by pathology.
CONCLUSIONS
BBT can show ovarian cystic, mixed cystic and solid type, and solid echo in 2D ultrasound. Unilateral ovarian fibrosis with punctate calcification is an important feature of BBT in 2D ultrasound. However, for solid adnexal masses and mixed cystic and solid masses with unclear diagnosis, if CEUS shows isoenhancement or hyperenhancement, the possibility of BBT cannot be excluded.
PubMed: 38525416
DOI: 10.3389/fonc.2024.1337806 -
Clinical and Translational Medicine Jun 2019Glioblastoma is the most common and malignant brain tumor in adults. Glioblastoma is usually fatal 12-15 months after diagnosis and the current possibilities in therapy...
BACKGROUND
Glioblastoma is the most common and malignant brain tumor in adults. Glioblastoma is usually fatal 12-15 months after diagnosis and the current possibilities in therapy are mostly only palliative. Therefore, new forms of diagnosis and therapy are urgently needed. Since tumor-associated macrophages are key players in tumor progression and survival there is large potential in investigating their immunological characteristics in glioblastoma patients. Recent evidence shows the expression of variable immunoglobulins and TCRαβ in subpopulations of monocytes, in vitro polarized macrophages and macrophages in the tumor microenvironment. We set out to investigate the immunoglobulin sequences of circulating monocytes and tumor-associated macrophages from glioblastoma patients to evaluate their potential as novel diagnostic or therapeutic targets.
RESULTS
We routinely find consistent expression of immunoglobulins in tumor-associated macrophages (TAM) and circulating monocytes from all glioblastoma patients analyzed in this study. However, the immunoglobulin repertoires of circulating monocytes and TAM are generally more restricted compared to B cells. Furthermore, the immunoglobulin expression in the macrophage populations negatively correlates with the tumor volume. Interestingly, the comparison of somatic mutations, V-chain usage, CDR3-length and the distribution of used heavy chain genes on the locus of chromosome 14 of the immunoglobulins from myeloid to B cells revealed virtually no differences.
CONCLUSIONS
The investigation of the immunoglobulin repertoires from TAM and circulating monocytes in glioblastoma-patients revealed a negative correlation to the tumor volume, which could not be detected in the immunoglobulin repertoires of the patients' B lymphocytes. Furthermore, the immunoglobulin repertoires of monocytes were more diverse than the repertoires of the macrophages in the tumor microenvironment from the same patients suggesting a tumor-specific immune response which could be advantageous for the use as diagnostic or therapeutic target.
PubMed: 31155685
DOI: 10.1186/s40169-019-0235-8 -
Human Pathology Jul 2011Recent morphologic, immunohistochemical, and molecular genetic studies have led to the development of a new paradigm for the pathogenesis and origin of epithelial... (Review)
Review
Recent morphologic, immunohistochemical, and molecular genetic studies have led to the development of a new paradigm for the pathogenesis and origin of epithelial ovarian cancer based on a dualistic model of carcinogenesis that divides epithelial ovarian cancer into 2 broad categories designated types I and II. Type I tumors comprise low-grade serous, low-grade endometrioid, clear cell and mucinous carcinomas, and Brenner tumors. They are generally indolent, present in stage I (tumor confined to the ovary), and are characterized by specific mutations, including KRAS, BRAF, ERBB2, CTNNB1, PTEN, PIK3CA, ARID1A, and PPP2R1A, which target specific cell signaling pathways. Type I tumors rarely harbor TP53 mutations and are relatively stable genetically. Type II tumors comprise high-grade serous, high-grade endometrioid, malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinomas. They are aggressive, present in advanced stage, and have a very high frequency of TP53 mutations but rarely harbor the mutations detected in type I tumors. In addition, type II tumors have molecular alterations that perturb expression of BRCA either by mutation of the gene or by promoter methylation. A hallmark of these tumors is that they are genetically highly unstable. Recent studies strongly suggest that fallopian tube epithelium (benign or malignant) that implants on the ovary is the source of low-grade and high-grade serous carcinoma rather than the ovarian surface epithelium as previously believed. Similarly, it is widely accepted that endometriosis is the precursor of endometrioid and clear cell carcinomas and, as endometriosis, is thought to develop from retrograde menstruation; these tumors can also be regarded as involving the ovary secondarily. The origin of mucinous and transitional cell (Brenner) tumors is still not well established, although recent data suggest a possible origin from transitional epithelial nests located in paraovarian locations at the tuboperitoneal junction. Thus, it now appears that type I and type II ovarian tumors develop independently along different molecular pathways and that both types develop outside the ovary and involve it secondarily. If this concept is confirmed, it leads to the conclusion that the only true primary ovarian neoplasms are gonadal stromal and germ cell tumors analogous to testicular tumors. This new paradigm of ovarian carcinogenesis has important clinical implications. By shifting the early events of ovarian carcinogenesis to the fallopian tube and endometrium instead of the ovary, prevention approaches, for example, salpingectomy with ovarian conservation, may play an important role in reducing the burden of ovarian cancer while preserving hormonal function and fertility.
Topics: Carcinoma, Ovarian Epithelial; Female; Humans; Mutation; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Tumor Suppressor Protein p53
PubMed: 21683865
DOI: 10.1016/j.humpath.2011.03.003 -
Modern Pathology : An Official Journal... Feb 2014Brenner tumors are ovarian tumors, usually benign, containing epithelium that resembles transitional epithelium. As with other epithelial tumors there exist frankly...
Brenner tumors are ovarian tumors, usually benign, containing epithelium that resembles transitional epithelium. As with other epithelial tumors there exist frankly malignant tumors and tumors that display greater proliferation than the benign Brenner tumors but lack destructive infiltrative growth, and these have been designated 'atypical proliferative' (borderline) Brenner tumors. There have been no well-documented cases of atypical proliferative Brenner tumors that have exhibited malignant behavior. Based on shared morphologic features it is generally believed that atypical proliferative Brenner tumors develop from benign Brenner tumors. The aim of the present study was to confirm this impression by investigating the immunohistochemical and molecular genetic features of benign and atypical proliferative Brenner tumors. Immunohistochemical staining for p16, fluorescence in-situ hybridization (FISH) for CDKN2A (p16-encoding gene) and mutational analysis of the genes commonly mutated in ovarian tumors were performed. p16 immunostaining was positive in the epithelial component of 12 (92%) of 13 benign Brenner tumors, but completely negative in all 7 atypical proliferative Brenner tumors. FISH identified homozygous deletion of CDKN2A in the epithelial component of all atypical proliferative Brenner tumors, but CDKN2A was retained in all benign Brenner tumors. Two PIK3CA somatic mutations were detected in the stromal component in 1 (5%) of 20 Brenner tumors and 3 somatic mutations (1 in KRAS and 2 in PIK3CA) were identified in the atypical epithelial component of 2 (29%) of 7 atypical proliferative Brenner tumors. In summary, our findings suggest that loss of CDKN2A and, to a lesser extent, KRAS and PIK3CA somatic mutations have a role in the progression of a benign to an atypical proliferative Brenner tumor.
Topics: Brenner Tumor; Class I Phosphatidylinositol 3-Kinases; Cyclin-Dependent Kinase Inhibitor p16; DNA Mutational Analysis; Disease Progression; Female; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Laser Capture Microdissection; Mutation; Ovarian Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Reverse Transcriptase Polymerase Chain Reaction; ras Proteins
PubMed: 23887305
DOI: 10.1038/modpathol.2013.142