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Biochimica Et Biophysica Acta. Reviews... Jan 2024Pancreatic cancer (PC) remains a leading cause of mortality worldwide due to the absence of early detection methods and the low success rates of traditional therapeutic... (Review)
Review
Pancreatic cancer (PC) remains a leading cause of mortality worldwide due to the absence of early detection methods and the low success rates of traditional therapeutic strategies. Drug resistance in PC is driven by its desmoplastic stroma, which creates a barrier that shields cancer niches and prevents the penetration of drugs. The PC stroma comprises heterogeneous cellular populations and non-cellular components involved in aberrant ECM deposition, immunosuppression, and drug resistance. These components can influence PC development through intricate and complex crosstalk with the PC cells. Understanding how stromal components and cells interact with and influence the invasiveness and refractoriness of PC cells is thus a prerequisite for developing successful stroma-modulating strategies capable of remodeling the PC stroma to alleviate drug resistance and enhance therapeutic outcomes. In this review, we explore how non-cellular and cellular stromal components, including cancer-associated fibroblasts and tumor-associated macrophages, contribute to the immunosuppressive and tumor-promoting effects of the stroma. We also examine the signaling pathways underlying their activation, tumorigenic effects, and interactions with PC cells. Finally, we discuss recent pre-clinical and clinical work aimed at developing and testing novel stroma-modulating agents to alleviate drug resistance and improve therapeutic outcomes in PC.
Topics: Humans; Pancreatic Neoplasms; Signal Transduction; Pancreas; Extracellular Matrix; Cancer-Associated Fibroblasts
PubMed: 38160899
DOI: 10.1016/j.bbcan.2023.189065 -
The British Journal of Radiology Feb 2022The peritoneum is a unique serosal membrane, which can be the site of primary tumors and, more commonly, secondary pathologic processes. Peritoneal carcinomatosis is the... (Review)
Review
The peritoneum is a unique serosal membrane, which can be the site of primary tumors and, more commonly, secondary pathologic processes. Peritoneal carcinomatosis is the most common malignant condition to affect the peritoneal cavity, and the radiologist plays an important role in making the diagnosis and assessing the extent of disease, especially in sites that may hinder surgery. In this review, we address the role of the radiologist in the setting of peritoneal pathology, focusing on peritoneal carcinomatosis as this is the predominant malignant process, followed by revising typical imaging findings that can guide the differential diagnosis.We review the most frequent primary and secondary peritoneal tumor and tumor-like lesions, proposing a systemic approach based on clinical history and morphological appearance, namely distinguishing predominantly cystic from solid lesions, both solitary and multiple.
Topics: Ascites; Ascitic Fluid; Carcinoma; Desmoplastic Small Round Cell Tumor; Diagnosis, Differential; Echinococcosis; Endometriosis; Female; Humans; Lymphangioma; Lymphoma; Magnetic Resonance Imaging; Mesothelioma; Neoplasms, Neuroepithelial; Peritoneal Neoplasms; Peritoneum; Peritonitis; Positron Emission Tomography Computed Tomography; Pseudomyxoma Peritonei; Splenosis; Tomography, X-Ray Computed
PubMed: 34767464
DOI: 10.1259/bjr.20210346 -
Expert Opinion on Investigational Drugs Apr 2021Cholangiocarcinomas (CCAs) are biliary epithelial tumors with rising incidence over the past 3 decades. Early diagnosis of CCAs remains a significant challenge and the... (Review)
Review
Cholangiocarcinomas (CCAs) are biliary epithelial tumors with rising incidence over the past 3 decades. Early diagnosis of CCAs remains a significant challenge and the majority of patients present at an advanced stage. CCAs are heterogeneous tumors and currently available standard systemic therapy options are of limited effectiveness. Immune checkpoint inhibition (ICI) has transformed cancer therapy across a spectrum of malignancies. However, the response rate to ICI has been relatively disappointing in CCAs owing to its desmoplastic tumor microenvironment (TME).: Tumor microenvironment of CCAs consists of innate and adaptive cells, stromal cells, and extracellular components (cytokines, chemokines, exosomes, etc.). This intricate microenvironment has multiple immunosuppressive elements that promote tumor cell survival and therapeutic resistance. Accordingly, there is a need for the development of effective therapeutic strategies that target the TME. Herein, we review the components of the CCA TME, and potential therapies targeting the CCA TME.: CCAs are desmoplastic tumors with a dense tumor microenvironment. An enhanced understanding of the various components of the CCA TME is essential in the effort to develop novel biomarkers for patient stratification as well as combination therapeutic strategies that target the tumor plus the TME.
Topics: Animals; Bile Duct Neoplasms; Biomarkers, Tumor; Cholangiocarcinoma; Drug Development; Humans; Immune Checkpoint Inhibitors; Molecular Targeted Therapy; Neoplasm Staging; Tumor Microenvironment
PubMed: 33322977
DOI: 10.1080/13543784.2021.1865308 -
The Journal of Pathology. Clinical... Jul 2020Among visceral metastatic sites, cutaneous melanoma (CM) metastasises initially to the liver in ~14-20% of cases. Liver metastases in CM patients are associated with...
Among visceral metastatic sites, cutaneous melanoma (CM) metastasises initially to the liver in ~14-20% of cases. Liver metastases in CM patients are associated with both poor prognosis and poor response to immunotherapy. Histopathological growth patterns (HGPs) of liver metastases of the replacement and desmoplastic type, particularly from colorectal cancer and uveal melanoma (UM), may impart valuable biological and prognostic information. Here, we have studied HGP in 43 CM liver metastases resected from 42 CM patients along with other prognostic factors from three institutions. The HGPs (replacement, desmoplastic, pushing) were scored at the metastasis-liver interface with two algorithms: (1) 100% desmoplastic growth pattern (dHGP) and any (≥1%) replacement pattern (any-rHGP) and (2) >50% dHGP, >50% rHGP or mixed (<50% dHGP and/or rHGP, pushing HGP). For 1 patient with 2 metastases, an average was taken to obtain 1 final HGP yielding 42 observations from 42 patients. 22 cases (52%) had 100% dHGP whereas 20 (48%) had any replacement. Cases with rHGP demonstrated vascular co-option/angiotropism. With the development of liver metastasis, only rHGP (both algorithms), male gender and positive resection margins predicted diminished overall survival (p = 0.00099 and p = 0.0015; p = 0.034 and p = 0.024 respectively). On multivariate analysis, only HGP remained significant. 7 of 42 (17%) patients were alive with disease and 21 (50%) died with follow-up after liver metastases ranging from 1.8 to 42.2 months (mean: 20.4 months, median: 19.0 months). 14 (33%) patients with previously-treated metastatic disease had no evidence of disease at last follow up. In conclusion, we report for the first time replacement and desmoplastic HGPs in CM liver metastases and their prognostic value, as in UM and other solid cancers. Of particular importance, any rHGP significantly predicted diminished overall survival while 100% dHGP correlated with increased survival. These results contribute to a better understanding of the biology of CM liver metastases and potentially may be utilised in managing patients with these metastases.
Topics: Adult; Aged; Cell Proliferation; Colorectal Neoplasms; Female; Histocytochemistry; Humans; Liver; Liver Neoplasms; Male; Melanoma; Middle Aged; Neoplasms, Second Primary; Prognosis; Skin Neoplasms; Uveal Neoplasms; Young Adult; Melanoma, Cutaneous Malignant
PubMed: 32304183
DOI: 10.1002/cjp2.161 -
Virchows Archiv : An International... May 2021Stromal categorization has been used to classify many epithelial cancer types. We assessed the desmoplastic reaction and compared its significance with other stromal... (Comparative Study)
Comparative Study
Stromal categorization has been used to classify many epithelial cancer types. We assessed the desmoplastic reaction and compared its significance with other stromal characteristics in early (cT1-2N0) oral tongue squamous cell carcinoma (OTSCC). In this multi-institutional study, we included 308 cases treated for early OTSCC at five Finnish university hospitals or at the A.C. Camargo Cancer Center in São Paulo, Brazil. The desmoplastic reaction was classified as immature, intermediate, or mature based on the amount of hyalinized keloid-like collagen and myxoid stroma. We compared the prognostic value of the desmoplastic reaction with a stromal grading system based on tumor-stroma ratio and stromal tumor-infiltrating lymphocytes. We found that a high amount of stroma with a weak infiltration of lymphocytes was associated statistically significantly with a worse disease-free survival with a hazard ratio (HR) of 2.68 (95% CI 1.26-5.69), worse overall survival (HR 2.95, 95% CI 1.69-5.15), and poor disease-specific survival (HR 2.66, 95% CI 1.11-6.33). Tumors having a high amount of stroma with a weak infiltration of lymphocytes were also significantly associated with a high rate of local recurrence (HR 4.13, 95% CI 1.67-10.24), but no significant association was found with lymph node metastasis (HR 1.27, 95% CI 0.37-4.35). Categorization of the stroma based on desmoplastic reaction (immature, intermediate, mature) showed a low prognostic value for early OTSCC in all survival analyses (P > 0.05). In conclusion, categorization of the stroma based on the amount of stroma and its infiltrating lymphocytes shows clinical relevance in early OTSCC superior to categorization based on the maturity of stroma.
Topics: Brazil; Disease-Free Survival; Female; Finland; Humans; Lymphatic Metastasis; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Retrospective Studies; Squamous Cell Carcinoma of Head and Neck; Stromal Cells; Tongue Neoplasms; Tumor Microenvironment
PubMed: 32955604
DOI: 10.1007/s00428-020-02930-5 -
The American Journal of Surgical... Dec 2023Although mostly recognized in the metastatic setting dedifferentiated and undifferentiated melanomas are increasingly recognized as cutaneous and, less commonly, mucosal...
Although mostly recognized in the metastatic setting dedifferentiated and undifferentiated melanomas are increasingly recognized as cutaneous and, less commonly, mucosal primary tumors. Their diagnosis is challenging and dependent on sampling and recognition of a conventional melanoma precursor and/or detection of a mutation in a conventional melanoma driver gene. PRAME immunohistochemistry has recently become an important ancillary tool in the separation of melanoma from benign nevi, but no comprehensive studies exist regarding its value in the detection of dedifferentiated and undifferentiated melanomas and their separation from atypical fibroxanthoma and pleomorphic dermal sarcoma, the main differential diagnoses on sun-damaged skin. After retrieval from archival files, we performed PRAME immunohistochemistry on 11 primary and 10 metastatic dedifferentiated and undifferentiated melanomas, 11 atypical fibroxanthomas, and 10 pleomorphic dermal sarcomas. Nuclear staining was assigned extent (ranging from 0 to 4 and reflecting the percentage of PRAME-positive tumor nuclei) and intensity scores (graded as absent, weak, moderate, and strong, with assigned scores ranging from 0 to 3) with combined scores ranging from 0 to 7. Both primary and metastatic dedifferentiated and undifferentiated melanomas showed strong and diffuse nuclear PRAME staining with median combined scores of 7. Strong and diffuse staining was also seen in all conventional melanoma precursors except for desmoplastic melanoma. In contrast, PRAME staining in atypical fibroxanthoma and pleomorphic dermal sarcoma was patchy and weak with median combined scores of 2. Our data emphasize the diagnostic utility of PRAME staining as a first screening tool in the detection and workup of dedifferentiated and undifferentiated melanomas, both in the primary and metastatic settings. PRAME immunohistochemistry is particularly helpful as it is also positive in tumors without a recognizable conventional melanoma precursor and in those associated with desmoplastic melanomas, where PRAME is typically found to be negative.
Topics: Humans; Biomarkers, Tumor; Melanoma; Skin Neoplasms; Transcription Factors; Diagnosis, Differential; Sarcoma; Antigens, Neoplasm
PubMed: 37727938
DOI: 10.1097/PAS.0000000000002125 -
Journal of Neuro-oncology Nov 2021Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) are classified together as grade I neuronal and mixed neuronal-glial tumor of the... (Meta-Analysis)
Meta-Analysis
PURPOSE
Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) are classified together as grade I neuronal and mixed neuronal-glial tumor of the central nervous system by the World Health Organization (WHO). These tumors are rare and have not been well characterized in terms of clinical outcomes. We aimed to identify clinical predictors of mortality and tumor recurrence/progression by performing an individual patient data meta-analysis (IPDMA) of the literature.
METHODS
A systematic literature review from 1970 to 2020 was performed, and individualized clinical data for patients diagnosed with DIA/DIG were extracted. Aggregated data were excluded from collection. Outcome measures of interest were mortality and tumor recurrence/progression, as well as time-to-event (TTE) for each of these. Participants without information on these outcome measures were excluded. Cox regression survival analyses were performed to determine predictors of mortality and tumor recurrence / progression.
RESULTS
We identified 98 articles and extracted individual patient data from 188 patients. The cohort consisted of 58.9% males with a median age of 7 months. The majority (68.1%) were DIGs, while 24.5% were DIAs and 7.5% were non-specific desmoplastic infantile tumors; DIAs presented more commonly in deep locations (p = 0.001), with leptomeningeal metastasis (p = 0.001), and was associated with decreased probability of gross total resection (GTR; p = 0.001). Gender, age, and tumor pathology were not statistically significant predictors of either mortality or tumor recurrence/progression. On multivariate survival analysis, GTR was a predictor of survival (HR = 0.058; p = 0.007) while leptomeningeal metastasis at presentation was a predictor of mortality (HR = 3.27; p = 0.025). Deep tumor location (HR = 2.93; p = 0.001) and chemotherapy administration (HR = 2.02; p = 0.017) were associated with tumor recurrence/progression.
CONCLUSION
Our IPDMA of DIA/DIG cases reported in the literature revealed that GTR was a predictor of survival while leptomeningeal metastasis at presentation was associated with mortality. Deep tumor location and chemotherapy were associated with tumor recurrence / progression.
Topics: Astrocytoma; Brain Neoplasms; Female; Ganglioglioma; Humans; Infant; Male; Meningeal Carcinomatosis; Neoplasm Recurrence, Local
PubMed: 34613581
DOI: 10.1007/s11060-021-03860-1 -
Medicina Oral, Patologia Oral Y Cirugia... Mar 2021Desmoplastic Ameloblastoma (DA) is a rare, true neoplasm of jaws with reported incidence of 4-13% among other variants of Ameloblastoma, however this appears distinct... (Review)
Review
BACKGROUND
Desmoplastic Ameloblastoma (DA) is a rare, true neoplasm of jaws with reported incidence of 4-13% among other variants of Ameloblastoma, however this appears distinct than the classic Ameloblastoma in anatomical distribution and clinical presentation. This is often mistaken as a fibro-osseous lesion because of its similar radiological appearance.
MATERIAL AND METHODS
To describe the clinical, radiographic and histopathological characteristics through a series of new cases of histologically proven DA including a case of an exceptionally large, recurrent lesion along with retrospective analysis of cases from literature available for an improved understanding of the behaviour and prognosis of DA. A total of 50 cases were analysed for the anatomical distribution, radiographic presentation and management. Out of the 50 cases, 47 cases were from the English literature reported from 2011 to 2019 and 3 were new cases.
RESULTS
DA showed a slight male predilection (male: female=1.17:1) with a predominance in the fourth and fifth decade of life. Mandibular involvement (52%) was more commonly seen with a marked tendency for the anterior region. Radiographically, most of the lesions presented mixed radiopacity with radiolucency(80%) and root displacement was observed in only 70.27 % cases. Recurrence rate of 26 .47 % was observed. Cases treated with resection resulted in lesser recurrence as compared to those treated with enucleation and curettage.
CONCLUSIONS
DA is distinguished by a peculiar display of clinicalopathological parameters. DA has tendency of local disposition and propensity of recurrence, which thus necessitates its aggressive management. It is not possible to conclude or report on the aggressive/recurrent nature and appropriate treatment modality for DA due to inadequate follow-up results.
Topics: Ameloblastoma; Female; Humans; Male; Mandible; Mandibular Neoplasms; Neoplasm Recurrence, Local; Radiography; Retrospective Studies
PubMed: 33037797
DOI: 10.4317/medoral.24152 -
World Neurosurgery Jan 2021Subungual melanoma (SUM) is a rare form of melanoma confined to the nailbed and is rarely of the desmoplastic subtype. The often subtle nature of SUM, initially starting...
BACKGROUND
Subungual melanoma (SUM) is a rare form of melanoma confined to the nailbed and is rarely of the desmoplastic subtype. The often subtle nature of SUM, initially starting as a small dark spot or line in the nailbed, means deeper invasion can occur before a patient seeks clinical evaluation for a large, ulcerated lesion. We report the only known case of perineural spread of SUM of the lower extremity and describe its extensive path of perineural spread from the toe.
CASE DESCRIPTION
A 72-year-old man with a distant history of SUM status post second ray amputation, presented for evaluation of ipsilateral foot drop. Imaging revealed nodular involvement of tibial, peroneal, and sciatic nerves. Biopsies revealed desmoplastic melanoma and he was treated with nivolumab.
CONCLUSIONS
We report the only known case of perineural spread of SUM of the lower extremity and describe the pathoanatomy of perineural spread. A high index of suspicion for recurrent disease should be maintained even many years after completion of treatment.
Topics: Amputation, Surgical; Antineoplastic Agents; Biopsy; Electromyography; Humans; Lower Extremity; Magnetic Resonance Imaging; Male; Melanoma; Middle Aged; Nail Diseases; Neoplasms; Nivolumab; Positron Emission Tomography Computed Tomography; Toes; Treatment Outcome
PubMed: 32916345
DOI: 10.1016/j.wneu.2020.09.010 -
Child's Nervous System : ChNS :... Dec 2021Medulloblastoma is an embryonal brain tumor that predominantly occurs in childhood with a wide histological and molecular variability. Our aim was to investigate the...
PURPOSE
Medulloblastoma is an embryonal brain tumor that predominantly occurs in childhood with a wide histological and molecular variability. Our aim was to investigate the expression of Toll-like receptors (TLRs), their association with the infiltration of immune cells and with the histological subgroups, and, also, with the overall survival of patients.
METHODS
Fifty-six paraffin-preserved biopsies from children with medulloblastoma of the classic, desmoplastic, and anaplastic subtypes were included. Microarrays of tissues were performed, and the infiltration of T and NK cells was quantified, as well as the expression of TLR7, TLR8, and TLR9. For all statistical analyses, significance was p < 0.05.
RESULTS
CD4 + and CD8 + T lymphocytes and NK cells were found infiltrating the tumor. The infiltration of NK and CD4 + cells was greater in the classic and desmoplastic subtypes than in anaplastic. We found an important expression of TLRs in all medulloblastomas, but TLR7 and TLR8 were considerably higher in classic and desmoplastic subtypes than in anaplastic. Importantly, we observed that TLR7 was a prognostic factor for survival.
CONCLUSIONS
Medulloblastomas present cellular infiltration and a differential expression of TLRs depending on the histological subtype. TLR7 is a prognostic factor of survival that is dependent on treatment and age.
Topics: Brain Neoplasms; Cerebellar Neoplasms; Child; Humans; Medulloblastoma; Survival Rate; Toll-Like Receptor 7; Toll-Like Receptor 8
PubMed: 34480601
DOI: 10.1007/s00381-021-05347-w