Purpose
To evaluate the efficacy of the different diagnostic tests for vitreoretinal lymphoma (VRL).
Methods
A cohort of 150 patients with a presumed diagnosis of VRL. Vitrectomy samples were ...analysed for cytology, monoclonality polymerase chain reaction (PCR) and cytokine levels, and anterior chamber taps were analysed for cytokine levels. Vitreoretinal lymphoma (VRL) was diagnosed after confirming the clinical suspicion with vitreal or brain cytology.
Results
Vitreoretinal lymphoma (VRL) was diagnosed in 78 patients. Vitreal cytology was positive for 53/132 patients (40.2%), 36/53 had positive cytology from both the eye and the brain. Additional 25 patients had positive brain cytology. Vitreal PCR for monoclonality was positive for 32/91 patients (35.2%). Vitreal cytokine levels of interleukin (IL)‐10/IL‐6 were >1 for 47/110 patients (43.1%). For cytology, PCR and cytokine analysis, the respective sensitivity was 73.6%, 46.0% and 81.4%, and the accuracy of the tests was 85.6%, 60.4% and 80.9%, respectively. All three tests were available for 79 patients. In this subset, for cytology, PCR and cytokine analysis the respective sensitivity was 79.5%, 41.0% and 82.1%, respectively, and the accuracy of the tests was 89.9%, 60.8% and 81.0%, respectively.
Conclusion
Cytokines analysis has an important role in the diagnosis of VRL. We suggest analysing cytokines levels in all cases suspected of VRL along with cytology and PCR analysis.
Breast cancer subtypes display distinct biological traits that influence their clinical behavior and response to therapy. Recent studies have highlighted the importance of chromatin structure ...regulators in tumorigenesis. The RNF20-RNF40 E3 ubiquitin ligase complex monoubiquitylates histone H2B to generate H2Bub1, while the deubiquitinase (DUB) USP44 can remove this modification. We found that RNF20 and RNF40 expression and global H2Bub1 are relatively low, and USP44 expression is relatively high, in basal-like breast tumors compared with luminal tumors. Consistent with a tumor-suppressive role, silencing of RNF20 in basal-like breast cancer cells increased their proliferation and migration, and their tumorigenicity and metastatic capacity, partly through upregulation of inflammatory cytokines. In contrast, in luminal breast cancer cells, RNF20 silencing reduced proliferation, migration and tumorigenic and metastatic capacity, and compromised estrogen receptor transcriptional activity, indicating a tumor-promoting role. Notably, the effects of USP44 silencing on proliferation and migration in both cancer subtypes were opposite to those of RNF20 silencing. Hence, RNF20 and H2Bub1 have contrasting roles in distinct breast cancer subtypes, through differential regulation of key transcriptional programs underpinning the distinctive traits of each subtype.
Regulatory factors controlling stem cell identity and self-renewal are often active in aggressive cancers and are thought to promote their growth and progression. TCF3 (also known as TCF7L1) is a ...member of the TCF/LEF transcription factor family that is central in regulating epidermal and embryonic stem cell identity. We found that TCF3 is highly expressed in poorly differentiated human breast cancers, preferentially of the basal-like subtype. This suggested that TCF3 is involved in the regulation of breast cancer cell differentiation state and tumorigenicity. Silencing of TCF3 dramatically decreased the ability of breast cancer cells to initiate tumor formation, and led to decreased tumor growth rates. In culture, TCF3 promotes the sphere formation capacity of breast cancer cells and their self-renewal. We found that in contrast to ES cells, where it represses Wnt-pathway target genes, TCF3 promotes the expression of a subset of Wnt-responsive genes in breast cancer cells while repressing another distinct target subset. In the normal mouse mammary gland, Tcf3 is highly expressed in terminal end buds, structures that lead duct development. Primary mammary cells are dependent on Tcf3 for mammosphere formation, and its overexpression in the developing gland disrupts ductal growth. Our results identify TCF3 as a central regulator of tumor growth and initiation, and a novel link between stem cells and cancer.
Concerns have been mounting regarding the underdiagnosis of HIV among respiratory co-infections associated with the COVID-19 pandemic. The delay in recognizing HIV/AIDS may be attributed to the ...similarities in clinical, laboratory (lymphopenia) and imaging presentations, which are typical for advanced AIDS but could also be indicative of a COVID-19 infection.
Herein, we present a case of a 38-year-old ultraorthodox Jew with a late diagnosis of AIDS in the context of COVID-19 infection. This occurred after several months of recurrent respiratory infections compounded by SARS-COV 2 infection, during which no HIV testing was conducted. As a result, a cascade of various opportunistic infections ensued, leading to an extended hospitalization period, ultimately culminating in the patient's demise despite receiving optimal treatment.
Germline
pathogenic variant (PV) carriers have high lifetime risk of developing breast cancer and therefore subjected to intense lifetime screening. However, solid data on the effectiveness of ...high-risk screening of the
carrier population is limited.
Retrospectively, we analyzed 346 women diagnosed with breast tumors. Patients were divided according to the timing of
PVrecognition, before (BRCA-preDx awareness, N = 62) or after (BRCA-postDx awareness group, N = 284) cancer diagnosis.
Median follow-up times were 131.42 and 93.77 months in the BRCA-preDx awareness and BRCA-postDx awareness groups, respectively. In the BRCA-preDx awareness group, 78.7% of the patients had invasive tumors and 21.3% were diagnosed with pure ductal carcinoma
. In contrast, in the BRCA-postDx awareness group over 93% of women were diagnosed with invasive cancer and only 6.4% had
disease. The mode of tumor detection differed significantly between the groups: 71.9% in the BRCA-postDx awareness group and 26.2% in the BRCA-preDx awareness group were diagnosed after personally palpating a lump. Tumor size and nodal involvement were significantly more favorable in the BRCA-preDx awareness group. T stage was significantly lower in the BRCA-preDx awareness group: 54.84% at T1 and 20.96% at Tis. In the BRCA-postDx awareness group, only 37.54% were at T1 and 6.49% at Tis. The N stage was also significantly lower in the BRCA-preDx awareness group: 71% had no lymph node metastases, compared with 56.1% in the BRCA-postDx awareness group. Additionally, therapeutic procedures varied between the groups: BRCA-preDx awareness group patients underwent more breast conserving surgeries. Axillary lymph node dissection was done in 38% of women in the BRCA-postDx awareness group and in only 8.7% of the BRCA-preDx awareness group patients. Interestingly, improved survival was found among patients who underwent high-risk screening (hazard ratio=0.34).
High-risk screening might facilitate downstaging of detected breast tumor among
carrier population.
Breast cancer (BC) and obesity are two heterogeneous conditions with a tremendous impact on health. BC is the most commonly diagnosed neoplasm and the leading cause of cancer-related mortality among ...women, and the prevalence of obesity in women worldwide reaches pandemic proportions. Obesity is a significant risk factor for both incidence and worse prognosis in estrogen receptor positive (ER+) BC. Yet, the mechanisms underlying the association between excess adiposity and increased risk/therapy resistance/poorer outcome of ER+, but not ER−negative (ER−), BC are not fully understood. Tumor-promoting action of obesity, predominantly in ER + BC patients, is often attributed to the augmented production of estrogen in ‘obese’ adipose tissue. However, in addition to the estrogen production, expression levels of ER represent a key determinant in hormone-driven breast tumorigenesis and therapy response. Here, utilizing in vitro and in vivo models of BC, we show that macrophages, whose adverse activation by obesogenic substances is fueled by heparanase (extracellular matrix-degrading enzyme), are capable of upregulating ER expression in tumor cells, in the setting of obesity-associated BC. These findings underscore a previously unknown mechanism through which interplay between cellular/extracellular elements of obesity-associated BC microenvironment influences estrogen sensitivity—a critical component in hormone-related cancer progression and resistance to therapy.
While protease-activated-receptor 1 (PAR(1)) plays a central role in tumor progression, little is known about the cell signaling involved.
We show here the impact of PAR(1) cellular activities using ...both an orthotopic mouse mammary xenograft and a colorectal-liver metastasis model in vivo, with biochemical analyses in vitro. Large and highly vascularized tumors were generated by cells over-expressing wt hPar1, Y397Z hPar1, with persistent signaling, or Y381A hPar1 mutant constructs. In contrast, cells over-expressing the truncated form of hPar1, which lacks the cytoplasmic tail, developed small or no tumors, similar to cells expressing empty vector or control untreated cells. Antibody array membranes revealed essential hPar1 partners including Etk/Bmx and Shc. PAR(1) activation induces Etk/Bmx and Shc binding to the receptor C-tail to form a complex. Y/A mutations in the PAR(1) C-tail did not prevent Shc-PAR(1) association, but enhanced the number of liver metastases compared with the already increased metastases obtained with wt hPar1. We found that Etk/Bmx first binds via the PH domain to a region of seven residues, located between C378-S384 in PAR(1) C-tail, enabling subsequent Shc association. Importantly, expression of the hPar1-7A mutant form (substituted A, residues 378-384), which is incapable of binding Etk/Bmx, resulted in inhibition of invasion through Matrigel-coated membranes. Similarly, knocking down Etk/Bmx inhibited PAR(1)-induced MDA-MB-435 cell migration. In addition, intact spheroid morphogenesis of MCF10A cells is markedly disrupted by the ectopic expression of wt hPar1. In contrast, the forced expression of the hPar1-7A mutant results in normal ball-shaped spheroids. Thus, by preventing binding of Etk/Bmx to PAR(1) -C-tail, hPar1 oncogenic properties are abrogated.
This is the first demonstration that a cytoplasmic portion of the PAR(1) C-tail functions as a scaffold site. We identify here essential signaling partners, determine the hierarchy of binding and provide a platform for therapeutic vehicles via definition of the critical PAR(1)-associating region in the breast cancer signaling niche.
Mammalian heparanase degrades heparan sulfate, the main polysaccharide of the basement membrane. Heparanase is an important determinant in cancer progression, acting via the breakdown of ...extracellular barriers for invasion, as well as release of heparan sulfate-bound angiogenic and growth-promoting factors. The present study was undertaken to elucidate molecular mechanisms responsible for heparanase overexpression in breast cancer.
To characterize heparanase regulation by estrogen and tamoxifen and its clinical relevance for breast tumorigenesis, we applied immunohistochemical analysis of tissue microarray combined with chromatin immunoprecipitation assay, reverse transcription-PCR, and Western blot analysis.
A highly significant correlation (P<0.0001) between estrogen receptor (ER) positivity and heparanase overexpression was found in breast cancer. Binding of ER to heparanase promoter accompanied estrogen-induced increase in heparanase expression by breast carcinoma cells. Surprisingly, heparanase transcription was also stimulated by tamoxifen, conferring a proliferation advantage to breast carcinoma cells grown on a naturally produced extracellular matrix. Heparanase overexpression was invariably detected in ER-positive second primary breast tumors, developed in patients receiving tamoxifen for the initial breast carcinoma. The molecular mechanism of the estrogenlike effect of tamoxifen on heparanase expression involves recruitment of transcription coactivator AIB1 to the heparanase promoter.
Heparanase induction by ligand-bound ER represents an important pathway in breast tumorigenesis and may be responsible, at least in part, for the failure of tamoxifen therapy in some patients. Our study provides new insights on breast cancer progression and endocrine therapy resistance, offering future strategies for delaying or reversing this process.
Heparanase is a mammalian endo-β-D-glucuronidase that cleaves heparan sulfate side chains at a limited number of sites. Such enzymatic activity is thought to participate in degradation and remodeling ...of the extracellular matrix and to facilitate cell invasion associated with tumor metastasis, angiogenesis and inflammation. Traditionally, heparanase activity was well correlated with the metastatic potential of a large number of tumor-derived cell types. More recently, heparanase upregulation has been documented in an increasing number of primary human tumors, correlating with poor postoperative survival and increased tumor vascularity. Here, we employed anti-heparanase 733 polyclonal antibody that preferentially recognizes the 50 kDa active heparanase subunit over the 65 kDa proenzyme, as well as anti-heparanase 92.4 monoclonal antibody that recognizes both the latent and the active enzyme, to follow heparanase expression, processing and localization throughout the adenoma–carcinoma transition of the colon epithelium. Normal (nondysplastic) mucosa of the large bowel near epithelial neoplasms, as well as areas of mild dysplasia in adenomas, exhibited a strong reactivity with antibody 733 that became even stronger in foci of moderate dysplasia. Interestingly, although reactivity with antibody 733 was markedly reduced in severe dysplasia and in colorectal carcinoma, response to antibody 92.4 exhibited the opposite trend and staining intensities increased in parallel with tumor stage, the highest being in carcinoma cells. Involvement of latent heparanase (detected by 92.4, but not by 733 antibody) in tumor progression was suggested by activation of the Akt/PKB signal transduction pathway upon heparanase overexpression or exogenous addition to HT29 human colon carcinoma cells. These results suggest that heparanase expression is induced during colon carcinogenesis, and that its processing, conformation and localization are tightly regulated during the course of colon adenoma–carcinoma progression.
Objectives
Current surgical policy recommends comprehensive excision of tumorous calcifications in breast cancer patients following neoadjuvant chemotherapy (NAC) regardless of MRI outcomes, despite ...MRI defining tumor response superior to mammography. The current study examines MRI prediction of response in tumors with vs without calcifications, using post-NAC surgical pathology as the standard of reference.
Methods
Retrospective analysis of 114 NAC patients between 2011 and 2018 including demographics, mammography, 3 T-MRI, and pathology compared two sub-groups: without (
n
= 62) or with (
n
= 52) mammographic calcifications. In the calcification cohort, the mammographic extent of calcifications and MRI enhancement overlapped. MRI prediction of response to NAC was correlated with pathology. Two-tailed paired
T
and Fisher’s exact tests and Cohen’s kappa coefficient were applied for analysis.
Results
There was no significant difference between the two sub-groups regarding demographics. Tumors demonstrated equivalent features regarding size, lymph node involvement, and DCIS component. ER-negative/HER2-positive tumors more commonly exhibited calcifications (33%
n
= 17 calcified vs 13%
n
= 8 non-calcified;
p
< 0.05); triple negative pathology rarely calcified (6%
n
= 3 calcified vs 33%
n
= 20 non-calcified;
p
< 0.05). NME was more common with calcifications (62%
n
= 32 calcified vs 29%
n
= 18 non-calcified;
p
< 0.05) and mass enhancement without (90%
n
= 56 non-calcified vs 81%
n
= 42 calcified;
p
< 0.05). Both groups responded similarly to NAC (pCR = 37% non-calcified vs 38% calcified); response on MRI equally correlated with pathology (69% both subgroups;
p
= 0.988).
Conclusion
We propose utilizing post-NAC MRI findings rather than mammography in planning surgery, as MRI prediction is independent of the presence or absence of calcifications. Prospective studies to evaluate this approach are warranted.
Key Points
•
No difference was found in demographic, clinical, pathology, or imaging characteristics between patients with or without tumoral calcifications on mammography prior to neoadjuvant chemotherapy
.
•
Residual mammographic calcifications are inadequate predictors of residual invasive disease. MRI accurately recognized complete response and correctly correlated with post-treatment surgical pathology in 69% of patients, regardless of the presence or absence of mammographic calcifications
.
•
We propose utilizing post-NAC MRI findings rather than mammography in planning post-NAC surgery, as MRI prediction of response is independent of the presence or absence of calcifications
.
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