Biomedical subjects

Tarek A Bismar

Publications and source records attributed to Tarek A Bismar.

14 recordsLinked to original sources

PubMed2026

GPNMB-directed CAR T cell therapy against MiT/TFE-family fusion-driven solid tumors.

Chimeric antigen receptor (CAR) T cell therapy for solid tumors is constrained by the scarcity of safe, uniformly expressed cell-surface targets. Here we identify glycoprotein NMB (GPNMB)-an MiT/TFE-family fusion-driven protein-as being highly, homogeneously and stably expressed in primary and relapsed alveolar soft-part sarcoma (ASPS) and translocation renal cell carcinoma. We develop a GPNMB-directed CAR T cell product, GCAR1, which demonstrates potent activity against patient-matched cells, organoids and xenograft models. Post hoc interim analysis of a first-in-human open-label, individual-participant trial ( NCT07104682 ) for a participant with relapsed/refractory, metastatic ASPS showed that GCAR1 induces stable disease for up to 3 months, accompanied by resolution of many nontarget lesions (primary endpoint), and is well tolerated. GCAR1 T cells expand in peripheral blood as a polyclonal population and remain detectable for 1 month. Spatial transcriptomics identified immunosuppressive niches in a treatment-resistant lesion and immune checkpoint blockade synergized with GCAR1 in a xenograft model. Altogether, our data provide a proof of concept for treating GPNMB-expressing solid tumors with GCAR1 and more broadly targeting surface antigens driven by oncogenic gene fusions with CAR T cell therapies.

Animals↗

PubMed2006

Prognostic factors in lymph node-positive prostate cancer.

OBJECTIVES: To characterize lymph node metastasis of prostate cancer (PCa) and identify the parameters associated with patient outcome. The incidence of clinically localized PCa with concurrent lymph node metastasis has decreased to less than 1% in the United States but is between 10% and 15% in other countries. METHODS: Our study cohort of 1148 patients underwent radical prostatectomy in Ulm, Germany, between 1986 and 2002, and 201 (18%) had lymph node-positive PCa. RESULTS: The metastases showed growth architecture resembling primary PCa. We assigned a Gleason pattern and evaluated for size, extranodal extension, and lymphovascular invasion (LVI). Of 201 patients, 155 had original pathology slides available; 36 of the 155 were excluded because of preoperative hormonal ablation therapy. Of the remaining 119 patients, 22 (19%) were assigned Gleason pattern 3, 93 (78%) Gleason pattern 4, and 4 (3%) Gleason pattern 5. Extranodal extension was present in 66 (55%) of 119 patients and LVI in 29 (25%). An increased risk of prostate-specific antigen (PSA) recurrence was found for Gleason pattern 4/5 (hazard ratio [HR] 2.5, P = 0.038), LVI in the lymph nodes (HR 1.9, P = 0.038), and nuclear grade of the primary tumor (HR 2, P = 0.025). Independent predictors of PSA recurrence included LVI and nuclear grade (HR 1.9, P = 0.03 and HR 2, P = 0.03, respectively). CONCLUSIONS: Lymph node metastases of PCa are heterogeneous and have a close relation to the corresponding primary tumor. Most patients with lymph node-positive PCa remained disease free for up to 13 years after radical prostatectomy. Independent predictors of PSA recurrence among those with lymph node-positive PCa included LVI in the lymph nodes and the nuclear grade of the primary tumor. These parameters may be useful in predicting PSA recurrence in lymph node-positive PCa and could be included in patient follow-up.

Aged↗

PubMed2006

Defining aggressive prostate cancer using a 12-gene model.

The critical clinical question in prostate cancer research is: How do we develop means of distinguishing aggressive disease from indolent disease? Using a combination of proteomic and expression array data, we identified a set of 36 genes with concordant dysregulation of protein products that could be evaluated in situ by quantitative immunohistochemistry. Another five prostate cancer biomarkers were included using linear discriminant analysis, we determined that the optimal model used to predict prostate cancer progression consisted of 12 proteins. Using a separate patient population, transcriptional levels of the 12 genes encoding for these proteins predicted prostate-specific antigen failure in 79 men following surgery for clinically localized prostate cancer (P = .0015). This study demonstrates that cross-platform models can lead to predictive models with the possible advantage of being more robust through this selection process.

Biomarkers, Tumor↗

PubMed2006

ErbB receptors and epithelial-cadherin-catenin complex in human carcinomas.

The ErbB family of receptor tyrosine kinases have important roles in maintaining normal epithelial cell function. The ErbBs are involved in the interaction between cells and cell-matrix adhesion molecules and have proven critical in maintaining the integrity of the epithelial cell environment. Deregulation of these tyrosine receptors has been associated with several human diseases. In particular, the expression or activation of epidermal growth factor receptor (EGFR) and ErbB2 is altered in many epithelial tumors. Epithelial (E)-cadherin is another major molecule expressed by epithelial cells. To create efficient cell-cell adhesion, E-cadherin couples its cytoplasmic domain to catenins and the actin cytoskeleton. The loss of intercellular adhesion appears to be a fundamental aspect of the neoplastic phenomena. In addition, EGFR and ErbB2 signaling associated with the E-cadherin-catenin complex has been demonstrated in normal and cancer cells. This signaling is involved in regulating cell adhesion and the invasive growth of cancers. This article provides an overview of the interaction between the ErbB tyrosine receptors and the E-cadherin-catenin complex in human carcinomas.

Cadherins↗

PubMed2005

A germ line mutation that delays prostate cancer progression and prolongs survival in a murine prostate cancer model.

Circulating insulin-like growth factor-I (IGF-I) levels have been shown to be related to risk of prostate cancer in epidemiologic studies. While specific genetic loci responsible for interindividual variation in circulating IGF-I levels in normal men have not been identified, candidate genes include those involved in the growth hormone (GH)-IGF-I axis such as the hypothalamic factors GH releasing hormone (GHRH) and somatostatin and their receptors. To investigate the role of the GH-IGF-I axis on in vivo prostate carcinogenesis and neoplastic progression, we generated mice genetically predisposed to prostate cancer (the TRAMP model) to be homozygous for lit, a mutation that inactivates the GHRH receptor (GHRH-R) and reduces circulating levels of GH and IGF-I. The lit mutation significantly reduced the percentage of the prostate gland showing neoplastic changes at 35 weeks of age (P=0.0005) and was also associated with improved survival (P<0.01). These data provide an example of a germ line mutation that reduces risk in an experimental prostate carcinogenesis model. The results suggest that prostate carcinogenesis and progression may be influenced by germ line variation of genes encoding signalling molecules in the GH-IGF-I axis.

Animals↗

PubMed2005

Decreased alpha-methylacyl CoA racemase expression in localized prostate cancer is associated with an increased rate of biochemical recurrence and cancer-specific death.

Alpha-methylacyl CoA racemase (AMACR) is overexpressed in prostate cancer relative to benign prostatic tissue. AMACR expression is highest in localized prostate cancer and decreases in metastatic prostate cancer. Herein, we explored the use of AMACR as a biomarker for aggressive prostate cancer. AMACR protein expression was determined by immunohistochemistry using an image analysis system on two localized prostate cancer cohorts consisting of 204 men treated by radical prostatectomy and 188 men followed expectantly. The end points for the cohorts were time to prostate-specific antigen (PSA) failure (i.e., elevation >0.2 ng/mL) and time to prostate cancer death in the watchful waiting cohort. Using a regression tree method, optimal AMACR protein expression cut-points were determined to best differentiate prostate cancer outcome in each of the cohorts separately. Cox proportional hazard models were then employed to examine the effect of the AMACR cut-point on prostate cancer outcome, and adjusted for clinical variables. Lower AMACR tissue expression was associated with worse prostate cancer outcome, independent of clinical variables (hazard ratio, 3.7 for PSA failure; P = 0.018; hazard ratio, 4.1 for prostate cancer death, P = 0.0006). Among those with both low AMACR expression and high Gleason score, the risk of prostate cancer death was 18-fold higher (P = 0.006). The AMACR cut-point developed using prostate cancer-specific death as the end point predicted PSA failures independent of Gleason score, PSA, and margin status. This is the first study to show that AMACR expression is significantly associated with prostate cancer progression and suggests that not all surrogate end points may be optimal to define biomarkers of aggressive prostate cancer.

Biomarkers, Tumor↗

PubMed2004

Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program.

Understanding the biology of prostate cancer metastasis has been limited by the lack of tissue for study. We studied the clinical data, distribution of prostate cancer involvement, morphology, immunophenotypes, and gene expression from 30 rapid autopsies of men who died of hormone-refractory prostate cancer. A tissue microarray was constructed and quantitatively evaluated for expression of prostate-specific antigen, androgen receptor, chromogranin, synaptophysin, MIB-1, and alpha-methylacylCoA-racemase markers. Hierarchical clustering of 16 rapid autopsy tumor samples was performed to evaluate the cDNA expression pattern associated with the morphology. Comparisons were made between patients as well as within the same patient. Metastatic hormone-refractory prostate cancer has a heterogeneous morphology, immunophenotype, and genotype, demonstrating that "metastatic disease" is a group of diseases even within the same patient. An appreciation of this heterogeneity is critical to evaluating diagnostic and prognostic biomarkers as well as to designing therapeutic targets for advanced disease.

Aged↗

PubMed2004

Relating biopsy and clinical variables to radical prostatectomy findings: can insignificant and advanced prostate cancer be predicted in a screening population?

OBJECTIVES: To assess the capacity of several clinical and needle biopsy pathologic parameters to predict insignificant and advanced prostate carcinoma (CaP) in radical prostatectomy tissue from men enrolled in a prostate-specific antigen screening program. METHODS: We captured multiple clinical variables and measures of needle biopsy tumor extent from 152 men with Stage T1c CaP with a mean of six biopsy cores who were treated with radical prostatectomy. Insignificant CaP was defined as a tumor volume of less than 0.5 cm(3) that was organ confined with a Gleason score less than 7. Advanced CaP was defined by a formula that combined the Gleason score, pathologic stage, and margin status. Bivariate and logistic regression analyses were used to identify variables predictive of either insignificant or advanced CaP. RESULTS: Of the cases of CaP, 25.7% were pathologically insignificant, and 14.5% were pathologically advanced. The best model for predicting insignificant CaP was less than 10% tumor as the greatest percentage of carcinoma in any core and a biopsy Gleason score of less than 7, yielding a sensitivity of 76.9% and specificity of 75.2%. For predicting advanced CaP, the best model was a total biopsy length of CaP greater than 3 mm, Gleason high-grade pattern 4 or 5 disease, perineural invasion in the biopsy, and more than one in six biopsy cores containing CaP, yielding a sensitivity of 13.6% and specificity of 100%. CONCLUSIONS: The prediction of insignificant and advanced CaP on an individual basis in patients from a prostate-specific antigen screening study is a challenging problem. However, several histopathologic features of CaP in needle biopsy tissue contain useful information about the severity of disease.

Adenocarcinoma↗

PubMed2004

Prostate needle biopsy reporting: how are the surgical members of the Society of Urologic Oncology using pathology reports to guide treatment of prostate cancer patients?

Recent trends in prostate needle biopsy reporting have resulted in the inclusion of more information and new diagnostic categories. The goal of the current study was to survey surgical Members of the Society of Urologic Oncology to determine what information academic urologists consider important in the management of their prostate cancer (PCa) patients. A questionnaire was developed to investigate several areas of PCa biopsy reporting, which vary from institution to institution. Urologists were sent questionnaires and asked to return anonymous responses; 42 questionnaires were completely evaluated with a response rate of 76% (42 of 55). The urologists targeted for this survey were highly experienced with an average of 22 years in clinical practice (range, 6-35 years). On average, they performed 92 radical prostatectomies per year and 449 over the past 5 years (range, 60-1500) for a group total of 18,840 radical prostatectomies; 94% have their patient's biopsy reviewed prior to surgery. The primary and secondary Gleason pattern was required by 60% (25 of 42) of the respondents. In prostate needle biopsies containing only a single minute focus of PCa, only 41% (17 of 42) of respondents would request a Gleason score if not provided in the initial report. Interestingly, in biopsies with multiple positive cores from separate locations, 81% (34 of 42) use the highest Gleason score, regardless of the overall percentage involvement, to determine their treatment plan. Other pathology parameters requested by the respondents in descending order included: % involvement of the core by PCa (67%), the presence or absence of perineural invasion (38%), the number of cores with PCa (33%), and the length of core involvement (29%). Only 24% (10 of 42) of respondents use perineural invasion status to guide nerve-sparing surgery. The more radical prostatectomies performed by a surgeon, the greater the likelihood that they considered perineural invasion clinically important (Mann-Whitney, two-tailed, P = 0.015). The term atypical small acinar proliferation was uniformly considered sufficient to re-biopsy by 98% (41 of 42) of the urologists. This is the first study to survey urologists as to what information they require from prostate needle biopsy reports in their treatment planning of men with clinically localized PCa. With the exception of Gleason score, the use of detailed pathology information was variably used to guide treatment. PNI was not considered important by the majority of respondents. In contrast, atypical small acinar proliferation, a more recent diagnostic category, was recognized as important by nearly all respondents. Knowledge of how pathology biopsy reports are being used should help evaluate what data should be uniformly part of standard biopsy pathology report and help improve communication between pathologists and urologists.

Attitude of Health Personnel↗

PubMed2004

Desmoplastic small cell tumor in the pancreas.

Desmoplastic small cell tumor (DSCT) is a distinct type of small blue cell tumors and is characterized by the unique karyotypic aberration involving the fusion of the Ewing's sarcoma (EWS) gene and Wilms' tumor (WT1) gene. Typically, it grows along serosal surfaces; however, in some cases, the tumor presents as a dominant mass in an internal organ. Examples of DSCT forming a primary mass in ovary, testes, and brain have been described, but its presentation as a primary pancreatic mass has not been reported previously. The case reported here is a 31-year-old woman who presented with a 14-cm mass in the pancreas. There were smaller nodules on the peritoneal surfaces that were regarded clinically as metastasis from a primary pancreatic tumor. During the frozen section, the diagnosis of a poorly differentiated endocrine carcinoma of pancreatic origin was rendered and patient underwent subtotal pancreatectomy. On microscopic examination, the tumor was composed of large nests and broad bands of small blue cells, separated by fibrous stroma. Immunohistochemical stains showed positivity of the tumor cells for cytokeratins (AE1:AE3 and CAM5.2), neuron specific enolase, desmin and WT1, whereas chromogranin, S-100, and CD99 were negative. Since this immunoprofile is characteristic of DSCT, molecular analysis was performed which revealed the presence of EWS-WT1 gene fusion characteristic of DSCT. This case shows that in addition to primary pancreatic tumors characterized by prominent cellularity such as solid pseudopapillary tumors, acinar cell carcinoma, pancreatoblastoma, endocrine tumors, and other small blue cell tumors, the differential diagnosis of cellular, stroma-poor neoplasia in the pancreas also includes DSCT. This case is also another demonstrative example of how DSCT may form a dominant mass in intraabdominal organs.

12E7 Antigen↗

PubMed2003

Quantification of G250 mRNA expression in renal epithelial neoplasms by real-time reverse transcription-PCR of dissected tissue from paraffin sections.

AIM: Renal cell carcinoma (RCC) represents the most common malignant tumour in the kidney and is resistant to conventional therapies. G250 is a tumour-associated antigen and is expressed mainly in clear cell RCC. It is a potential therapeutic target as well as a diagnostic marker for RCC. Previous studies relating to G250 protein or G250 mRNA expression in RCC using human tissue have largely been limited to immunohistochemical or conventional RT-PCR approaches that lack reproducibility, are subject to observer bias and are at most semi-quantitative. In this study, we evaluated the feasibility of using real-time RT-PCR in quantifying G250 mRNA expression using tissue dissected from paraffin sections of renal epithelial neoplasms. Using this approach, we performed a preliminary study investigating the relationship between G250 expression and tumor behavior in clear cell RCC. METHODS: A total of 53 radical nephrectomy specimens with renal epithelial neoplasms (nine oncocytoma, seven chromophobe RCC, four papillary RCC and 33 clear cell RCC) were included in this study. SYBR Green real-time RT-PCR was performed using the ABI PRISM 7700 Sequence Detection System. A TATA box-binding protein (TBP) was used as an endogenous reference gene. RESULTS: Our study showed that real-time RT-PCR is a reliable approach in quantifying G250 mRNA expression using paraffin sections. Using this methodology, G250 mRNA was detected in all of the clear cell RCCs, but none of the other types of tumours studied or in normal kidney tissue. Our study also suggested that the expression of G250 mRNA might correlate with tumour stage and overall survival. CONCLUSION: Among common renal epithelial neoplasms, G250 is a specific marker for clear cell RCC. Quantification of G250 mRNA expression by real-time RT-PCR using paraffin sections is a feasible approach for future clinical studies in evaluating the prognostic and predictive value of G250 in clear cell RCC.

Antigens, Neoplasm↗

PubMed2003

Multiple measures of carcinoma extent versus perineural invasion in prostate needle biopsy tissue in prediction of pathologic stage in a screening population.

The capacity of perineural invasion by carcinoma in prostate needle biopsy tissue to independently predict pathologic stage in radical prostatectomy tissues remains uncertain. We sought to determine, in a prostate specific antigen-based screening population, the ability of needle biopsy histologic grade, tumor extent, and perineural invasion to independently predict pathologic stage and margin status in the whole prostate gland. Perineural invasion, Gleason grade, percentage Gleason pattern 4/5 carcinoma, and multiple measures of needle biopsy tumor extent, including number of positive cores, percentage of positive cores, total percentage of carcinoma, greatest percentage of carcinoma in a single core, and total carcinoma length in millimeters, were captured for 215 men from a prostate specific antigen-based screening program diagnosed with prostate cancer in a median of six procured needle biopsy cores. Pathologic stage and surgical margin status were evaluated in corresponding completely embedded radical prostatectomy specimens. A logistic regression model was used to relate the endpoints of extraprostatic extension by carcinoma and/or positive margins to needle biopsy tissue findings. In univariate analyses, total percentage of carcinoma (p = 0.003), greatest percentage of carcinoma in a single core (p = 0.004), total tumor length in millimeters (p = 0.009), and fraction of positive cores (p = 0.02) were all significantly associated with extraprostatic (pT3) carcinoma, whereas all five measures of carcinoma extent in needle biopsy tissue were related to positive margins. Correlation coefficient determinations showed that all five measures of needle biopsy carcinoma extent were highly interrelated. In multivariate analyses, total percentage of carcinoma was significantly related to pathologic T stage (p = 0.003) and positive margins (p = 0.0002). In a multivariate model with the radical prostatectomy whole gland endpoint of either pT3 disease or positive margins, fraction of positive cores (p = 0.00001) was the only variable with significant predictive value. Perineural invasion by carcinoma in needle biopsy tissue was detected in 11% of cases. Neither presence nor absence of perineural carcinoma nor number nor percentage of positive nerves related to pathologic stage in univariate or multivariate analyses. Amount of carcinoma in prostate needle biopsy tissue, using multiple measurements but not perineural invasion, is a significant histologic attribute predictive of pathologic stage and margin status for men with prostate specific antigen screening detected prostatic carcinoma. Reporting of several measures of carcinoma extent in needle biopsy tissue is recommended.

Adult↗

PubMed2003

Metastatic foci of signet ring cell carcinoma in a tubular adenoma of the colon.

We describe a case of adenomatous polyp of the colon that harbored small foci of signet ring cell carcinoma. The patient was a 64-year-old woman with end-stage renal disease and sepsis who underwent colonoscopy to evaluate the possibility of pseudomembranous colitis. A polyp was found incidentally in the right colon and a biopsy was performed. Histologic examination of the polyp revealed typical features of tubular adenoma without evidence of high-grade dysplasia. However, 2 small foci of signet ring cell carcinoma were identified that infiltrated the lamina propria. In contrast to adenomatous epithelium, the signet ring cells were immunohistochemically positive for cytokeratin 7 and negative for cytokeratin 20, suggesting a metastasis rather than a primary tumor. Multiple random biopsies from the right and left colon, as well as the ileum, exhibited no histologic evidence of malignancy. Subsequently, signet ring cell carcinoma with similar morphology and identical immunophenotype was detected in biopsies from the endometrium, an unusual location for primary signet ring cell carcinoma. Preliminary workup excluded the breast as a possible primary site, but further investigation was not possible because of the patient's death with no autopsy granted. To the best of our knowledge, this is the first reported case of metastatic signet ring cell carcinoma to an adenomatous polyp of the colon. This case illustrates the necessity of submitting all polyps entirely and the importance of examining them carefully.

Adenoma↗

PubMed2002

Livebirths with placental hemorrhagic endovasculitis: interlesional relationships and perinatal outcomes.

BACKGROUND AND OBJECTIVE: Hemorrhagic endovasculitis (HEV) is a vasodisruptive alteration of fetal-placental blood vessels that has been associated with perinatal morbidity and mortality and abnormalities of growth and development. Clinicopathologic conditions that are often identified in pregnancies with HEV-affected placentas include villitis of unknown etiology, chorionic vessel thrombi, villous erythroblastosis, meconium staining, and maternal hypertension. The clinical implications of HEV are often disputed. This case-control study assesses the clinical relevance of HEV in placentas of viable infants and examines the interplay of coexistent intraplacental lesions. METHODS: We reviewed clinical records and slides from 104 livebirths with placentas affected by HEV above a specified severity level (cases) and 104 matched livebirths with placentas that were not affected by HEV (controls). We evaluated incidences of perinatal complications with increasing HEV severity indices in placentas with and without coexistent lesions. Interlesional relationships were established by matching HEV severity indices with severity indices of coexistent lesions. Hemorrhagic endovasculitis was subcategorized into active, bland, and healed forms and clustered capillary lesions (hemorrhagic villitis). RESULTS: Lesions that were frequently coexistent in HEV-affected placentas included villitis of unknown etiology, chorionic thrombi, villous fibrosis, erythroblastosis, and primary infarcts. Compared with the control group, the case group had higher incidences of abnormal fetal heart rate tracings (P <.003), fetal distress (P <.001), and growth restriction (P <.001). Increasing severities of HEV and coexistent lesions were associated with higher rates of perinatal complications. Complication rates were higher in HEV cases, with or without coexistent lesions. The complication rate was higher in cases affected by HEV and hemorrhagic villitis than in cases affected by HEV alone (P <.03). Significant interlesional relationships were evident between HEV and villitis of unknown etiology, chorionic thrombi, villous fibrosis, and erythroblastosis. CONCLUSIONS; Severe forms of HEV can occur in placentas of livebirths. The severity of HEV and associated lesions and the presence of hemorrhagic villitis have important clinical implications. Interlesional relationships between HEV and thrombotic, chronic inflammatory, and chronic vaso-occlusive lesions exist. Pregnancies with HEV-affected placentas with or without coexistent lesions are at risk for perinatal complications.

Chorionic Villi↗