Impact of genomic testing on urologists' treatment preference in favorable risk prostate cancer: A randomized trial.

INTRODUCTION: The Oncotype Dx Genomic Prostate Score (GPS) is a 17-gene relative expression assay that predicts adverse pathology at prostatectomy. We conducted a novel randomized controlled trial to assess the impact of GPS on urologist's treatment preference for favorable risk prostate cancer (PCa): active surveillance versus active treatment (i.e., prostatectomy/radiation). This is a secondary endpoint from the ENACT trial which recruited from three Chicago hospitals from 2016 to 2019. METHODS: Ten urologists along with men with very low to favorable-intermediate risk PCa were included in the study. Participants were randomly assigned to standardized counseling with or without GPS assay. The main outcome was urologists' preference for active treatment at Visit 2 by study arm (GPS versus Control). Multivariable best-fit binary logistic regressions were constructed to identify factors independently associated with urologists' treatment preference. RESULTS: Two hundred men (70% Black) were randomly assigned to either the Control (96) or GPS arm (104). At Visit 2, urologists' preference for prostatectomy/radiation almost doubled in the GPS arm to 29.3% (29) compared to 14.1% (13) in the Control arm (p = 0.01). Randomization to the GPS arm, intermediate NCCN risk level, and lower patient health literacy were predictors for urologists' preference for active treatment. DISCUSSION: Limitations included sample size and number of urologists. In this study, we found that GPS testing reduced urologists' likelihood to prefer active surveillance. CONCLUSIONS: These findings demonstrate how obtaining prognostic biomarkers that predict negative outcomes before treatment decision-making might influence urologists' preference for recommending aggressive therapy in men eligible for active surveillance.

Risk Factors Associated With COVID-19 Symptoms and Potential Vertical Transmission During Pregnancy: A Retrospective Cohort Study.

Objective The COVID-19 pandemic is of special concern for pregnant women. A growing body of evidence suggests the virus can have a deleterious impact upon outcomes related to birth and newborn health. There is a paucity of published research demonstrating the factors that influence disease severity among those who are pregnant, while a growing body of evidence demonstrates that vertical transmission occurs. Our study investigated the impact of maternal characteristics upon COVID-19 outcomes, as well as whether disease severity impacted pregnancy outcomes. Methods We conducted a retrospective cohort study of pregnant women with COVID-19 who were admitted to two public hospitals in our state between April-August, 2020. Pregnancy outcomes and clinical, laboratory, and placental data were collected. Results Thirty-four pregnant women tested positive for SARS-CoV-2. Among them, 55% (19/34) were symptomatic. Of those who were symptomatic, 68% (13/19) presented with fever and cough. Those with symptoms had a statistically significant higher pregestational mean body mass index (BMI) compared with asymptomatic women (35.7±7.9 vs 26.7±6.9, P=0.004). Screening of biochemical records demonstrated that symptomatic women had lower potassium levels compared with those who were asymptomatic (median: 3.70 mEq/L vs 4.30 mEq/L, P=0.009). The lowest potassium level (3.0 mEq/L) and one of the highest BMIs (42.4 kg/m2) was observed in the only case of postpartum mortality among the symptomatic women. We did not observe any influence of maternal COVID-19 severity on placental histopathology/infant health or evidence of vertical transmission. Conclusion High pregestational BMI and lower potassium levels were associated with the presence of COVID-19 symptoms among pregnant women.

Impact of a Genomic Test on Treatment Decision in a Predominantly African American Population With Favorable-Risk Prostate Cancer: A Randomized Trial.

PURPOSE: The Genomic Prostate Score (GPS), performed on biopsy tissue, predicts adverse outcome in prostate cancer (PCa) and has shown promise for improving patient selection for active surveillance (AS). However, its impact on treatment choice in high-risk populations of African Americans is largely unknown and, in general, the effect of the GPS on this difficult decision has not been evaluated in randomized trials. METHODS: Two hundred men with National Comprehensive Cancer Network very low to low-intermediate PCa from three Chicago hospitals (70% Black, 16% college graduates) were randomly assigned at diagnosis to standard counseling with or without a 12-gene GPS assay. The primary end point was treatment choice at a second postdiagnosis visit. The proportion of patients choosing AS was compared, and multivariable modeling was used to estimate the effects of various factors on AS acceptance. RESULTS: AS acceptance was high overall, although marginally lower in the intervention group (77% v 88%; P = .067), and lower still when men with inadequate specimens were excluded (P = .029). Men with lower health literacy who received a GPS were seven-fold less likely to choose AS compared with controls, whereas no difference was seen in men with higher health literacy (Pinteraction = .022). Among men with low-intermediate risk, 69% had GPS values consistent with unfavorable intermediate or high-risk cancer. AS choice was also independently associated with a family history of PCa and having health insurance. CONCLUSION: In contrast to other studies, the net effect of the GPS was to move patients away from AS, primarily among men with low health literacy. These findings have implications for our understanding of how prognostic molecular assays that generate probabilities of poor outcome can affect treatment decisions in diverse clinical populations.

Performance of prostate health index and PSA density in a diverse biopsy-naïve cohort with mpMRI for detecting significant prostate cancer.

Objective: To compare Prostate Health Index (PHI) and prostate-specific antigen (PSA) density as secondary tests after multiparametric magnetic resonance imaging (mpMRI) in improving the detection accuracy of Gleason grade group (GG) 2-5 prostate cancer (PCa) and in decreasing unnecessary biopsies in a multiethnic biopsy-naïve population. Methods: From February 2017 to February 2020, we recruited consecutive biopsy-naïve men in participating urology clinics for elevated PSA levels. They all had a PHI score, mpMRI, and prostate biopsy. Experienced genitourinary radiologists read all mpMRI studies based on PIRADS version 2.0. Logistic regression models were used to generate receiver operating characteristic curves. Models were tested for effect modification between Race (Black vs White) and both PHI and PSA density, and Race and PIRADS to determine if race impacted their prediction accuracy. Sensitivity, specificity, and predictive values of PHI and PSA density thresholds were calculated by PIRADS scores. The primary outcome was GG2-5 PCa, that is, Gleason score ≥3 + 4. Results: The study included 143 men, of which 65 (45.5%) were self-reported Black. Median age was 62.0 years and 55 men (38.4%) had GG2-5 PCa. Overall, 18.1% had PIRADS 1-2, 32.9% had PIRADS 3, and 49.0% had PIRADS 4-5. For the binary logistic regressions, the interactions between PIRADS and Race (P = .08), Log (PHI) and Race (P = .17), and Log (PSA density) and Race (P = .42) were not statistically significant. Within PIRADS 3 lesions, a PHI ≥49 prevented unnecessary biopsies in 55% of men and missed no GG2-5 PCa, yielding a negative predictive value of 100%. There was no reliable PHI or PSA density threshold to avoid PCa biopsies in PIRADS 1-2 or 4-5. Conclusions: PHI and PSA density can be used after mpMRI to improve the detection of GG2-5 PCa in a biopsy-naïve cohort. PHI may be superior to PSA density in PIRADS 3 lesions by avoiding 55% of unnecessary biopsies. Using both PHI and PSA density in series may further increase specificity and lead to fewer unnecessary biopsies, but further larger studies are warranted to determine the optimal threshold of each biomarker.

Malignant paraganglioma of the thyroid gland with synchronous bilateral carotid body tumors.

We describe a case of primary malignant paraganglioma of the thyroid gland that was found in a 55-year-old woman who had undergone surgery for bilateral carotid body tumors. The paraganglioma was treated with a total thyroidectomy followed by radiation therapy, and the patient was disease-free after more than 2 years of follow-up. Malignant paragangliomas of the thyroid gland are extremely rare. The diagnosis of malignancy is based on histopathologic findings, tumor behavior, and metastasis. These tumors can be misdiagnosed as other types of thyroid malignancies, thus resulting in less than optimal treatment. A genetic etiology was suspected in our patient.

Race and the prognostic influence of p53 in women with breast cancer.

BACKGROUND: Prior study suggests that p53 status behaves as an independent marker of prognosis in African American (AA) women with breast cancer. We investigate whether the influence of p53 is unique to AAs or is present in other race/ethnic groups, and how this compares with known prognostic factors. METHODS: Cox regression models [hazard ratios (HRs), 95% confidence intervals (CIs)] were used to select and evaluate factors prognostic for all-cause mortality in 331 AA and 203 non-AA consecutively treated women. RESULTS: Statistically significant baseline prognostic factors were as follows. For AAs: stage [(III/I) HR 5.57; 95% CI 3.08-10.09], grade [(higher/low) HR 1.55; 95% CI 1.14-2.11], estrogen receptor (ER)/progesterone receptor (PR) status [(-/+) HR 2.01; 95% CI 1.38-2.93], triple negative (ER-, PR-, HER2-) subtype [(+/-) HR 1.95; 95% CI 1.33-2.85], and p53 status [(+/-) HR 1.69; 95% CI 1.10-2.58]. For non-AAs: stage [HR 11.93; 95% CI 2.80-50.84], grade [HR 1.61; 95% CI 0.96-2.71], and ER/PR status [HR 2.13; 95% CI 1.19-3.81]. There was a differential effect of race within p53 groups (P=0.05) and in multivariate modeling p53-positive status remained an adverse prognostic factor in AAs only [HR 1.82; 95% CI 1.04-3.17]. Compared to non-AAs, 5-year unadjusted survival was worse for AAs overall (73.4% vs. 63.6%; P=0.032), and also for AAs with p53-positive status (80.3% vs. 54.2%; P=0.016), but not for AAs with p53-negative disease (68.4% vs. 67.9%; P=0.81). CONCLUSIONS: Among women with breast cancer of different race/ethnicity, an adverse prognostic effect as a result of p53 positivity was only observed in AA women.

p53 as a marker of prognosis in African-American women with breast cancer.

BACKGROUND: p53 overexpression has been identified as a poor prognostic marker in breast cancer. We investigate the value of p53 status within the context of stage and intrinsic subtype classification (subtype), in a group of African-American (AA) women of lower socioeconomic status (SES) with primary breast cancer. METHODS: Participants were 331 consecutive AA women treated at an urban hospital (median follow-up 41 months) with known subtype [luminal A = estrogen receptor (ER)+ and/or progesterone receptor (PR)+, human epidermal growth factor receptor 2 (HER2)-; luminal B = ER+ and/or PR+, HER2+; HER2+ = ER-, PR-, HER2+; basal = ER-, PR-, HER2-, cytokeratin (CK)5/6+, and/or HER1+; and unclassified = negative for all five markers] and p53 (Pab1801 antibody) immunohistochemical status. Proportional hazards regression models were used to select and evaluate factors prognostic for all-cause mortality. RESULTS: p53+ status was associated with grade 3 tumors, ER/PR- status, and basal subtype. On univariate analysis, factors related to survival were stage, grade [(3/1) hazard ratio (HR) = 2.64; 95% confidence interval (CI), 1.15-6.07], subtype [(ex. basal/luminal A) HR = 2.15; 95% CI, 1.34-3.45], and p53 status [(+/-) HR = 1.77; 95% CI, 1.15-2.72]. Multivariable modeling indicated that p53+ status remained a negative prognostic factor (HR = 1.63; 95% CI, 1.01-2.59) after adjustment for effects of age, stage, grade, and subtype; 5-year adjusted survival was significantly greater for p53- (66.7%) than p53+ cases (54.7%). CONCLUSION: p53 status is an independent predictor of survival after consideration of other strong prognostic factors such as stage, tumor grade, and subtype, and thus may be useful in identifying AA women at high risk of breast cancer mortality.

Papillary lesions of the breast discovered on percutaneous large core and vacuum-assisted biopsies: reliability of clinical and pathological parameters in identifying benign lesions.

BACKGROUND: A review of the literature reveals conflicting evidence on whether core biopsy, complemented with concordant imaging, is sufficient in differentiating benign from malignant papillary lesions. Our objective was to evaluate whether in our patient population, commonly used clinical and pathological parameters could predict benignity, thus eliminating the need to proceed with excision. METHODS: A retrospective review of clinical variables and pathologic slides of 39 patients in whom both core biopsy and excisional biopsy were available for evaluation. RESULTS: Excision revealed malignancy in 44%. Risk factors for malignancy, palpability, size, or Breast Imaging Reporting and Data System (American College of Radiology, Reston, VA) did not help differentiate benign from malignant disease. Younger age and core biopsies revealing minimal or no atypia were predictive of benignity. However, 4 (25%) of 20 patients whose core biopsies were classified as probably benign were found to have malignancy on excision. CONCLUSIONS: Caution should be used in recommending nonoperative management after a core biopsy revealing a papillary lesion.

Inflammatory myofibroblastic tumor presenting with tracheal obstruction in a pregnant woman.

Inflammatory myofibroblastic tumor (IMT), also known as inflammatory pseudotumor, is a benign lesion predominantly found in the lung and abdomen. Sporadic cases have been reported in the trunk, genitourinary tract, and extremities as well as in the head and neck. Of critical importance is this entity's correct histopathologic diagnosis that differentiate it from malignant neoplasms such as spindle cell carcinoma and fibrosarcoma, benign tumors such as neurofibroma, and other pseudoneoplastic lesions such as nodular fasciitis. Correct diagnosis is followed by wide local excision to prevent recurrence; however, treatment must be tailored to the location of tumor and the condition of the patient. We present a unique case of IMT of the trachea presenting with acute upper airway obstruction in a pregnant woman. Diagnostic considerations as well as the anesthetic and surgical approach are discussed.

Up-regulation of cyclooxygenase-2 expression and prostaglandin synthesis in endometrial stromal cells by malignant endometrial epithelial cells. A paracrine effect mediated by prostaglandin E2 and nuclear factor-kappa B.

We investigated the regulation of prostaglandin production in normal endometrial stromal cells (ESC) by malignant endometrial epithelial cells. We found that cyclooxygenase (COX)-2 mRNA and protein levels and prostaglandin (PG)E(2) production in ESC were significantly increased by Ishikawa malignant endometrial epithelial cell conditioned medium (MECM). By using transient transfection assays, we found that the -360/-218-bp region of the COX-2 promoter gene was critical for MECM induction of promoter activity. This MECM-responsive region contained a variant nuclear factor (NF)-kappa B site at -222 to -213 that, when mutated, completely abolished COX-2 promoter activation by MECM. Employing electrophoretic mobility shift assays, we further demonstrated that binding of NF-kappa B p65 to this NF-kappa B-binding site is, in part, responsible for the COX-2 promoter activation by MECM. To investigate further the potential effects of MECM on COX-2 mRNA stability, ESC were treated with MECM in the absence or presence of actinomycin D, a general transcription inhibitor. We found that MECM significantly increased COX-2 mRNA stability. Intriguingly, we found that PGE(2) was one of the major factors in MECM, which was responsible for up-regulating COX-2 expression in ESC. ECC-1 and HEC-1A malignant endometrial epithelial cell lines also produced significantly increased quantities of PGE(2). In conclusion, malignant endometrial epithelial cells secrete PGE(2) that induces COX-2 expression in normal endometrial stromal cells in a paracrine fashion through activation of transcription and stabilization of COX-2 mRNA.

Regulation of aromatase P450 expression in endometriotic and endometrial stromal cells by CCAAT/enhancer binding proteins (C/EBPs): decreased C/EBPbeta in endometriosis is associated with overexpression of aromatase.

In human endometriotic stromal cells, markedly high levels of aromatase P450 (P450arom) mRNA and promoter II activity are present and can be vigorously stimulated by PGE(2) via a cAMP-dependent pathway to give rise to physiologically significant estrogen biosynthesis. Stromal cells of eutopic endometrium, on the other hand, do not express sufficient levels of P450arom for detectable enzyme activity. Because P450arom is up-regulated in the ovaries of CCAAT/enhancer binding protein (C/EBP) beta knockout mice and activation of the ovarian-type P450arom promoter (II) is responsible for aberrant P450arom expression in endometriosis, we sought here to evaluate the possible roles of C/EBP isoforms in the regulation of P450arom expression in endometriotic vs. eutopic endometrial stromal cells. We previously found that the -517-bp flanking region of promoter II contained the critical cis-acting elements for baseline and cAMP (analog)-induced activity. In this study, we disrupted several potential sequences and found that mutations of a -211/-197-bp cAMP-response element (CRE) and a -317/-304-bp C/EBP binding site abolished both baseline and cAMP-induced promoter II activity. Ectopic expression of C/EBPalpha increased both baseline and cAMP-dependent promoter II activity significantly in endometriotic cells, whereas ectopic expression of C/EBPbeta or C/EBPdelta abolished promoter II activity in both untreated and cAMP-treated endometriotic stromal cells. Comparable changes in promoter II activity were observed using endometrial stromal cells, which showed, however, seemingly diminished levels of baseline and cAMP-induced promoter II activity in comparison with endometriotic cells. EMSA using a probe containing the critical -317/-304-bp C/EBP site upstream of promoter II demonstrated a distinct DNA-protein complex in endometriotic, but not in endometrial stromal cells. This specific complex, however, could not be altered using antibodies against C/EBPalpha, -beta, or -delta. Because CRE is another potential DNA motif that can bind C/EBP isoforms, we next used EMSA using a probe containing the -211/-197-bp CRE and demonstrated that specific DNA-protein complexes contained C/EBPalpha but not C/EBPbeta or C/EBPdelta in endometriotic stromal cells. In contrast, C/EBPbeta and C/EBPdelta but not C/EBPalpha were detected in DNA-protein complexes using nuclear extracts from endometrial stromal cells. Western blotting and immunohistochemistry demonstrated expression of C/EBPalpha, -beta, and -delta in human endometriotic and endometrial stroma and epithelium. Intriguingly, C/EBPbeta was expressed at increased levels in stromal cells of human eutopic endometrium compared with simultaneously biopsied endometriotic tissues. We conclude that both -317/-304 and -211/-197-bp elements in promoter II are critical for the robust cAMP-dependent induction in endometriosis. C/EBPalpha up-regulates, whereas C/EBPbeta and C/EBPdelta inhibit P450arom promoter activity via binding primarily to the -211/-197-bp CRE under in vitro conditions. In vivo down-regulation of C/EBPbeta in endometriotic stromal cells and its up-regulation in endometrial stromal cells may in part account for the induction of P450arom expression in endometriosis and its inhibition in endometrium.

Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo.

OBJECTIVE: Mesenchymal stem cells (MSCs), multipotential cells that reside within the bone marrow, can be induced to differentiate into various components of the marrow microenvironment, such as bone, adipose, and stromal tissues. The bone marrow microenvironment is vital to the development, differentiation, and regulation of the lymphohematopoietic system. We hypothesized that the activities of MSCs in the bone marrow microenvironment might also include immunomodulatory effects on lymphocytes. METHODS: Baboon MSCs were tested in vitro for their ability to elicit a proliferative response from allogeneic lymphocytes, to inhibit an ongoing allogeneic response, and to inhibit a proliferative response to potent T-cell mitogens. In vivo effects were tested by intravenous administration of donor MSCs to MHC-mismatched recipient baboons prior to placement of autologous, donor, and third-party skin grafts. RESULTS: MSCs failed to elicit a proliferative response from allogeneic lymphocytes. MSCs added into a mixed lymphocyte reaction, either on day 0 or on day 3, or to mitogen-stimulated lymphocytes, led to a greater than 50% reduction in proliferative activity. This effect could be maximized by escalating the dose of MSCs and could be reduced with the addition of exogenous IL-2. In vivo administration of MSCs led to prolonged skin graft survival when compared to control animals: 11.3 +/- 0.3 vs 7 +/- 0. CONCLUSIONS: Baboon MSCs have been observed to alter lymphocyte reactivity to allogeneic target cells and tissues. These immunoregulatory features may prove useful in future applications of tissue regeneration and stem cell engineering.

Primary hyperparathyroidism in an adult female olive baboon (Papio anubis).

During an annual physical examination, a middle-aged adult female olive baboon (Papio anubis) in the time-mated breeding colony at the Biologic Resources Laboratory at the University of Illinois at Chicago was found to have a high serum calcium value (> 12 mg/dl). To determine the cause of the hypercalcemia, additional diagnostic tests, including thoracic and abdominal radiographs and a parathyroid panel (parathyroid hormone (PTH), ionized calcium, and parathyroid hormone-related protein (PTH-rp) assays), were performed. The radiographs did not reveal lesions suggestive of neoplasia. A parathyroid panel was obtained twice. Both times the PTH (23.4 and 46.4 pmol/L, normal = 2.91 to 4.57 pmol/L) and ionized calcium (1.68 and 2.10 mmol/L, normal = 1.31 to 1.37 mmol/L) were increased above values for adult females with normal calcium concentration. A tentative diagnosis of primary hyperparathyroidism was made. After a gamma-radiation scan and magnetic resonance imaging of the neck were done, exploratory surgery was performed to identify and remove the affected gland. After gland removal, the baboon's serum calcium, PTH (1.6 pmol/L), and ionized calcium (1.59 mmol/L) values decreased. Results of histologic examination confirmed the diagnosis of benign solitary parathyroid adenoma.