Inflammation as a chemoprevention target in asbestos-induced malignant mesothelioma.

Malignant mesothelioma (MM) is an incurable cancer of the serosal lining that is often caused by exposure to asbestos. Therefore, novel agents for the prevention and treatment of this disease are urgently needed. Asbestos induces the release of pro-inflammatory cytokines such as IL-1ß and IL-6, which play a role in MM development. IL-6 is a component of the JAK-STAT3 pathway that contributes to inflammation-associated tumorigenesis. Glycoprotein 130 (gp130), the signal transducer of this signaling axis, is an attractive drug target because of its role in promoting neoplasia via the activation of downstream STAT3 signaling. The anticancer drug, SC144, inhibits the interaction of gp130 with the IL-6 receptor (IL6R), effectively blunting signaling from this inflammatory axis. To test whether the inflammation-related release of IL-6 plays a role in the formation of MM, we evaluated the ability of SC144 to inhibit asbestos-induced carcinogenesis in a mouse model. The ability of sulindac and anakinra, an IL6R antagonist/positive control, to inhibit MM formation in this model was tested in parallel. Asbestos-exposed Nf2+/-;Cdkn2a+/- mice treated with SC144, sulindac or anakinra showed significantly prolonged survival compared to asbestos-exposed vehicle-treated mice. STAT3 activity was markedly decreased in MM specimens from SC144-treated mice. Furthermore, SC144 inhibited STAT3 activation by IL-6 in cultured normal mesothelial cells, and in vitro treatment of MM cells with SC144 markedly decreased the expression of STAT3 target genes. The emerging availability of newer, more potent SC144 analogs showing improved pharmacokinetic properties holds promise for future trials, benefitting individuals at high risk of this disease.

Adverse Events Reported by Patients With Cancer After Administration of a 2-Dose mRNA COVID-19 Vaccine.

BACKGROUND: Most safety and efficacy trials of the SARS-CoV-2 vaccines excluded patients with cancer, yet these patients are more likely than healthy individuals to contract SARS-CoV-2 and more likely to become seriously ill after infection. Our objective was to record short-term adverse reactions to the COVID-19 vaccine in patients with cancer, to compare the magnitude and duration of these reactions with those of patients without cancer, and to determine whether adverse reactions are related to active cancer therapy. PATIENTS AND METHODS: A prospective, single-institution observational study was performed at an NCI-designated Comprehensive Cancer Center. All study participants received 2 doses of the Pfizer BNT162b2 vaccine separated by approximately 3 weeks. A report of adverse reactions to dose 1 of the vaccine was completed upon return to the clinic for dose 2. Participants completed an identical survey either online or by telephone 2 weeks after the second vaccine dose. RESULTS: The cohort of 1,753 patients included 67.5% who had a history of cancer and 12.0% who were receiving active cancer treatment. Local pain at the injection site was the most frequently reported symptom for all respondents and did not distinguish patients with cancer from those without cancer after either dose 1 (39.3% vs 43.9%; P=.07) or dose 2 (42.5% vs 40.3%; P=.45). Among patients with cancer, those receiving active treatment were less likely to report pain at the injection site after dose 1 compared with those not receiving active treatment (30.0% vs 41.4%; P=.002). The onset and duration of adverse events was otherwise unrelated to active cancer treatment. CONCLUSIONS: When patients with cancer were compared with those without cancer, few differences in reported adverse events were noted. Active cancer treatment had little impact on adverse event profiles.

Cystoscopy and Systematic Bladder Tissue Sampling in Predicting pT0 Bladder Cancer: A Prospective Trial.

PURPOSE: Concern for discordance between clinical staging and final pathology drives current management of patients deemed appropriate candidates for radical cystectomy. Therefore, we set out to prospectively investigate reliability and shortcomings of cystoscopic evaluation in radical cystectomy candidates. MATERIALS AND METHODS: Patients undergoing radical cystectomy for urothelial carcinoma were enrolled in a prospective single-arm study to evaluate reliability of Systematic Endoscopic Evaluation in predicting pT0 urothelial carcinoma (NCT02968732). Systematic Endoscopic Evaluation consisted of cystoscopy and tissue sampling at the time of radical cystectomy. Systematic Endoscopic Evaluation results were compared to radical cystectomy pathology. The primary end point was the negative predictive value of Systematic Endoscopic Evaluation findings in predicting radical cystectomy pathology. RESULTS: A total of 61 patients underwent Systematic Endoscopic Evaluation and radical cystectomy. Indications included muscle invasive bladder cancer in 42 (68.9%) and high risk nonmuscle invasive bladder cancer in 19 (31.1%). In all, 38 (62.3%, 90.5% of patients with muscle invasive bladder cancer) received neoadjuvant chemotherapy. On Systematic Endoscopic Evaluation, 31 (50.8%) patients demonstrated no visual nor biopsy-based evidence of disease (seeT0), yet 16/31 (51.6%) harbored residual disease (>pT0), including 8 (8/31, 25.8%) with residual ≥pT2 disease upon radical cystectomy. The negative predictive value of Systematic Endoscopic Evaluation predicting a pT0 bladder was 48.4% (CI 30.2-66.9), which was below our prespecified hypothesis. Therefore, the trial was stopped for futility. CONCLUSIONS: Approximately 1 of 4 patients with seeT0 at the time of radical cystectomy harbored residual muscle invasive bladder cancer. These prospective data definitively confirm major limitations of endoscopic assessment for pT0 bladder cancer. Future work should focus on novel imaging and biomarker strategies to optimize evaluations before radical cystectomy for improved decision making regarding bladder preservation.

Clinical and Histological Basis of Adenosquamous Carcinoma of the Pancreas: A 30-year Experience.

BACKGROUND: Adenosquamous carcinoma (ASC) of the pancreas is a rare form of malignancy with a poor prognosis. We herein report our case series with review of the contemporary literature. METHODS: With institutional review board approval, we identified 23 patients with pancreatic ASC. RESULTS: ASC was more common in women (61%), with a median age of 73 y at presentation. The tumor was in the head of the pancreas in 65% of cases. Six cases (26%) had resectable disease, three (13%) were borderline resectable, and eight (34.7%) were locally advanced or metastatic. First-line treatment included pancreatic resection in eight cases (34.8%), concurrent neoadjuvant chemoradiation in three (13%), and neoadjuvant chemotherapy in two (8.7%). Most resected tumors had pathological T3 stage (80%). Pathological nodal disease was demonstrated in 60%, and margins were positive in three cases. Complete pathological response was not observed, although fibrosis presented in only one case (10%). Eventually, twenty patients developed metastatic disease. Overall survival is 11.5 [95% confidence interval 6, 14.5] months. CONCLUSIONS: ASC demonstrates a more aggressive malignant phenotype and carries a worse prognosis. Oncological resection is the mainstay of treatment. Neoadjuvant chemoradiation is an emerging approach in the management of ASC that has been extrapolated from the adenocarcinoma neoadjuvant trials.

Sporadic Angiomyolipomas Growth Kinetics While on Everolimus: Results of a Phase II Trial.

PURPOSE: Everolimus decreases tumor volume of renal angiomyolipomas in patients with tuberous sclerosis. No prospective data are available regarding the effect of everolimus on the growth kinetics in patients with sporadic angiomyolipomas. We sought to determine the safety and efficacy of everolimus in the volumetric reduction of sporadic angiomyolipomas. MATERIALS AND METHODS: This multi-institutional, prospective, phase II trial, enrolled patients with 3 cm or larger sporadic angiomyolipomas who were candidates for surgical resection or percutaneous angioembolization. Patients received 10 mg everolimus daily for 4 planned 28-day cycles. Response was defined as a 25% or greater volumetric reduction of patient angiomyolipoma. Baseline, 4, 6 and 12-month volumetric analyses were performed using magnetic resonance imaging. Everolimus was discontinued in those with less than 25% volumetric reduction after 4 cycles. Those with 25% or greater volumetric reduction received 2 additional cycles. The primary outcomes were the efficacy of everolimus in the volumetric reduction of angiomyolipomas by 25% or more, and the safety and tolerability of everolimus. RESULTS: Overall 20 patients were enrolled at 5 centers. Of these patients 11 (55%) completed 4 cycles and 7 (35%) completed 6 cycles. Efficacy was demonstrated, with 10 of 18 (55.6%) patients exhibiting a 25% or greater reduction in tumor volume at 4 months (median 58.5%) and 10 of 14 (71.4%) patients exhibiting a 25% or greater reduction in tumor volume at 6 months (median 58.2%). Four (20%) patients were withdrawn due to protocol defined toxicities and 8 (40%) self-withdrew from the study due to side effects. CONCLUSIONS: Everolimus was effective in causing volumetric reduction of angiomyolipomas by 25% or greater in most patients but was associated with a high rate of treatment discontinuation.

Preoperative Delays in the Treatment of DCIS and the Associated Incidence of Invasive Breast Cancer.

BACKGROUND: Although treatment delays have been associated with survival impairment for invasive breast cancer, this has not been thoroughly investigated for ductal carcinoma in situ (DCIS). With trials underway to assess whether DCIS can remain unresected, this study was performed to determine whether longer times to surgery are associated with survival impairment or increased invasion. METHODS: A population-based study of prospectively collected national data derived from women with a clinical diagnosis of DCIS between 2004 and 2014 was conducted using the National Cancer Database. Overall survival (OS) and presence of invasion were assessed as functions of time by evaluating five intervals (≤ 30, 31-60, 61-90, 91-120, 121-365 days) between diagnosis and surgery. Subset analyses assessed those having pathologic DCIS versus invasive cancer on final pathology. RESULTS: Among 140,615 clinical DCIS patients, 123,947 had pathologic diagnosis of DCIS and 16,668 had invasive ductal carcinoma. For all patients, 5-year OS was 95.8% and unadjusted median delay from diagnosis to surgery was 38 days. With each delay interval increase, added relative risk of death was 7.4% (HR 1.07; 95% CI 1.05-1.10; P < 0.001). On final pathology, 5-year OS for noninvasive patients was 96.0% (95% CI 95.9-96.1%) versus 94.9% (95% CI 94.6-95.3%) for invasive patients. Increasing delay to surgery was an independent predictor of invasion (OR 1.13; 95% CI 1.11-1.15; P < 0.001). CONCLUSIONS: Despite excellent OS for invasive and noninvasive cohorts, invasion was seen more frequently as delay increased. This suggests that DCIS trials evaluating nonoperative management, which represents infinite delay, require long term follow up to ensure outcomes are not compromised.

Genomic signature of parity in the breast of premenopausal women.

BACKGROUND: Full-term pregnancy (FTP) at an early age confers long-term protection against breast cancer. Previously, we reported that a FTP imprints a specific gene expression profile in the breast of postmenopausal women. Herein, we evaluated gene expression changes induced by parity in the breast of premenopausal women. METHODS: Gene expression profiling of normal breast tissue from 30 nulliparous (NP) and 79 parous (P) premenopausal volunteers was performed using Affymetrix microarrays. In addition to a discovery/validation analysis, we conducted an analysis of gene expression differences in P vs. NP women as a function of time since last FTP. Finally, a laser capture microdissection substudy was performed to compare the gene expression profile in the whole breast biopsy with that in the epithelial and stromal tissues. RESULTS: Discovery/validation analysis identified 43 differentially expressed genes in P vs. NP breast. Analysis of expression as a function of time since FTP revealed 286 differentially expressed genes (238 up- and 48 downregulated) comparing all P vs. all NP, and/or P women whose last FTP was less than 5 years before biopsy vs. all NP women. The upregulated genes showed three expression patterns: (1) transient: genes upregulated after FTP but whose expression levels returned to NP levels. These genes were mainly related to immune response, specifically activation of T cells. (2) Long-term changing: genes upregulated following FTP, whose expression levels decreased with increasing time since FTP but did not return to NP levels. These were related to immune response and development. (3) Long-term constant: genes that remained upregulated in parous compared to nulliparous breast, independently of time since FTP. These were mainly involved in development/cell differentiation processes, and also chromatin remodeling. Lastly, we found that the gene expression in whole tissue was a weighted average of the expression in epithelial and stromal tissues. CONCLUSIONS: Genes transiently activated by FTP may have a role in protecting the mammary gland against neoplastically transformed cells through activation of T cells. Furthermore, chromatin remodeling and cell differentiation, represented by the genes that are maintained upregulated long after the FTP, may be responsible for the lasting preventive effect against breast cancer.

Computed Tomography Colonography vs Colonoscopy for Colorectal Cancer Surveillance After Surgery.

BACKGROUND & AIMS: Recommendations for surveillance after curative surgery for colorectal cancer (CRC) include a 1-year post-resection abdominal-pelvic computed tomography (CT) scan and optical colonoscopy (OC). CT colonography (CTC), when used in CRC screening, effectively identifies colorectal polyps ≥10 mm and cancers. We performed a prospective study to determine whether CTC, concurrent with CT, could substitute for OC in CRC surveillance. METHODS: Our study enrolled 231 patients with resected stage 0-III CRC, identified at 5 tertiary care academic centers. Approximately 1 year after surgery, participants underwent outpatient CTC plus CT, followed by same-day OC. CTC results were revealed after endoscopic visualization of sequential colonic segments, which were re-examined for discordant findings. The primary outcome was performance of CTC in the detection of colorectal adenomas and cancers using endoscopy as the reference standard. RESULTS: Of the 231 participants, 116 (50.2%) had polyps of any size or histology identified by OC, and 15.6% had conventional adenomas and/or serrated polyps ≥6 mm. No intra-luminal cancers were detected. CTC detected patients with polyps of ≥6 mm with 44.0% sensitivity (95% CI, 30.2-57.8) and 93.4% specificity (95% CI, 89.7-97.0). CTC detected polyps ≥10 mm with 76.9% sensitivity (95% CI, 54.0-99.8) and 89.0% specificity (95% CI, 84.8-93.1). Similar values were found when only adenomatous polyps were considered. The negative predictive value of CTC for adenomas ≥6 mm was 90.7% (95% CI, 86.7-94.5) and for adenomas ≥10 mm the negative predictive value was 98.6% (95% CI, 97.0-100). CONCLUSIONS: In a CRC surveillance population 1 year following resection, CTC was inferior to OC for detecting patients with polyps ≥6 mm. Clinical Trials.gov Registration Number: NCT02143115.

Post-operative colorectal cancer surveillance: preference for optical colonoscopy over computerized tomographic colonography.

PURPOSE: Post-operative surveillance strategies for colorectal cancer (CRC) include periodic optical colonoscopy (OC) and abdominal-pelvic CT scan. Adherence with these recommendations is limited. For CRC screening, CT colonography (CTC) identifies larger adenomas and cancers nearly as well as OC. Most screening studies demonstrate that patients prefer CTC. However, CTC has never been compared to OC in the post-operative surveillance setting. METHODS: We hypothesized that CTC might represent an attractive substitute for the standard OC/CT scan combination. Here, 223 patients underwent CTC followed by same day OC 1 year after curative CRC resection. RESULTS: Of the 144/223 (64.6%) participants with a preference, 65.9% (95/144) preferred OC. This preference was more pronounced in women and in patients with polyps detected. No additional patient level factors significantly altered this primary result. CONCLUSIONS: In contrast to CRC screening, this first study in CRC post-operative surveillance patients demonstrates a preference for OC. Assuming patient preference is an important determinant, introduction of CTC as a method to increase patient adherence with CRC surveillance is unlikely to be effective. TRIAL REGISTRATION: Clinical Trials.gov registration number: NCT02143115.

Transcriptomic changes in the prefrontal cortex of rats as a function of age and cognitive engagement.

Although changes in cognitive functions including attention are well documented in aging, the neurobiological basis for such alterations is not fully understood. Increasing evidence points towards the contribution of genetic factors in age-related cognitive decline. However, genetic studies have remained inconsistent in characterizing specific genes that could predict functional decline in aging. Here we utilized next generation RNA sequencing (RNA-seq) to identify patterns of differentially expressed genes in the prefrontal cortex (PFC), a brain region implicated in attention, of young and aged animals that were either cognitively trained or had limited cognitive engagement. Consistent with previous investigations, aging alone was associated with increased expression of genes involved in multiple facets of innate and adaptive immune responses. On the contrary, the expression of immunity-related transcripts was reduced by cognitive engagement. In addition, transcripts across a wide range of cellular processes, including those associated with neuronal remodeling and plasticity, were upregulated by this behavioral manipulation. Surprisingly, aged subjects accounted for higher mean counts of upregulated transcripts and lower mean counts for downregulated transcripts as compared to the young subjects. Because aged rats exhibited lower attentional capacities, it is plausible that transcriptional changes associated with performance in these animals were reflective of compensatory changes that occurred to cope with the declining integrity of PFC functioning. Interestingly, the effects of both aging and cognitive engagement resulted in an upregulation of transcripts linked to extracellular exosomes, suggesting such extracellular vesicles may moderate a reciprocal gene by environment interaction in order to facilitate the reorganization of PFC circuitry and maintain functionality. Taken together, these findings provide novel insights into the capacities of both cognitive engagement as well as aging to alter gene expression in the PFC, and how the effects of such dynamic factors relate to variation in age-related cognitive abilities.

Two-sample binary phase 2 trials with low type I error and low sample size.

We address design of two-stage clinical trials comparing experimental and control patients. Our end point is success or failure, however measured, with null hypothesis that the chance of success in both arms is p0 and alternative that it is p0 among controls and p1  > p0 among experimental patients. Standard rules will have the null hypothesis rejected when the number of successes in the (E)xperimental arm, E, sufficiently exceeds C, that among (C)ontrols. Here, we combine one-sample rejection decision rules, E⩾m, with two-sample rules of the form E - C > r to achieve two-sample tests with low sample number and low type I error. We find designs with sample numbers not far from the minimum possible using standard two-sample rules, but with type I error of 5% rather than 15% or 20% associated with them, and of equal power. This level of type I error is achieved locally, near the stated null, and increases to 15% or 20% when the null is significantly higher than specified. We increase the attractiveness of these designs to patients by using 2:1 randomization. Examples of the application of this new design covering both high and low success rates under the null hypothesis are provided. Copyright © 2017 John Wiley & Sons, Ltd.

Patterns of Chemotherapy Administration in High-Risk Soft Tissue Sarcoma and Impact on Overall Survival.

BACKGROUND: Conflicting data exist on the benefit of chemotherapy in the management of high-risk soft tissue sarcoma (STS). Use of chemotherapy may be dependent on patient, tumor, and facility characteristics. This study sought to identify these factors and compare survival between treatment groups. PATIENTS AND METHODS: Patients with stage III STS were identified from the National Cancer Data Base (NCDB) from 1998 to 2012. Multiple logistic regression analysis was used to determine factors that influenced the probability of receiving chemotherapy. In a subset of patients, we determined the relationship between chemotherapy use and overall survival, using Kaplan-Meier curves and Cox regression analysis with propensity score adjustment. We also examined the effect of chemotherapy by histologic subgroup using interaction models. RESULTS: A total of 16,370 patients were included (N=5,377 for survival analysis). Patients who were younger than 40 years; male; privately insured; earned a higher income; had no comorbidities; had synovial sarcoma, angiosarcoma or "other" histology; and whose tumors were high-grade, greater than 10 cm, or from the lower extremity were significantly more likely to receive chemotherapy. Median unadjusted overall survival (OS) in the nonchemotherapy and chemotherapy groups was 51.3 and 82.7 months, respectively (P<.001). On adjusted analysis, the survival benefit remained significant (hazard ratio [HR], 0.85; P=.004). The benefit was particularly strong in the undifferentiated pleomorphic sarcoma (UPS) group on adjustment, with a median OS of 49.1 and 77.8 months for nonchemotherapy versus chemotherapy, respectively (HR, 0.77; P=.02). CONCLUSIONS: In addition to expected tumor and patient factors, histology, location of primary tumor, and socioeconomic status are associated with receipt/nonreceipt of chemotherapy in stage III STS. Chemotherapy use was associated with improved OS in the overall population, and specifically in the UPS subgroup.

Characteristics of clinical trials that require participants to be fluent in English.

BACKGROUND/AIMS: Diverse samples in clinical trials can make findings more generalizable. We sought to characterize the prevalence of clinical trials in the United States that required English fluency for participants to enroll in the trial. METHODS: We randomly chose over 10,000 clinical trial protocols registered with ClinicalTrials.gov and examined the inclusion and exclusion criteria of the trials. We compared the relationship of clinical trial characteristics with English fluency inclusion requirements. We merged the ClinicalTrials.gov data with US Census and American Community Survey data to investigate the association of English-language restrictions with ZIP-code-level demographic characteristics of participating institutions. We used Chi-squared tests, t-tests, and logistic regression models for analyses. RESULTS: English fluency requirements have been increasing over time, from 1.7% of trials having such requirements before 2000 to 9.0% after 2010 (p < 0.001 from Chi-squared test). Industry-sponsored trials had low rates of English fluency requirements (1.8%), while behavioral trials had high rates (28.4%). Trials opening in the Northeast of the United States had the highest regional English requirement rates (10.7%), while trials opening in more than one region had the lowest (3.3%, p<0.001). Since 1995, trials opening in ZIP codes with larger Hispanic populations were less likely to have English fluency requirements (odds ratio=0.92 for each 10% increase in proportion of Hispanics, 95% confidence interval=0.86-0.98, p=0.013). Trials opening in ZIP codes with more residents self-identifying as Black/African American (odds ratio=1.87, 95% confidence interval=1.36-2.58, p<0.001 for restricted cubic spline term) or Asian (odds ratio=1.16 for linear term, 95% confidence interval=1.07-1.25, p<0.001) were more likely to have English fluency requirements. ZIP codes with higher poverty rates had trials with more English-language restrictions (odds ratio=1.06 for a 10% poverty rate increase, 95% confidence interval=1.001-1.11, p=0.045). There was a statistically significant interaction between year and intervention type, such that the increase in English fluency requirements was more common for some interventions than for others. CONCLUSION: The proportion of clinical trials registered with ClinicalTrials.gov that have English fluency requirements for study inclusion has been increasing over time. English-language restrictions are associated with a number of characteristics, including the demographic characteristics of communities in which the sponsoring institutions are located.

Acculturative stress and inflammation among Chinese immigrant women.

OBJECTIVE: Among Chinese immigrant populations, increasing duration of US residence is associated with elevated risk for various chronic diseases. Although life-style changes after migration have been extensively studied in immigrant populations, the psychosocial impact of acculturative stress on biological markers of health is less understood. Thus, the purpose of the present study is to examine associations between acculturative stress and inflammatory markers in a Chinese immigrant population. METHODS: Study participants (n = 407 foreign-born Chinese American women) completed questionnaires assessing levels of stress, including acculturative stress and positive and negative life events in the previous year. Participant height and weight were measured using standard protocols, and blood samples were drawn for assessment of circulating serum levels of C-reactive protein (CRP) and soluble tumor necrosis factor receptor 2 (sTNFR2). RESULTS: Higher levels of acculturative stress were significantly associated with higher levels of CRP (B = 0.07, 95% confidence interval = 0.01-0.13, p = .031) and sTNFR2 (B = 0.02, 95% confidence interval = 0.004-0.03, p = .012), adjusting for age and body mass index. The latter association was no longer statistically significant when overall acculturation (i.e., identification with American culture) was included in the model. Life events were not associated with CRP or sTNFR2. CONCLUSIONS: This is one of the first studies to demonstrate that acculturative stress is associated with inflammatory markers in a Chinese immigrant population. Replication in other immigrant samples is needed to fully establish the biological correlates and clinical consequences of acculturative stress.