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Objective: Oral cancer examinations seek to clinically identify early oral cancers and discover premalignancies prior to their progression to invasive cancer. Method and materials: A cross-sectional study was conducted between April and August 2017 to explore and quantify the diagnostic approach used by United States (US) general dental practitioners following discovery of an oral lesion suspicious for malignancy/premalignancy. US licensed general dental practitioners who were clinically active members of the US National Dental Practice-Based Research Network were eligible to participate. Data for analysis were obtained via two questionnaires. Results: The majority of participants were males, practiced full-time, had a suburban primary practice, were born during the 1950s, and graduated dental school in the 1980s or 2000s. After identifying an oral lesion suspicious for premalignancy/malignancy, the next action of most general dental practitioner respondents (65.4%) was to refer the patient for consultation/biopsy. Most general dental practitioners (87.2%) referred to an oral and maxillofacial surgeon; 22% of general dental practitioners reported personally biopsying suspicious lesions. There was a relatively weak association between completing an Advanced Education in General Dentistry or General Practice Residency and subsequently personally performing biopsies on patients with oral lesions suspicious for malignancy/premalignancy (OR 1.33, P = .06). Most written referrals took place electronically and often included information, including lesion location (87.0%), lesion sign/symptoms (85.3%), lesion history (83.9%), radiographs (59.3%), medical history (50.6%), dental history (48.8%), and photographs (42.4%). When a referral biopsy was performed, referring clinicians were most frequently informed of the findings via a written report (96.7%, when positive for malignancy/premalignancy, and 95.4% when negative). Conclusion: A snapshot is presented of current actions taken by US general dental practitioners following the discovery of oral abnormalities suspicious for premalignancy/malignancy. [ABSTRACT FROM AUTHOR]

To examine whether the endometrial cancer (EC) survival disadvantage among Black populations is US-specific, a comparison between African-descent populations from different countries with a high development index is warranted. We analyzed 28 213 EC cases from cancer registries in Florida (2005-2018) and the French Caribbean islands of Martinique (2005-2018) and Guadeloupe (2008-2018) combined. Kaplan-Meier and all-cause Cox proportional hazards models were used to compare survival. Models were stratified by EC histology type and the main predictor examined was race/ethnicity (non-Hispanic White [NHW] and no-Hispanic Black [NHB] women in the United States versus Black women residing in the Caribbean). For endometrioid and nonendometrioid EC, after adjusting for age, histology, stage at diagnosis, receipt of surgery, period of diagnosis, and poverty level, US NHB women and Caribbean Black women had a higher risk of death relative to US NHW women. There was no difference between US NHB and Caribbean Black women (hazard ratio [HR] = 1.07; 95% CI, 0.88-1.30) with endometrioid EC. However, Caribbean Black women with nonendometrioid carcinomas had a 40% higher risk of death (HR = 1.40; 95% CI, 1.13-1.74) than US NHB women. The low EC survival among US Black women extends to foreign populations of African descent. For the aggressive nonendometrioid ECs, survival among Caribbean Black women outside of the United States is considerably worse. This article is part of a Special Collection on Gynecological Cancers. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Prostatic carcinosarcoma comprises <1% of all prostate neoplasms. The literature on this disease is limited to a few case studies, primarily due to the rarity of this malignancy. We aimed to investigate the demographic, clinical, and histologic factors, prognosis, and survival of prostatic carcinosarcoma. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients with prostatic carcinosarcoma from 2000-2018. Demographic and clinical data, including age, race, sex, tumor grade, stage, tumor size, lymph node status, metastasis, and treatment modalities, were recorded. RESULTS: Patients with prostatic carcinosarcoma had a median age of 72 years at diagnosis, most cases among White individuals (93%). When reported, the histologic grade comprised moderately differentiated (3.3%), poorly differentiated (56.7%), and undifferentiated/anaplastic (40%) subtypes. In patients with reported data, tumor size varied between 2-5 cm (15.8%) and >5 cm (84.2%). Distant metastasis most commonly occurred in the liver (12.5%) and lung (12.5%), followed by the bone (8.3%). The most common treatment performed was surgery with radiation (32.4%). The five-year overall survival was 11.9%. CONCLUSIONS: Prostatic carcinosarcoma affects men in the seventh decade of life. Regional and distant tumor stage is considered an indicator of survival. Prostate carcinosarcoma is rare; due to its aggressive nature, a deeper understanding, and an improved personalized therapeutic approach are necessary for improving patient outcomes in this challenging arena of oncology. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with stage IIB and IIC melanoma are considered to have high-risk localized disease and, in some cases, demonstrate worse recurrence-free and overall survival than patients with stage IIIA and even IIIB disease. The mainstay of treatment for patients with high-risk clinical stage II melanoma is surgical resection of the primary tumor and sentinel lymph node biopsy (SLNB), which confers accurate pathologic staging and prognostication for further treatment decisions. Building on the success of adjuvant therapy for stage III melanoma, the KEYNOTE-716 and CheckMate 76K trials found improved recurrence-free survival for patients with high-risk stage II melanoma with adjuvant pembrolizumab and nivolumab, respectively, after complete resection with SLNB. Given these findings, the National Comprehensive Cancer Network now recommends discussing adjuvant pembrolizumab or nivolumab with patients with high-risk stage IIB/C melanoma, weighing the risks of recurrence against the risks of treatment-related adverse events when making the decision regarding adjuvant therapy. Melanoma is the fifth most common cancer in the United States and accounts for the majority of all skin cancer-related deaths, making it the most lethal cutaneous malignancy. Systemic adjuvant therapy for stage IIB-IV melanoma is now approved for patients who have undergone surgical resection, given the appreciable risk of recurrence and mortality in this patient population. Despite the lower stage, high-risk stage II melanoma (stage IIB/IIC) can often exhibit an even more aggressive course when compared to stage IIIA/IIIB disease, thus justifying consideration of adjuvant therapy in these patients. In this review, we highlight the current standard of practice for the treatment of stage IIB/C melanoma, with a focus on adjuvant therapies supported by published landmark clinical trials, including anti-PD-1 therapy. Notably, adjuvant therapies approved thus far in this patient population have demonstrated an improvement in recurrence-free survival, while their impact on overall survival is pending. Finally, this review highlights currently ongoing trials and future directions for research and treatment possibilities for high-risk clinical stage II melanoma. [ABSTRACT FROM AUTHOR]

Infiltrating ductal adenocarcinoma of the pancreas, referred to here as "pancreatic cancer," is one of the deadliest of all of the solid malignancies. The five-year survival rate in the United States for individuals diagnosed today with pancreatic cancer is a dismal 12%. Many invasive cancers, including pancreatic cancer, however, arise from histologically and genetically well-characterized precursor lesions, and these precancers are curable. Precursor lesions therefore are an attractive target for early detection and treatment. This is particularly true for individuals with an increased risk of developing invasive cancer, such as individuals with a strong family history of pancreatic cancer, and individuals with a germline variant known to increase the risk of developing pancreatic cancer. There is therefore a need to understand the precursor lesions that can give rise to invasive pancreatic cancer in these individuals. [ABSTRACT FROM AUTHOR]

Aims: We aimed to develop an elaborative nomogram that predicts cancer-specific survival (CSS) in American and Chinese octogenarians treated with radical resection for CRC. Methods: The patient data of newly diagnosed patients aged 80 years or older who underwent radical resection for CRC from 2010 to 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database and then randomly divided into a training cohort and a validation cohort. The patients collected from our hospital were defined as the external validation cohort. Univariate and multivariate Cox regression was used to select independent predictive factors for the construction of a nomogram to predict 1-, 2- and 3-year CSS. Results: The multivariate Cox regression model identified age, T stage, N stage, perineural invasion, chemotherapy, tumour deposits, carcinoembryonic antigen level, number of lymph node metastases, and number of solid organ metastases as independent predictors of survival. The C-index of the nomogram for 1-, 2- and 3-year CSS was 0.758, 0.762, and 0.727, respectively, demonstrating significant clinical value and substantial reliability compared to the TNM stage. The calibration curve and area under the curve also indicated considerable predictive accuracy. In addition, decision curve analysis demonstrated desirable net benefits in clinical application. Conclusion: We constructed a nomogram for predicting the CSS of individual octogenarian patients with CRC who underwent radical resection. The nomogram performed better than the TNM staging system in this particular population and could guide clinicians in clinical follow-up and individual therapeutic plan formulation. Highlights: This study explored the exclusive characteristics of octogenarians treated with radical resection for colorectal cancer. This study is the first to develop a nomogram for predicting the cancer-specific survival of individual octogenarian patients after radical resection for colorectal cancer with the substantial reliability (C-index: 0.758 compared to the AJCC pathological staging system (C-index: 0.713). Internal validation of this nomogram in a cohort of American patients (N = 1644) and external validation in a cohort of Chinese patients (N = 368) confirmed its accuracy. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the most common cancer among men in the United States and the leading cause of cancer-related death. The Solute Carrier Family 14 Member 1 (SLC14A1) is a member of urea transporters which are important for the regulation of urine concentration. However, the physiological significance of SLC14A1 in PCa still remains unclear. In the present study, via bioinformatics analysis and experiments, we found that expression of SLC14A1 is significantly decreased in PCa progression, which could be attributed to hypermethylation on SLC14A1 promoter region. Moreover, its low expression and hypermethylation on SLC14A1 promoter are closely related to the poor prognosis of PCa patients. On the other hand, overexpression of SLC14A1 inhibited cell proliferation and metastasis while its overexpression also suppressed CDK1/CCNB1 pathway and mTOR/MMP-9 signaling pathway. Additionally, SLC14A1 expression is enriched in prostate basal-type cells. In summary, our study indicates that its low expression level and promoter hypermethylation of SLC14A1 may represent novel indicators for PCa progression and prognosis, and SLC14A1 could inhibit the progression of PCa. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is a significant cause of female cancer-related deaths in the US. Checking how severe the cancer is helps in planning treatment. Modern AI methods are good at grading cancer, but they are not used much in hospitals yet. We developed and utilized ensemble deep learning algorithms for addressing the tasks of classifying (1) breast cancer subtype and (2) breast cancer invasiveness from whole slide image (WSI) histopathology slides. The ensemble models used were based on convolutional neural networks (CNNs) known for extracting distinctive features crucial for accurate classification. In this paper, we provide a comprehensive analysis of these models and the used methodology for breast cancer diagnosis tasks. Cancer diagnosis and classification are pivotal for effective patient management and treatment planning. In this study, a comprehensive approach is presented utilizing ensemble deep learning techniques to analyze breast cancer histopathology images. Our datasets were based on two widely employed datasets from different centers for two different tasks: BACH and BreakHis. Within the BACH dataset, a proposed ensemble strategy was employed, incorporating VGG16 and ResNet50 architectures to achieve precise classification of breast cancer histopathology images. Introducing a novel image patching technique to preprocess a high-resolution image facilitated a focused analysis of localized regions of interest. The annotated BACH dataset encompassed 400 WSIs across four distinct classes: Normal, Benign, In Situ Carcinoma, and Invasive Carcinoma. In addition, the proposed ensemble was used on the BreakHis dataset, utilizing VGG16, ResNet34, and ResNet50 models to classify microscopic images into eight distinct categories (four benign and four malignant). For both datasets, a five-fold cross-validation approach was employed for rigorous training and testing. Preliminary experimental results indicated a patch classification accuracy of 95.31% (for the BACH dataset) and WSI image classification accuracy of 98.43% (BreakHis). This research significantly contributes to ongoing endeavors in harnessing artificial intelligence to advance breast cancer diagnosis, potentially fostering improved patient outcomes and alleviating healthcare burdens. [ABSTRACT FROM AUTHOR]

The loss of RAB25 expression—RAS superfamily of GTPase characteristic of numerous breast cancers—corresponds with H-RAS point mutations, particularly in triple-negative breast cancers (TNBC), a subtype associated with a poor prognosis. To address the poorly understood factors dictating the progression of TNBC tumors, we examine the cooperative effects that loss of RAB25 expression in human mammary epithelial cell (HMEC) lines with H-RAS mutations confers in tumorigenesis. HMECs were immortalized by transduction with LXSN CDK4 R24C, a mutant form of cyclin-dependent kinase, followed by transduction with hTERT, a catalytic subunit of the telomerase enzyme. We found that with the loss of RAB25 and overexpression of mutant H-RAS61L, immortal HMECs transformed toward anchorage-independent growth and acquired an increased ability to migrate. Furthermore, cells express low CD24, high CD44, and low claudin levels, indicating stem-like properties upon transformation. Besides, loss of RAB25 and overexpression of H-RAS61L resulted in increased expression of transcription factors Snail and Slug that drive these cells to lose E-cadherin and undergo epithelial-mesenchymal transition (EMT). This study confirms that loss of RAB25 and overexpression of mutant H-RAS can drive HMECs toward a mesenchymal stem-like state. Our findings reveal that RAB25 functions as a tumor suppressor gene, and loss of RAB25 could serve as a novel biomarker of the claudin-low type of TNBC. [ABSTRACT FROM AUTHOR]

Objectives: Although invasive cervical cancer (ICC) rates have declined since the advent of screening, the annual age-adjusted ICC rate in the United States remains 7.5 per 100,000 women. Failure of recommended screening and management often precedes ICC diagnoses. The study aimed to evaluate characteristics of women with incident ICC, including potential barriers to accessing preventive care. Materials and Methods: We abstracted medical records for patients with ICC identified during 2008–2020 in five U.S. population-based surveillance sites covering 1.5 million women. We identified evidence of adverse social and medical conditions, including uninsured/underinsured, language barrier, substance use disorder, incarceration, serious mental illness, severe obesity, or pregnancy at diagnosis. We calculated descriptive frequencies and compared potential barriers by race/ethnicity, and among women with and without symptoms at diagnosis using chi-square tests. Results: Among 1,606 women with ICC (median age: 49 years; non-White: 47.4%; stage I: 54.7%), the majority (68.8%) presented with symptoms. Forty-six percent of women had at least one identified potential barrier; 15% had multiple barriers. The most common potential barriers among all women were being underinsured/uninsured (17.3%), and language (17.1%). Presence of any potential barrier was more frequent among non-White women and women with than without symptoms (p < 0.05). Conclusions: In this population-based descriptive study of women with ICC, we identified adverse circumstances that might have prevented women from seeking screening and treatment to prevent cancer. Interventions to increase appropriate cervical cancer screening and management are critical for reducing cervical cancer rates. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is an aggressive and lethal cancer of the blood, which leads to the death of over 11,000 patients in the United States each year. Research on identifying, characterizing, and treating AML is crucial in the fight against this deadly disease. Recent studies have examined the role of CLEC11A in cancer, including AML. However, there have been conflicting reports related to tumor progression and survival. Because survival is based on a variety of factors, including classification of the tumor, genetic risk factors, and demographics, it is imperative that we determine what role CLEC11A may have in cancer survival. Therefore, utilizing data from the Genomic Data Commons, we analyzed CLEC11A methylation in 108 AML patients compared to FAB classification, cytogenetic risk factors, age, race, and gender. Our results show statistically significant correlations between methylation of CLEC11A and FAB classification as well as poor genetic risk factors. However, no difference was observed in CLEC11A methylation when compared to demographic data. Our results, matched with a known biological function of CLEC11A in early hematopoiesis, indicate that CLEC11A may be an important marker for AML diagnosis and prognosis and provide relevant data in the ongoing search for novel therapeutics to improve AML survival. [ABSTRACT FROM AUTHOR]

Objective: The overall 5-year survival for oral squamous cell carcinoma (OSCC) has not changed in the last 20 years despite advances in treatment. Lymphovascular invasion (LVI) has been shown to be a negative prognostic factor in other cancers, however its role in the prognosis of OSCC remains unclear. This study aims to determine if LVI is a predictor of cervical lymph node metastasis and/or recurrence in OSCC. Methods: We conducted a retrospective cohort review of patients from our institutional cancer registry who were treated for OSCC between 2004 and 2018. Patient demographics, surgical pathology results, and clinical outcome data were collected. A multivariable logistic regression analysis was performed to determine if LVI was an independent predictor of cervical lymph node metastasis and/or recurrence. Results: 442 patients were included, 32.8% were female and median age at time of diagnosis was 61.2 years. LVI was present in 32.8% of patients. When controlled for age, sex, t-classification, perineural invasion, depth of invasion (DOI), and margin status, LVI was a significant predictor of the presence of cervical node metastasis (OR: 3.42, CI: 2.17-5.39, P <.001). There was no significant association found between LVI and local recurrence (OR: 1.03, CI: 0.57-1.84, P =.92), regional recurrence (OR: 1.10, CI: 0.57-2.11, P =.78), or distant recurrence (OR: 1.59, CI: 0.87-2.94, P =.13). Conclusion: The results of this study suggest that LVI is a significant predictor of the presence of cervical lymph node metastasis at presentation independent of other known prognostic factors. LVI, however, was not found to be a significant independent predictor of locoregional or distant recurrence. Level of Evidence: Level III [ABSTRACT FROM AUTHOR]

Background HER2 immunohistochemistry (IHC) reproducibility is suboptimal for HER-low cases (IHC 1+ or 2+). Methods The Yale cohort included 214 stages I-II estrogen receptor positive breast cancers with IHC scores 0, 1+, and 2+ and routine Oncotype DX Recurrence Score (RS) results. The Exact Sciences (ES) cohort included 9 57 624 patients who had an Oncotype DX RS assay that assigns HER2-negative, equivocal, or positive status based on HER2 mRNA levels. Results HER2 mRNA levels varied across IHC categories but with increasing medians of 9.10 (n  = 89), 9.20 (n  = 71), and 9.45 (n  = 54) in IHC 0, 1+, and 2+, respectively. 22.4% of HER2-low (1+/2+) cancer had RS > 25. Over 98% of HER-low cancers were HER2-negative by Oncotype DX assignment. Conclusions Cancers with higher mRNA levels exist within IHC 0 and low categories, most of the HER2-low patients by IHC have low RS indicating no benefit from current adjuvant chemotherapies. [ABSTRACT FROM AUTHOR]

Cancer is among the top causes of death, accounting for an estimated 9.6 million deaths in 2018, it appeared that approximately 500,000 people die from cancer in the United States alone annually. The SHP2 plays a major role in regulation of cell growth, proliferation, and differentiation, and functional upregulation of this enzyme is linked to oncogenesis and developmental disorders. SHP2 activity has been linked to several cancer types for which no drugs are currently available. In our study, we aimed to design peptide inhibitors against the SHP2 mutant. The crystal structure of the human Src SH2-PQpYEEIPI peptide mutant was downloaded from the protein databank. We generated several peptides from the native wild peptide using an in silico mutagenesis method, which showed that changes (P302W, Y304F, E306Q, and Q303A) might boost the peptide's affinity for binding to SHP2. Furthermore, the dynamical stability and binding affinities of the mutated peptide were confirmed using Molecular dynamics simulation and Molecular Mechanics with Generalized Born and Surface Area Solvation free energy calculations. The proposed substitution greatly enhanced the binding affinity at the residue level, according to a study that decomposed energy into its component residues. Our proposed peptide may prevent the spread of cancer by inhibiting SHP2, according to our detailed analyses of binding affinities. [ABSTRACT FROM AUTHOR]

Objective: To assess effectiveness of a web-based educational intervention on women's health care provider knowledge of breast cancer risk models and high-risk screening recommendations. Methods: A web-based pre- and post-test study including 177 U.S.-based women's health care providers was conducted in 2019. Knowledge gaps were defined as fewer than 75% of respondents answering correctly. Pre- and post-test knowledge differences (McNemar test) and associations of baseline characteristics with pre-test knowledge gaps (logistic regression) were evaluated. Results: Respondents included 131/177 (74.0%) physicians; 127/177 (71.8%) practiced obstetrics/gynecology. Pre-test, 118/177 (66.7%) knew the Gail model predicts lifetime invasive breast cancer risk; this knowledge gap persisted post-test [(121/177, 68.4%); P = 0.77]. Just 39.0% (69/177) knew the Gail model identifies women eligible for risk-reducing medications; this knowledge gap resolved. Only 48.6% (86/177) knew the Gail model should not be used to identify women meeting high-risk MRI screening guidelines; this deficiency decreased to 66.1% (117/177) post-test (P = 0.001). Pre-test, 47.5% (84/177) knew the Tyrer-Cuzick model is used to identify women meeting high-risk screening MRI criteria, 42.9% (76/177) to predict BRCA1/2 pathogenic mutation risk, and 26.0% (46/177) to predict lifetime invasive breast cancer risk. These knowledge gaps persisted but improved. For a high-risk 30-year-old, 67.8% (120/177) and 54.2% (96/177) pre-test knew screening MRI and mammography/tomosynthesis are recommended, respectively; 19.2% (34/177) knew both are recommended; and 53% (94/177) knew US is not recommended. These knowledge gaps resolved or reduced. Conclusion: Web-based education can reduce important provider knowledge gaps about breast cancer risk models and high-risk screening recommendations. [ABSTRACT FROM AUTHOR]

IMbrave150 has established the superiority of atezolizumab plus bevacizumab over sorafenib in patients with unresectable hepatocellular carcinoma (HCC). We generated a prospectively maintained database including patients treated with atezolizumab plus bevacizumab for unresectable HCC across Europe, Asia and USA. Clinico-pathologic characteristics were assessed for their prognostic influence on overall survival (OS) and progression-free survival (PFS) in univariable and multivariate analyses. Overall response rate by RECIST v1.1 and treatment-related adverse events (TRAEs) per CTCAE v.5.0 were reported. Out of 433 patients, 296 Child-Pugh A and ECOG performance status01 patients received atezolizumab plus bevacizumab in first line and were included. Patients were mostly male (82.7%), cirrhotic (75%) with history of viral hepatitis (65.9%). Overall, 68.9% had Barcelona Clinic Liver Cancer C-stage HCC with portal vein tumour thrombosis (PVTT, 35%) and extrahepatic spread (EHS, 51.7%). After a median follow-up of 10.0 months (95% confidence interval (CI): 9.4–10.4), median OS and PFS were 15.7 (95% CI: 14.5-NE) and 6.9 months (95% CI: 6.1–8.3), respectively. In the response-evaluable patients (n = 273), overall response rate was 30.8%. Overall, 221 patients (74.6%) developed TRAEs, with 70 (23.6%) reporting grade 3 or higher TRAEs; 25 (8.4%) patients had bleeding events. OS was independently associated with baseline Albumin-bilirubin (ALBI) grade and PVTT. Shorter PFS was associated with AFP≥ 400 ng/ml, worse ALBI and presence of EHS. This global observational study confirms the reproducible safety and efficacy of atezolizumab plus bevacizumab in routine clinical practice. Within Child-Pugh-A criteria, the presence of PVTT and higher ALBI grade identify patients with poorer survival. • Atezolizumab plus bevacizumab (A + B) is the standard of care for patients with unresectable hepatocellular carcinoma. • We report data from a large cohort of patients treated with A + B in real-life. • Effectiveness and safety of the combination is reproducible in daily practice. • Liver function and macro-vascular invasion is with overall survival. • Radiological response predicts better outcomes. [ABSTRACT FROM AUTHOR]

Objectives: The availability of immunotherapies has expanded the options for treating metastatic NSCLC, but information is needed regarding outcomes of immunotherapy for patients treated outside of clinical trials. The aim of this retrospective study was to evaluate the outcomes of therapy with first-line pembrolizumab plus pemetrexed and carboplatin (pembrolizumabcombination) for patients with metastatic nonsquamous NSCLC in the realworld setting of oncology clinics in the United States (US). Methods: Using deidentified, longitudinal patient records from a nationwide, electronic health record-derived US database, we identified patients with metastatic nonsquamous NSCLC, without EGFR/ALK/ROS1 genomic alterations, who had received no previous systemic anticancer therapy. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and initiated first-line pembrolizumabcombination therapy from 11-May-2017 to 31-January-2019; data cutoff was 31-August-2020. Patients treated in a clinical trial were excluded. Manual chart review supplemented technology-enabled abstraction to identify disease progression and tumor response. Time-to-event endpoints from initiation of pembrolizumab-combination therapy were determined using Kaplan-Meier. Results: Of 377 patients with metastatic nonsquamous NSCLC, 105 (28%), 104 (28%), and 103 (27%) had programmed death-ligand 1 (PD-L1) expression =50%, 1-49%, and <1%, respectively; PD-L1 expression was not documented for 65 patients (17%). Median age was 66 years, and 227 patients (60%) were men. Median follow-up time from first-line therapy initiation to data cutoff was 31.2 months (range, 19.0-39.6 months). Median pembrolizumab real-world time on treatment (rwToT) was 5.8 months (95% CI, 5.0-6.7); 12- and 24-month ontreatment rates for pembrolizumab were 28.0% and 14.9%, respectively. Median overall survival (OS) was 17.2 months (95% CI, 13.6-19.9). For patients in PD-L1 expression =50%, 1-49%, <1%, and unknown cohorts, the 12-month survival rates were 66.0%, 58.5%, 54.5%, and 58.3%, respectively, and 24-month survival rates were 43.1%, 37.2%, 35.6%, and 42.0%, respectively. Median realworld progression-free survival was 6.2 months (95% CI, 5.5-7.1); and the realworld response rate was 39.3%, with median duration of response of 13.1 months (95% CI, 10.5-16.8). Conclusions: These findings demonstrate the benefits of first-line pembrolizumab-combination therapy for patients with EGFR/ALK-wild-type, metastatic nonsquamous NSCLC and good performance status who are treated at US community oncology clinics. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is the fourth leading cause of cancer death in the United States. Themainmethods of treating pancreatic cancer are surgery and chemotherapy, but the treatment efficacy is low with a poor prognosis. Immunotherapy represented by PD-1/PD-L1 has brought amilestone progress in the treatment of pancreatic cancer. However, the unique tumor microenvironment of pancreatic cancer presents challenges for immunotherapy. In addition, m6A is a common RNA modification and a potentialmolecular target in tumor therapy. The expression pattern of m6A in pancreatic cancer is still unclear. LncRNAs also play an essential role in pancreatic cancer development and treatment. In this study, we found that some m6A regulators were significantly elevated in pancreatic cancer and associated with the expression of PD-1/PD-L1. Moreover, we observed that METTL3 can increase the expression of PD-L1. Notably, METTL3 positively regulates the expression of lncRNA MALAT1 in pancreatic cancer cells. Strikingly, lncRNA MALAT1 increased the expression of PD-L1 in pancreatic cancer cells. This finding indicated that METTL3 regulated the expression of PD-L1 possibly via targeting lncRNA MALAT1 in pancreatic cancer cells. Lastly, MALAT1 governed the viability of pancreatic cancer cells. Taken together, lncRNA MALAT1 is involved in METTL3-mediated promotion of PD-L1 expression in pancreatic cancer. [ABSTRACT FROM AUTHOR]

A relatively high healthy lifestyle index (HLI) score, representing a healthy diet, participation in moderate to vigorous physical exercise, no smoking, low to no alcohol intake and a normal body mass index, has been associated with a reduced risk of invasive breast cancer. However, no study has shown an association between the HLI and the risk of ductal carcinoma in situ of the breast (DCIS), which is considered to be a nonobligate precursor of invasive breast cancer. We evaluated this association in a prospective cohort of 132 230 postmenopausal women, aged 50 to 79 years, recruited between 1993 and 1998 across the United States and enrolled in the Women's Health Initiative study. The HLI score was created and categorized into quartiles. During an average follow‐up of 15.4 years, 2035 DCIS cases were ascertained. Multivariable‐adjusted Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of HLI with the risk of DCIS. Women in the highest HLI quartile had a lower DCIS risk than those in the lowest quartile (HR4thQT = 0.80, 95% CI, 0.70‐0.92) and this association was stronger in women with a family history of breast cancer (HR4thQT = 0.70, 95% CI, 0.52‐0.93), and for ER+/PR+ DCIS (HR4thQT = 0.66, 95% CI, 0.52‐0.83). These findings suggest that there is an inverse association between HLI and risk of DCIS, and suggest that the adoption of a healthy lifestyle might lower the risk of DCIS. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the second most diagnosed cancer in the United States and is associated with metabolic reprogramming and significant disparities in clinical outcomes among African American (AA) men. While the cause is likely multi-factorial, the precise reasons for this are unknown. Here, we identified a higher expression of the metabolic enzyme UGT2B28 in localized PCa and metastatic disease compared to benign adjacent tissue, in AA PCa compared to benign adjacent tissue, and in AA PCa compared to European American (EA) PCa. UGT2B28 was found to be regulated by both full-length androgen receptor (AR) and its splice variant, AR-v7. Genetic knockdown of UGT2B28 across multiple PCa cell lines (LNCaP, LAPC-4, and VCaP), both in androgen-replete and androgen-depleted states resulted in impaired 3D organoid formation and a significant delay in tumor take and growth rate of xenograft tumors, all of which were rescued by re-expression of UGT2B28. Taken together, our findings demonstrate a key role for the UGT2B28 gene in promoting prostate tumor growth. [ABSTRACT FROM AUTHOR]

Background: Of the nearly 50,000 women in the United States who undergo treatment for ductal carcinoma in situ (DCIS) annually, many may not benefit from treatment. To better understand the impact of a DCIS diagnosis, patients self‐identified as having had DCIS were engaged regarding their experience. Methods: In July 2014, a web‐based survey was administered through the Susan Love Army of Women breast cancer listserv. The survey included open‐ended questions designed to assess patients' perspectives about DCIS diagnosis and treatment. Deductive and inductive codes were applied to the responses; common themes were summarized. Results: Among the 1832 women included in the analytic sample, the median age at diagnosis was 60 years. Four primary themes were identified: 1) uncertainty surrounding a DCIS diagnosis, 2) uncertainty about DCIS treatment, 3) concern about treatment side effects, and 4) concern about recurrence and/or developing invasive breast cancer. When diagnosed, participants were often uncertain about whether they had cancer or not and whether they should be considered a "survivor." Uncertainty about treatment manifested as questioning the appropriateness of the amount of treatment received. Participants expressed concern about the "cancer spreading" or becoming invasive and that they were not necessarily "doing enough" to prevent recurrence. Conclusions: In a large, national sample, participants with a history of DCIS reported confusion and concern about the diagnosis and treatment, which caused worry and significant uncertainty. Developing strategies to improve patient and provider communications regarding the nature of DCIS and acknowledging gaps in the current knowledge of management options should be a priority. Ductal carcinoma in situ (DCIS) survivors often report feelings of uncertainty and concern about their diagnosis and treatment. Developing strategies to improve communication regarding the nature of DCIS as well as the potential benefits and harms of different DCIS management options should be a priority. [ABSTRACT FROM AUTHOR]

Objectives: To determine the geographic distribution of muscle-invasive bladder cancer mortality according to race in the United States (US). African Americans (AAs) have up to two times the risk of bladder cancer mortality compared to Caucasians. Bladder cancer mortality increases exponentially once it invades the muscle. Geographic heterogeneity in bladder cancer mortality according to race remains to be determined. Design: Analysis of Surveillance, Epidemiology, and End Results (SEER)-Medicare data for 6,044 patients aged 66–85 diagnosed with clinical stage T2–T4 N0M0 bladder cancer from 1 January 2002 to 31 December 2011. Fine and Gray-competing risks regression models were used to assess the association of race with bladder cancer-specific mortality (BCSM) according to tumor registry. Results: Out of 6,044 patients, 5,408 (89.5%) were Caucasian, 352 (5.82%) were non-Hispanic AA, 85 (1.4%) were Hispanic, and 199 (3.29%) were other. Of the 18 registries, AAs with bladder cancer were largely concentrated in Louisiana (19%), New Jersey (17.9%), and Georgia (17.6%). New Jersey was the only registry where AAs had increased risk of BCSM than Caucasians and only for stage T2 disease: (AHR, 1.74; 95% CI 1.22–2.47, p = 0.002). According to treatment, AAs in New Jersey had worse BCSM than Caucasians when they underwent radical cystectomy (AHR, 2.05; 95% CI 1.26–3.35, p = 0.0039) and radiotherapy or chemotherapy alone (AHR, 1.55; 95% CI 1.03–2.35, p = 0.0367). Conclusions: We observed geographic variation in bladder cancer mortality which impacted only one registry with one of the largest population of AAs. These findings support further investigation into the social determinants of race (i.e., socioeconomic status and distance to healthcare facility) and culturally centered healthcare decision making which may drive these results. [ABSTRACT FROM AUTHOR]

Methods: Articles on inflammatory tumor microenvironment were retrieved from the Web of Science Core Collection, and the characteristics of the articles were analyzed by CiteSpace software. Background: The inflammatory tumor microenvironment is an essential feature of the tumor microenvironment. The way in which it promotes or inhibits tumor progression plays an important role in the outcome of a tumor treatment. This research aims to explore a scientific collaboration network, describe evolution of hotspots, and predict future trends through bibliometric analysis. Results: A total of 3,534 papers published by 390 institutions in 81 countries/regions were screened, and the annual quantity has been increasing rapidly in the past decades. United States was the leading country and has the most productive institutions in this field. The research topics were mainly focused on inflammation and immunity mediated by crucial factors as well as the mechanisms of angiogenesis. Additionally, the development and application of nanoparticles is currently a novel research frontier with bright prospect. Conclusion: The present scientometric study provides an overview of inflammatory tumor microenvironment research over the previous decades using quantitative and qualitative methods, and the findings of this study can provide references for researchers focusing on tumor treatment. [ABSTRACT FROM AUTHOR]

Introduction: We sought to investigate the association between insurance coverage history and cervical cancer screening among Davidson County, Tennessee, women diagnosed with incident cervical cancer.Methods: We reviewed medical records of women diagnosed with invasive cervical cancer from 2008 through 2018 identified via the state's cancer registry and by active surveillance of diagnostic pathology reports for the HPV-IMPACT project. Per 2012 United States Preventive Services Task Force recommended cervical cancer screening guidelines, women were characterized into three screening history categories: "no screening", "no follow-up" and "test/screening failure". Multivariable logistic regression measured the association of prior inadequate insurance (underinsurance) and screening history ("no screening/no follow-up" compared to "test/screening failure").Results: Of 212 women, most (77%) had not undergone recommended cervical cancer screening or follow-up prior to cancer diagnosis. Overall, 28% of women had history of underinsurance in 5 years prior to diagnosis. In adjusted analyses, underinsured women were more likely to have a "no screening/no follow-up" prior to cancer diagnosis (aOR 4.26; 95% CI 1.15-15.80) compared to "test/screening failure" history. Non-white race (aOR 2.73; 95% CI 0.98-7.61), older age (aOR 1.03 per year; 95% CI 1.00-1.07), and history of smoking (aOR 4.07; 95% CI 1.54-10.74) were also associated with increased likelihood of "no screening/no follow-up".Conclusions: Previous underinsurance was independently associated with non-adherence to cervical cancer screening and follow-up guidelines among women with incident cervical cancer. Further study of factors contributing to inadequate cervical cancer screening and interventions to increase cervical cancer screening in high-risk populations is needed. [ABSTRACT FROM AUTHOR]

Cutaneous squamous cell carcinoma (cSCC) is a common form of skin cancer with an estimated 750,000 cases diagnosed annually in the United States. Most cases are successfully treated with a simple excision procedure, but ~5% of cases metastasize and have a 5-year survival rate of 25-45%. Thus, identification of biomarkers correlated to cSCC progression may be useful in the early identification of high-risk cSCC and in the development of new therapeutic strategies. This work investigates the role of complement factor H (CFH) in the development of cSCC. CFH is a regulatory component of the complement cascade which affects cell mediated immune responses and increases in complement proteins are associated with poor outcomes in multiple cancer types. We provide evidence that sun exposure may increase levels of CFH, suggesting an immunomodulatory role for CFH early in the development of cSCC. We then document increased levels of CFH in cSCC samples, compared to adjacent normal tissue (ANT) routinely excised in a dermatology clinic which, in paired samples, received the same level of sun exposure. We also provide evidence that levels of CFH are even greater in more advanced cases of cSCC. To provide a potential link between CFH and immune modulation, we assessed immune system function by measuring interferon gamma (IFN-γ) and FOXP3 in patient samples. IFN-γ levels were unchanged in cSCC relative to ANT which is consistent with an ineffective cell-mediated immune response. FOXP3 was used to assess prevalence of regulatory T cells within the tissues, indicating either a derailed or inhibitory immune response. Our data suggest that FOXP3 levels are higher in cSCC than in ANT. Our current working model is that increased CFH downstream of sun exposure is an early event in the development of cSCC as it interferes with proper immune surveillance and decreases the effectiveness of the immune response, and creates a more immunosuppressive environment, thus promoting cSCC progression. [ABSTRACT FROM AUTHOR]

Objective: To examine the relationship between hospital volume and the management of bladder cancer variant histology. Variant histologies of bladder cancer are rare which limits the ability for providers to develop expertise however there is a clear hospital and/or surgeon-volume relationship for management of rare or complex surgical and/or medical diseases.Methods: We queried the National Cancer Database from 2004-2016 for all cases of bladder cancer, identifying cases of variant histology. Our primary outcome was overall survival while secondary outcomes included identifying treatment patterns. Hospitals were stratified into those that managed ≤2, >2-4, >4-6, and ≥6 cases per year of variant histology.Results: We identified 23,284 patients with bladder cancer of variant histology who were treated at 1301 hospitals. Few institutions had high volume experience with this disease: 18.5% (n = 241) treated >2 patients annually and 5.7% (n = 76) treated >4 cases annually. Hospital volume positively correlated with utilization of early radical cystectomy (RC) in non-muscle invasive disease and neoadjuvant chemotherapy in muscle-invasive disease. On multivariable analysis, increased hospital volume was associated with improved survival. After stratifying by sub-type, hospital volume continued to be associated with improved survival for squamous, small cell, and sarcomatoid cancers.Conclusion: Management of variant histology urothelial carcinoma at high-volume centers is associated with improved overall survival. The mechanisms of this are multifactorial, and future research should focus on improvement opportunities for low-volume hospitals, centralization of care, and/or increased access to care at high-volume centers. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancers affect thousands of women in the United States and disproportionately drive mortality from breast cancer. MicroRNAs are small, non-coding RNAs that negatively regulate gene expression post-transcriptionally by inhibiting target mRNA translation or by promoting mRNA degradation. We have identified that miRNA-203, silenced by epithelial-mesenchymal transition (EMT), is a tumor suppressor and can promote differentiation of breast cancer stem cells. In this study, we tested the ability of liposomal delivery of miR-203 to reverse aspects of breast cancer pathogenesis using breast cancer and EMT cell lines. We show that translationally relevant methods for increasing miR-203 abundance within a target tissue affects cellular properties associated with cancer progression. While stable miR-203 expression suppresses LASP1 and survivin, nanoliposomal delivery suppresses BMI1, indicating that suppression of distinct mRNA target profiles can lead to loss of cancer cell migration. [ABSTRACT FROM AUTHOR]

In the United States, one in 196 women is diagnosed with breast cancer under the age of 40 years. Adolescents and young adults (AYAs), of age 15-39 years at diagnosis, experience a number of unique challenges when confronting breast cancer. The incidence of invasive breast cancer has increased among AYA women in the United States since 2004, and most of this change is due to an increase in young women diagnosed with distant disease. AYAs are more likely than older women to present with aggressive subtypes and advanced disease, and they often require systemic staging at diagnosis. Clinical trials should be considered whenever possible, particularly in AYAs with locally advanced or metastatic disease at diagnosis and those with disease progression or recurrence. A significant proportion of AYAs carry germline cancer predisposition mutations, which necessitates prompt genetic testing for all AYAs at diagnosis and may influence choice of local therapy. Suppression of ovarian function, as an adjunct to chemotherapy, may improve breast cancer survival in AYAs. To provide optimal care for AYAs with breast cancer, clinicians should engage multidisciplinary teams that offer fertility preservation, genetic counseling, physical and occupational therapy, nutrition, and psychosocial support, along with medical expertise in tailoring cancer-directed therapy and symptom management toward young women. [ABSTRACT FROM AUTHOR]

Lung cancer is the deadliest malignancy in the United States. Non-small cell lung cancer (NSCLC) accounts for 85% of cases and is frequently driven by activating mutations in the gene encoding the KRAS GTPase (e.g., KRASG12D). Our previous work demonstrated that Argonaute 2 (AGO2)--a component of the RNA-induced silencing complex (RISC)--physically interacts with RAS and promotes its downstream signaling. We therefore hypothesized that AGO2 could promote KRASG12D-dependent NSCLC in vivo. To test the hypothesis, we evaluated the impact of Ago2 knockout in the KPC (LSL-Kras G12D/+;p53f/f;Cre) mouse model of NSCLC. In KPC mice, intratracheal delivery of adenoviral Cre drives lung-specific expression of a stopfloxed KRASG12D allele and biallelic ablation of p53. Simultaneous biallelic ablation of floxed Ago2 inhibited KPC lung nodule growth while reducing proliferative index and improving pathological grade. We next applied the KPHetC model, in which the Clara cell-specific CCSP-driven Cre activates KRASG12D and ablates a single p53 allele. In these mice, Ago2 ablation also reduced tumor size and grade. In both models, Ago2 knockout inhibited ERK phosphorylation (pERK) in tumor cells, indicating impaired KRAS signaling. RNA sequencing (RNA-seq) of KPC nodules and nodule-derived organoids demonstrated impaired canonical KRAS signaling with Ago2 ablation. Strikingly, accumulation of pERK in KPC organoids depended on physical interaction of AGO2 and KRAS. Taken together, our data demonstrate a pathogenic role for AGO2 in KRAS-dependent NSCLC. Given the prevalence of this malignancy and current difficulties in therapeutically targeting KRAS signaling, our work may have future translational relevance. [ABSTRACT FROM AUTHOR]

Objective: To identify racial and sex disparities in the treatment and outcomes of muscle-invasive bladder cancer (MIBC) using a nationwide oncology outcomes database.Methods: Using the National Cancer Database, we identified patients with muscle invasive bladder cancer from 2004 to 2014. Treatments analyzed included no treatment, cystectomy, neoadjuvant chemotherapy plus cystectomy ("optimal treatment"), cystectomy plus adjuvant chemotherapy, and chemoradiation. Propensity matching compared mortality outcomes between sexes. Logistic models evaluated predictors of receiving optimal treatment, as well as mortality.Results: Forty seven thousand two hundred and twenty nine patients were identified. Most patients were male (73.4%) and underwent cystectomy alone (69.0%). Propensity score matching demonstrated increased 90-day mortality in women vs men (13.0% vs 11.6%, P = .009), despite adjusting for differences in treatments between sexes. Logistic regression models showed no difference in receipt of optimal treatment between sexes (odds ratio [OR] 1.01, 95% confidence interval [CI] 0.83-1.22) although black patients were less likely to receive optimal treatment (OR 0.15, 95% CI 0.05-0.48). Logistic regression models confirmed increased 90-day mortality in female (OR 1.17, CI 1.08-1.27, P < .001) and black (OR 1.29, CI 1.11-1.50, P = .001) patients. Females had a lower overall survival on Cox regression analysis (Hazard Ratio 0.92, 95% CI 0.87-0.97).Conclusion: While there do not appear to be significant treatment disparities between sexes, women experience higher 90-day mortality and lower overall survival. Black patients are less likely to receive optimal treatment and have a higher risk of 90-day mortality. Additional research is needed to determine the variables leading to worse outcomes in females and identify impediments to black patients receiving optimal treatment. [ABSTRACT FROM AUTHOR]

Background: Parity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated.Methods: A pooled analysis of 10 470 invasive epithelial ovarian cancer cases and 16 942 controls was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race and ethnicity, age, and education level and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses.Results: Ever having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (2-sided Ptrend < .001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer.Conclusions: Incomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk. [ABSTRACT FROM AUTHOR]

Prostate cancer is one of the most common cancers diagnosed in men in the United States and the second leading cause of cancer-related deaths worldwide. Since over 60% of prostate cancer cases occur in men over 65 years of age, and this population will increase steadily in the coming years, prostate cancer will be a major cancer-related burden in the foreseeable future. Accumulating data from more recent research suggest that the tumor microenvironment (TME) plays a previously unrecognized role in every stage of cancer development, including initiation, proliferation, and metastasis. Prostate cancer is not only diagnosed in the late stages of life, but also progresses relatively slowly. This makes prostate cancer an ideal model system for exploring the potential of natural products as cancer prevention and/or treatment reagents because they usually act relatively slowly compared to most synthetic drugs. Resveratrol (RSV) is a naturally occurring stilbenoid and possesses strong anti-cancer properties with few adverse effects. Accumulating data from both in vitro and in vivo experiments indicate that RSV can interfere with prostate cancer initiation and progression by targeting the TME. Therefore, this review is aimed to summarize the recent advancement in RSV-inhibited prostate cancer initiation, proliferation, and metastasis as well as the underlying molecular mechanisms, with particular emphasis on the effect of RSV on TME. This will not only better our understanding of prostate cancer TMEs, but also pave the way for the development of RSV as a potential reagent for prostate cancer prevention and/or therapy. [ABSTRACT FROM AUTHOR]

Background: BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer.Methods: In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849.Findings: Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths.Interpretation: Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state.Funding: FKD Therapies Oy. [ABSTRACT FROM AUTHOR]

Background: The germline cancer predisposition genes associated with increased risk of each clinical subtype of breast cancer, defined by estrogen receptor (ER), progesterone receptor (PR), and HER2, are not well defined.Methods: A total of 54 555 invasive breast cancer patients with 56 480 breast tumors were subjected to clinical hereditary cancer multigene panel testing. Heterogeneity for predisposition genes across clinical breast cancer subtypes was assessed by comparing mutation frequencies by gene among tumor subtypes and by association studies between each tumor subtype and reference controls.Results: Mutations in 15 cancer predisposition genes were detected in 8.6% of patients with ER+/HER2-; 8.9% with ER+/HER2+; 7.7% with ER-/HER2+; and 14.4% of ER-/PR-/HER2- tumors. BRCA1, BRCA2, BARD1, and PALB2 mutations were enriched in ER- and HER2- tumors; RAD51C and RAD51D mutations were enriched in ER- tumors only; TP53 mutations were enriched in HER2+ tumors, and ATM and CHEK2 mutations were enriched in both ER+ and/or HER2+ tumors. All genes were associated with moderate (odds ratio > 2.00) or strong (odds ratio > 5.00) risks of at least one subtype of breast cancer in case-control analyses. Mutations in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53 had predicted lifetime absolute risks of at least 20.0% for breast cancer.Conclusions: Germline mutations in hereditary cancer panel genes confer subtype-specific risks of breast cancer. Combined tumor subtype, age at breast cancer diagnosis, and family history of breast and/or ovarian cancer information provides refined categorical estimates of mutation prevalence for women considering genetic testing. [ABSTRACT FROM AUTHOR]

Lung cancer remains the leading cause of cancer death in the United States. Since most lung cancers occur in aged individuals with chronic lung disorders characterized by inflammation and/or fibrosis, we hypothesized that aging and tissue inflammation/remodeling act in concert to promote lung cancer progression. To test this, we engaged in studies using young and aged C57BL/6 mice in conjunction with bleomycin treatment in a syngeneic model of lung cancer. Wildtype young (3 months) and aged (9 months) C57BL/6 mice were injected with Lewis Lung Carcinoma (LLC) cells at day 14 after injection with phosphate-buffered saline or bleomycin. Untreated aged mice were found to develop more lung metastases than young mice. Bleomycin induced weight loss and lung inflammation/remodeling in both young and aged mice, and it increased the number of lung metastases in aged lungs, but not in young lungs. Since aged lungs show alterations in the expression of fibronectin EDA, we repeated studies in aged WT and aged FN EDA KO mice. In the absence of tissue remodeling/inflammation, WT and FN EDA KO mice developed the same number of metastases when injected with LLC cells. However, the increase in lung metastasis due to bleomycin treatment was abolished in FN EDA KO mice, but only in aged and injured lungs. Together, these studies show increased lung cancer metastasis in aging animals and point to the influence of FN EDA and injury in this process. [ABSTRACT FROM AUTHOR]

Breast cancer is the most commonly diagnosed cancer in women and the second most common cause of cancer-related deaths in the United States. Although early detection has significantly decreased breast cancer mortality, patients diagnosed with distant metastasis still have a very poor prognosis. The most common site that breast cancer spreads to are local lymph nodes. Therefore, the presence of lymph node metastasis remains one of most important prognostic factors in breast cancer patients. Given its significant clinical implications, increased efforts have been dedicated to better understand the molecular mechanism governing lymph node metastasis in breast cancer. The identification of lymphatic-specific biomarkers, including podoplanin and LYVE-1, has propelled the field of lymphatic metastasis forward. In addition, several animal models such as cell line-derived xenografts, patient-derived xenografts, and spontaneous tumor models have been developed to recreate the process of lymphatic metastasis. Moreover, the incorporation of various -omic platforms have provided further insight into the genetic drivers facilitating lymphatic metastasis, as well as potential biomarkers and therapeutic targets. Here, we highlight various models of lymphatic metastasis, their potential pitfalls, and other tools available to study lymphatic metastasis including imaging modalities and -omic studies. [ABSTRACT FROM AUTHOR]

Aim: Testicular germ cell tumors (TGCT) are solid neoplasms common in young adult men and an important cause of cancer-related deaths during this period. Revisions in histopathological classification and staging affect prognosis and treatment. The aim of this study was to analyze our TGCT cases, to review prognostic parameters, and their relationship between germ cell neoplasia in situ (GCNIS), intratubular and intertubular tumors. Material and Methods: In this study, Hematoxylin&Eosin-stained sections of 77 TGCTs were re-evaluated. The presence of GCNIS, intratubular and intertubular germ cell tumors were recorded. Histopathological classification and staging were revised based on the changes in the 8th edition of American Joint Committee on Cancer (AJCC). Results: The majority of the patients were diagnosed as seminoma (n=42), followed by mixed germ cell tumors (n=33) and spermatocytic tumors (n=2). Rete testis invasion in 30 cases, epididymal invasion in 6 cases, hilar soft tissue invasion in 10 cases, tunica vaginalis invasion in 1 case, spermatic cord invasion in 4 cases, and lymphovascular invasion in 22 cases were detected. Intertubular seminoma in 25 cases, intratubular carcinoma in 16 cases, and GCNIS in 73 cases were detected. Conclusion: The major criteria to determine treatment choices are histopathological diagnosis, pathological tumor stage, serum tumor markers and presence of metastasis. According to AJCC 8th edition, addition of hilar soft tissue invasion to staging has increased the number of our pT2 cases. Moreover, assuming discontinuous tumor invasion of spermatic cord by vascular invasion as pM1 has also increased the number of metastatic testis tumors. [ABSTRACT FROM AUTHOR]

Background: The presumptive overdiagnosis of papillary thyroid microcarcinoma (PTMC) has led to an emerging trend of less-extensive operation and an inclination toward active surveillance when possible. In this study, we aimed to examine the risk of advanced PTMC at presentation.Study Design: We conducted a retrospective analysis using the National Cancer Database (2010 to 2014). Patients with PTMC who underwent surgical intervention were included and patients with a history of any cancer were excluded.Results: A total of 30,180 adult patients with PTMC were identified; 5,628 patients (18.7%) presented with advanced features, including central lymph node (LN) metastasis (8.0%), lateral LN metastasis (4.4%), microscopic extrathyroidal extension (ETE; 6.7%), gross ETE (0.3%), lymphovascular invasion (LVI; 4.4%), and distant metastasis (0.4%). All of those features were associated with a significantly lower survival rate (p < 0.05 each) except for microscopic ETE and LVI. There was a significant interrelation among those features, distant metastasis was associated with central LN metastasis (odds ratio [OR] 2.44; 95% CI, 1.48 to 4.23; p < 0.001), lateral LN metastasis (OR 3.18; 95% CI, 1.77 to 5.71; p < 0.001), and gross ETE (OR 9.91; 95% Cl, 3.83 to 25.64; p < 0.001). In turn, nodal metastasis was associated with microscopic ETE (OR 4.23; 95% CI, 3.82 to 4.70; p < 0.001) and LVI (OR 7.17; 95% CI, 6.36 to 8.08; p < 0.001).Conclusions: PTMC could exhibit advanced features in 19% of patients who underwent operation and some of those, such as LVI and microscopic ETE, are undetectable with preoperative workup. Clinicians need to be cognizant of this considerable risk in the era of less-aggressive management of PTMC. [ABSTRACT FROM AUTHOR]

Approximately 5.0% of gastric cancer (GC) patients are diagnosed before the age of 40 and are not candidates for screening programs in most countries and regions. The incidence of gastric cancer in young adults (GCYA) has declined over time in most countries except in the United States. Genetic alterations, environmental factors, and lifestyle may predispose some young adults to GC. According to molecular classifications, the cancer of most GCYA patients belongs to the genomically stable or microsatellite stable/epithelial-mesenchymal transition subtype, with the common genetic aberrations being mutations in CDH1. What characterizes GCYA are a higher prevalence in females, more aggressive tumor behaviors, diagnosis at advanced stages, fewer comorbidities and being better treatment candidates, and a similar or better survival outcome when compared with older patients. Considering the greater loss of life-years in younger patients, lowering the incidence of GC and diagnosing at a relatively early stage are the two most effective ways to decrease GC mortality. To achieve these goals, the low awareness of GCYA among general people, policy-makers, clinicians, and researchers should be changed. [ABSTRACT FROM AUTHOR]

The Research to Accelerate Cures and Equity (RACE) for Children Act was enacted in 2017 to authorize the US Food and Drug Administration (FDA) to require pediatric studies for new cancer drugs that have a molecular target relevant to the growth or progression of a pediatric cancer. To assess the possible scope of this new policy, we examined all 78 adult cancer drugs approved by the FDA from 2007 to 2017. Only 17 (21.8%) drugs received any pediatric labeling information. Based on the FDA's Pediatric Molecular Target List, we found that the RACE Act could have increased the proportion of cancer drugs potentially subject to pediatric study requirements from 0% to 78.2%. However, the actual effect of the legislation will depend on how often regulators require pediatric trials and on timely completion of such trials. [ABSTRACT FROM AUTHOR]

Objective: To examine potential ethnic disparities in cancer incidence and survival rates among the oldest old using data from the SEER Program. Design: Cases diagnosed with one of the leading four cancer sites (lung and bronchus, colon and rectum, female breast, prostate) and four cancer sites (stomach, liver and intrahepatic bile duct, gallbladder, and cervical) that disproportionally affect Hispanics were reported to one of 18 SEER registries. Differences in cancer incidence were examined for cases aged ≥85 years diagnosed during the most recent 5-year time period (2009–2013) and, to examine changes over time, from 1992 to 2013. Five-year relative cancer survival probability was examined for Hispanics and non-Hispanics aged ≥85 years diagnosed 2006–2012. Results: From 2009 to 2013, non-Hispanics aged ≥85 years had higher incidence rates compared to Hispanics for colon and rectum, lung and bronchus, female breast, and prostate cancers. Five-year survival probability for cancers of all stages combined was higher for non-Hispanics than Hispanics in this age group. However, Hispanics had higher survival probability of colon and rectum and lung and bronchus cancers diagnosed at regional (colon and rectum: 67.2% vs. 60.5%; lung and bronchus: 15.9% vs. 12.7%) and distant (colon and rectum: 5.4% vs. 3.8%; lung and bronchus: 2.8% vs. 2.2%) stages than non-Hispanics, respectively. Conclusion: Ethnic differences in cancer incidence and survival probability exist for the ≥85 population. Continued efforts are needed to understand and reduce ethnic disparities in cancer prevention and treatment for this population. [ABSTRACT FROM AUTHOR]

Purpose: Histopathologic grade provides an integrated measure of biologic features which affects cancer prognosis. In invasive ductal breast cancer (IDBC), the grade of the ductal carcinoma in situ (DCIS) and invasive components are usually concordant, suggesting grade is established early in tumorigenesis and may be linked to etiologic factors. In this study, we used prospectively collected data from postmenopausal women in the Cancer Prevention Study-II (CPS-II) Nutrition Cohort to compare risk factor associations among low-grade and high-grade DCIS, as well as low-grade and high-grade IDBC.Methods: Among 73,825 cancer-free women at enrollment in the CPS-II Nutrition Cohort in 1992-1993 (mean age: 62.1 years), we verified 802 diagnosed with DCIS (C50 8500/2; n = 430 low-grade and 372 high-grade) and 3,125 with IDBC (C50 8500/3; n = 2,221 low-grade and 904 high-grade) through June 2013. Person-time contribution was conditional on screening mammograms self-reported on biennial surveys. Multivariable-adjusted joint Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI).Results: A personal history of benign breast disease was more strongly associated with higher risk of low-grade DCIS (HR = 2.20, 95% CI 1.81-2.67; p for heterogeneity = 0.0004) than high-grade DCIS. Consumption of two or more alcoholic drinks/day was only associated with a higher risk of low-grade IDBC (HR = 1.58, 95% CI 1.33-1.88; p for heterogeneity = 0.005).Conclusions: These results suggest heterogeneity by grade for breast cancer etiology. Identification of potential risk factor differences among low-grade and high-grade DCIS and IDBC may help to clarify associations, and ultimately, improve breast cancer risk prediction models. [ABSTRACT FROM AUTHOR]

publisher‐imprint‐name Springer volume‐issue‐count 1 issue‐article‐count 0 issue‐toc‐levels 0 issue‐pricelist‐year 2019 issue‐copyright‐holder The Author(s) issue‐copyright‐year 2019 article‐contains‐esm No article‐numbering‐style Unnumbered article‐registration‐date‐year 2019 article‐registration‐date‐month 1 article‐registration‐date‐day 9 article‐toc‐levels 0 toc‐levels 0 volume‐type Regular journal‐product ArchiveJournal numbering‐style Unnumbered article‐grants‐type OpenChoice metadata‐grant OpenAccess abstract‐grant OpenAccess bodypdf‐grant OpenAccess bodyhtml‐grant OpenAccess bibliography‐grant OpenAccess esm‐grant OpenAccess online‐first false pdf‐file‐reference BodyRef/PDF/40169_2019_Article_221.pdf target‐type OnlinePDF issue‐type Regular article‐type ReviewPaper journal‐subject‐primary Medicine & Public Health journal‐subject‐secondary Medicine/Public Health, general journal‐subject‐collection Medicine open‐access true --> Pancreatic cancer is one of the leading causes of cancer‐related death in the United States and survival outcomes remain dismal despite significant advances in molecular diagnostics and therapeutics in clinical practice. The microenvironment of pancreatic cancer carries unique features with increased desmoplastic reaction and is infiltrated by regulatory T cells and myeloid‐derived suppressor cells which negatively impact the effector immune cells. Current evidence suggests that stellate cell‐induced hypovascular stroma may have direct effects on aggressive behavior of pancreatic cancer. Preclinical studies suggested improvement in drug delivery to cancer cells with stroma modifying agents. However these findings so far have not been confirmed in clinical trials. In this article, we elaborate current‐state‐of‐the science of the pancreatic cancer microenvironment and its impact on molecular behavior of cancer cells, chemotherapy resistance and druggability of stroma elements in combination with other agents to enhance the efficacy of therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: Bladder cancer is the most common urinary system malignancy in the United States and is characterized by its diverse prognosis and high recurrence rate. However, the molecular mechanisms underlying its progression remain unknown. Accumulating evidence suggests a critical role for miRNAs in bladder cancer progression. Methods and results: In this study, we found that miR-492 expression levels were significantly higher in bladder cancer tissue and the serum of bladder cancer patients by bioinformatics analysis and a panel of clinical samples. The results of receiver operating characteristic curve analysis suggested the potential diagnostic value of serum miR-492 for bladder cancer. In vitro and in vivo functional assays showed that knockdown of miR-492 suppressed proliferation and metastasis of bladder cancer cells. Gap junction beta-4 protein was predicted to be a direct target of miR-492, which was validated using a luciferase reporter assay. Further cellular functional assays showed that suppression of miR-492 abrogated bladder cancer cell proliferation and metastasis by targeting gap junction beta-4 protein. Conclusion: miR-492 promotes cancer progression by targeting GJB4 and is a novel biomarker for bladder cancer. [ABSTRACT FROM AUTHOR]

Allostatic load can reflect the body's response to chronic stress. However, little is known about the association between allostatic load and risk of breast cancer in postmenopausal women. This study used a large prospective cohort in the United States to examine the relationship between allostatic load and invasive breast cancer risk, and to evaluate the relationship by racial and ethnic identity and breast cancer subtypes. Among 161,808 postmenopausal participants in Women's Health Initiative, eligible were a subsample of 27,393 postmenopausal women aged 50–79 years old, who enrolled from 1993 to 1998, had serum test biomarkers, and were followed for breast cancer incidence through February 2022. Allostatic load at enrollment was computed based on eight biomarkers from lab serum tests and a questionnaire about participants' prescription drug use. The associations between allostatic scores and risk of breast cancer (overall and by subtypes) were assessed using Cox proportional hazards models. The race and ethnic differences were examined. Over a median follow-up time of 17.24 years, 1722 invasive breast cancer cases were identified. High allostatic load was associated with an increased risk of breast cancer (HR = 1.36, 95%CI: 1.20, 1.54 for third tertile vs first tertile, P trend < 0.0001). Similar trends were found in White women and non-Hispanic women. Higher allostatic load was associated with hormone receptor-positive and HER2/Neu-negative breast cancer (HR = 1.54, 95%CI: 1.30, 1.80 for third tertile vs first tertile, P trend < 0.0001). In this study, we found that higher allostatic load was significantly associated with an increased risk of breast cancer in postmenopausal women. • This study translates chronic stress to quantifiable AL as a risk factor. • High AL was associated with an increased risk of invasive breast cancer. • High AL was associated with hormone receptor-positive, HER2-negative breast cancer. [ABSTRACT FROM AUTHOR]

Background: Bladder cancer is the fifth most common cancer in the United States and smoking is the largest known risk factor. Tobacco-derived carcinogens may induce the accumulation of somatic mutations in urothelial cells, and likely promote tumorigenesis. However, it is still unknown whether smoking-induced bladder carcinogenesis results in tumors with distinctive molecular features that can be therapeutically exploited.Methods: We investigated the genomic alterations of human bladder cancer and examined their association with patient smoking history. We performed bioinformatic analyses and looked at differences in gene expression, somatic mutations, and DNA mutational signatures comparing nonsmokers, reformed smokers, and current smokers.Results: We detected a limited set of gene expression and gene mutation differences between smokers and nonsmokers. We also identified a specific mutational signature that is enriched in tumors from smokers. This mutational signature was described before and has been linked to specific DNA repair defects in human bladder tumors, as well as to the direct effect of nitrosamine carcinogens in the BBN murine model of bladder cancer.Conclusion: We showed associations between smoking status and selected mutational signatures, which could provide insights in the biology of bladder carcinogenesis and tumor progression. [ABSTRACT FROM AUTHOR]

Objective: To identify factors associated with nonmuscle invasive bladder cancer (NMIBC) American Urological Association (AUA) guideline compliance in a rural state, to evaluate compliance rates over time, and to assess the impact of patient and provider rurality on delivery of NMIBC care.Methods: We identified 847 Iowans in Surveillance, Epidemiology, and End Results-Medicare from 1992 to 2009 with high-grade NMIBC who survived 2 years and were not treated with cystectomy or radiation during this period. Compliance with AUA guidelines was assessed over time and compared to patient demographic, tumor, and treatment institution variables. Impact of rurality was analyzed using Surveillance, Epidemiology, and End Results ZIP code data travel distance of patient to nearest urologist practice location.Results: Overall compliance with AUA guidelines was low (<1%), and did not markedly improve over the study period. In the multivariable model, only care at an academic medical center (OR 11.68, 95% CI 7.07-19.29) and tumor stage (Tis; OR 3.24, 95% CI 1.86-5.63) increased the odds of compliance. Patients living closer (<10 miles) to their urologists underwent more cystoscopies than patients living further (>30 miles) but distance did not affect compliance with other measures. Compliance was not associated with cancer-specific survival.Conclusion: Compliance with post-Transurethral Resection of Bladder Tumor (TURBT) NMIBC treatment guidelines has improved but remains suboptimal in our rural state, and is highly associated with treatment at an academic cancer center for reasons that could not be fully explained with these data. [ABSTRACT FROM AUTHOR]