Evaluation of a National Quality Improvement Collaborative for Improving Cancer Screening.

Importance: Cancer screening deficits during the first year of the COVID-19 pandemic were found to persist into 2021. Cancer-related deaths over the next decade are projected to increase if these deficits are not addressed. Objective: To assess whether participation in a nationwide quality improvement (QI) collaborative, Return-to-Screening, was associated with restoration of cancer screening. Design, Setting, and Participants: Accredited cancer programs electively enrolled in this QI study. Project-specific targets were established on the basis of differences in mean monthly screening test volumes (MTVs) between representative prepandemic (September 2019 and January 2020) and pandemic (September 2020 and January 2021) periods to restore prepandemic volumes and achieve a minimum of 10% increase in MTV. Local QI teams implemented evidence-based screening interventions from June to November 2021 (intervention period), iteratively adjusting interventions according to their MTVs and target. Interrupted time series analyses was used to identify the intervention effect. Data analysis was performed from January to April 2022. Exposures: Collaborative QI support included provision of a Return-to-Screening plan-do-study-act protocol, evidence-based screening interventions, QI education, programmatic coordination, and calculation of screening deficits and targets. Main Outcomes and Measures: The primary outcome was the proportion of QI projects reaching target MTV and counterfactual differences in the aggregate number of screening tests across time periods. Results: Of 859 cancer screening QI projects (452 for breast cancer, 134 for colorectal cancer, 244 for lung cancer, and 29 for cervical cancer) conducted by 786 accredited cancer programs, 676 projects (79%) reached their target MTV. There were no hospital characteristics associated with increased likelihood of reaching target MTV except for disease site (lung vs breast, odds ratio, 2.8; 95% CI, 1.7 to 4.7). During the preintervention period (April to May 2021), there was a decrease in the mean MTV (slope, -13.1 tests per month; 95% CI, -23.1 to -3.2 tests per month). Interventions were associated with a significant immediate (slope, 101.0 tests per month; 95% CI, 49.1 to 153.0 tests per month) and sustained (slope, 36.3 tests per month; 95% CI, 5.3 to 67.3 tests per month) increase in MTVs relative to the preintervention trends. Additional screening tests were performed during the intervention period compared with the prepandemic period (170 748 tests), the pandemic period (210 450 tests), and the preintervention period (722 427 tests). Conclusions and Relevance: In this QI study, participation in a national Return-to-Screening collaborative with a multifaceted QI intervention was associated with improvements in cancer screening. Future collaborative QI endeavors leveraging accreditation infrastructure may help address other gaps in cancer care.

Annual report to the nation on the status of cancer, part 1: National cancer statistics.

BACKGROUND: The American Cancer Society, the Centers for Disease Control and Prevention, the National Cancer Institute, and the North American Association of Central Cancer Registries collaborate to provide annual updates on cancer occurrence and trends in the United States. METHODS: Data on new cancer diagnoses during 2001-2018 were obtained from the North American Association of Central Cancer Registries' Cancer in North America Incidence file, which is comprised of data from Centers for Disease Control and Prevention-funded and National Cancer Institute-funded, population-based cancer registry programs. Data on cancer deaths during 2001-2019 were obtained from the National Center for Health Statistics' National Vital Statistics System. Five-year average incidence and death rates along with trends for all cancers combined and for the leading cancer types are reported by sex, racial/ethnic group, and age. RESULTS: Overall cancer incidence rates were 497 per 100,000 among males (ranging from 306 among Asian/Pacific Islander males to 544 among Black males) and 431 per 100,000 among females (ranging from 309 among Asian/Pacific Islander females to 473 among American Indian/Alaska Native females) during 2014-2018. The trend during the corresponding period was stable among males and increased 0.2% on average per year among females, with differing trends by sex, racial/ethnic group, and cancer type. Among males, incidence rates increased for three cancers (including pancreas and kidney), were stable for seven cancers (including prostate), and decreased for eight (including lung and larynx) of the 18 most common cancers considered in this analysis. Among females, incidence rates increased for seven cancers (including melanoma, liver, and breast), were stable for four cancers (including uterus), and decreased for seven (including thyroid and ovary) of the 18 most common cancers. Overall cancer death rates decreased by 2.3% per year among males and by 1.9% per year among females during 2015-2019, with the sex-specific declining trend reflected in every major racial/ethnic group. During 2015-2019, death rates decreased for 11 of the 19 most common cancers among males and for 14 of the 20 most common cancers among females, with the steepest declines (>4% per year) reported for lung cancer and melanoma. Five-year survival for adenocarcinoma and neuroendocrine pancreatic cancer improved between 2001 and 2018; however, overall incidence (2001-2018) and mortality (2001-2019) continued to increase for this site. Among children (younger than 15 years), recent trends were stable for incidence and decreased for mortality; and among, adolescents and young adults (aged 15-39 years), recent trends increased for incidence and declined for mortality. CONCLUSIONS: Cancer death rates continued to decline overall, for children, and for adolescents and young adults, and treatment advances have led to accelerated declines in death rates for several sites, such as lung and melanoma. The increases in incidence rates for several common cancers in part reflect changes in risk factors, screening test use, and diagnostic practice. Racial/ethnic differences exist in cancer incidence and mortality, highlighting the need to understand and address inequities. Population-based incidence and mortality data inform prevention, early detection, and treatment efforts to help reduce the cancer burden in the United States.

Key risk factors for the relative and absolute 5-year risk of cancer to enhance cancer screening and prevention.

BACKGROUND: This study identifies populations who may benefit most from expanded cancer screening. METHODS: Two American Cancer Society prospective cohort studies, Cancer Prevention Study-II Nutrition Cohort and Cancer Prevention Study-3, were used to identify the risk factors associated with a > 2% absolute risk of any cancer within 5 years. In total, 429,991 participants with no prior personal history of cancer were followed for cancer for up to 5 years. Multivariable Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for association. By using these hazard ratios, individualized coherent absolute risk estimation was used to calculate absolute risks by age. RESULTS: Overall, 15,226 invasive cancers were diagnosed among participants within 5 years of enrollment. The multivariable-adjusted relative risk of any cancer was strongest for current smokers compared with never-smokers. In men, alcohol intake, family history of cancer, red meat consumption, and physical inactivity were also associated with risk (p < .05). In women, body mass index, type 2 diabetes, hysterectomy, parity, family history of cancer, hypertension, tubal ligation, and physical inactivity were associated (p < .05). The absolute 5-year risk exceeded 2% among nearly all participants older than 50 years and among some participants younger than 50 years, including current or former smokers (<30 years since quitting) and long-term nonsmokers with a body mass index >25 kg/m2 or a first-degree family history of cancer. The absolute 5-year risk was as high as 29% in men and 25% in women. CONCLUSIONS: Older age and smoking were the two most important risk factors associated with the relative and absolute 5-year risk of developing any cancer.

Progress in Reducing Disparities in Premature Mortality in the USA: a Descriptive Study.

BACKGROUND: Eliminating health disparities among different segments of the US population is an overarching goal of the US Healthy People 2020 objectives. OBJECTIVE: Examine changes in educational, rural-urban, and racial disparities in premature mortality during the past 10 years. DESIGN AND PARTICIPANTS: Descriptive analysis of US mortality data from 2007 to 2017. MAIN MEASURES: Relative and absolute rural-urban, educational attainment, and Black-White disparities in premature mortality for all-cause and top 10 causes of death among persons ages 25-74 years, estimated as rate ratios and rate differences between ≤12 and ≥16 years of education, rural versus urban, and non-Hispanic Black (Black) versus non-Hispanic White (White), respectively, in 2007 and 2017. KEY RESULTS: During 2007-2017, mortality rates in persons aged 25-74 years in the USA increased for several leading causes of death, especially in persons with <16 years of education, rural residents, and White people. As a result, disparity in mortality between 2007 and 2017 widened on both relative and absolute scales for all-cause and for 6 of the top 10 causes of death by education and for all-cause and for 9 of the top 10 causes by rural/urban residence. In contrast, Black-White disparities narrowed for all-cause and for all 7 causes that Black people had a higher rate than White people. For all-cause mortality for example, absolute disparities in the number of deaths per 100,000 person-years between 2007 and 2017 increased from 454.0 (95%CI, 446.0-462.1) to 542.7 (535.6-549.7) for educational attainment and from 85.8 (82.8-88.8) to 140.5 (137.6-143.4) for rural versus urban; in contrast, absolute Black-White disparity decreased from 315.3 (311.0-319.7) to 221.7 (218.1-225.3). CONCLUSIONS: Educational and rural-urban disparities in premature mortality widened, whereas Black-White disparities narrowed in the USA between 2007 and 2017, though overall rates remained considerably higher in Black people.

A national quality improvement study identifying and addressing cancer screening deficits due to the COVID-19 pandemic.

BACKGROUND: Cancer-related deaths over the next decade are expected to increase due to cancer screening deficits associated with the coronavirus disease 2019 (COVID-19) pandemic. Although national deficits have been quantified, a structured response to identifying and addressing local deficits has not been widely available. The objectives of this report are to share preliminary data on monthly screening deficits in breast, colorectal, lung, and cervical cancers across diverse settings and to provide online materials from a national quality improvement (QI) study to help other institutions to address local screening deficits. METHODS: This prospective, national QI study on Return-to-Screening enrolled 748 accredited cancer programs in the United States from April through June 2021. Local prepandemic and pandemic monthly screening test volumes (MTVs) were used to calculate the relative percent change in MTV to describe the monthly screening gap. RESULTS: The majority of facilities reported monthly screening deficits (colorectal cancer, 80.6% [n = 104/129]; cervical cancer, 69.0% [n = 20/29]; breast cancer, 55.3% [n = 241/436]; lung cancer, 44.6% [n = 98/220]). Overall, the median relative percent change in MTV ranged from -17.7% for colorectal cancer (interquartile range [IQR], -33.6% to -2.8%), -6.8% for cervical cancer (IQR, -29.4% to 1.7%), -1.6% for breast cancer (IQR, -9.6% to 7.0%), and 1.2% for lung cancer (IQR, -16.9% to 19.0%). Geographic differences were not observed. There were statistically significant differences in the percent change in MTV between institution types for colorectal cancer screening (P = .02). CONCLUSION: Cancer screening is still in need of urgent attention, and the screening resources made available online may help facilities to close critical gaps and address screenings missed in 2020. LAY SUMMARY: Question: How can the effects of the coronavirus disease 2019 pandemic on cancer screening be mitigated? FINDINGS: When national resources were provided, including methods to calculate local screening deficits, 748 cancer programs promptly enrolled in a national Return-to-Screening study, and the majority identified local screening deficits, most notably in colorectal cancer. Using these results, 814 quality improvement projects were initiated with the potential to add 70,000 screening tests in 2021. Meaning: Cancer screening is still in need of urgent attention, and the online resources that we provide may help to close critical screening deficits.

Identification of a Subset of Stage I Colorectal Cancer Patients With High Recurrence Risk.

BACKGROUND: A challenge in early-stage colorectal cancer (CRC) is identifying biomarkers that predict an increased risk for recurrence. A potential clinically adaptable biomarker is focal adhesion kinase (FAK), a tyrosine kinase that promotes invasion and metastasis. METHODS: An initial, single-institution, 298-patient cohort with all stages of CRC and long-term follow-up was assessed for FAK with tissue microarrays using immunohistochemistry. FAK expression was scored and dichotomized into high and low. Subsequently, a validation cohort of 517 early-stage CRCs from a separate institution was evaluated. All statistical tests were 2-sided. RESULTS: FAK overexpression did not correlate with any known histologic feature and was an early event in CRC, increasing from normal colon to stage I, and stage I to II, but not different at higher stages. High FAK was associated with decreased 10-year recurrence-free survival (RFS) among stage I patients (70.2% for high FAK vs 94.1% for low, P = .02), but not among higher stages in the initial cohort. The same finding was seen in the validation cohort (73.1% for high FAK vs 93.1% for low, P = .004). Multivariable survival analysis for stage I patients showed only two statistically significant factors predicting RFS: FAK (hazard ratio = 5.27, 95% confidence interval = 1.81 to 15.33, P = .002) and perineural invasion (hazard ratio = 7.38, 95% confidence interval = 1.01 to 53.96, P = .049). FAK was the only statistically significant factor in multivariable analysis across RFS, overall, and disease-specific survivals. CONCLUSIONS: High FAK expression identified a subset of stage I CRC patients with high incidence of recurrence and reduced survival, suggesting that FAK has important prognostic value. These patients would immediately benefit from more rigorous surveillance protocols for recurrent disease.

American Cancer Society's report on the status of cancer disparities in the United States, 2021.

In this report, the authors provide comprehensive and up-to-date US data on disparities in cancer occurrence, major risk factors, and access to and utilization of preventive measures and screening by sociodemographic characteristics. They also review programs and resources that have reduced cancer disparities and provide policy recommendations to further mitigate these inequalities. The overall cancer death rate is 19% higher among Black males than among White males. Black females also have a 12% higher overall cancer death rate than their White counterparts despite having an 8% lower incidence rate. There are also substantial variations in death rates for specific cancer types and in stage at diagnosis, survival, exposure to risk factors, and receipt of preventive measures and screening by race/ethnicity, socioeconomic status, and geographic location. For example, kidney cancer death rates by sex among American Indian/Alaska Native people are ≥64% higher than the corresponding rates in each of the other racial/ethnic groups, and the 5-year relative survival for all cancers combined is 14% lower among residents of poorer counties than among residents of more affluent counties. Broad and equitable implementation of evidence-based interventions, such as increasing health insurance coverage through Medicaid expansion or other initiatives, could substantially reduce cancer disparities. However, progress will require not only equitable local, state, and federal policies but also broad interdisciplinary engagement to elevate and address fundamental social inequities and longstanding systemic racism.

The association between breast cancer capacity and resources with incidence and mortality in Arizona's low populous counties.

INTRODUCTION: While cancer deaths have decreased nationally, declines have been much slower in rural areas than in urban areas. Previous studies on rural cancer service capacity are limited to specific points along the cancer care continuum (eg screening, diagnosis or treatment) and require updating to capture the current rural health landscape since implementation of the 2010 Affordable Care Act in the USA. The association between current rural cancer service capacity across the cancer care continuum and cancer incidence and death is unclear. This cross-sectional study explored the association between breast cancer service capacity and incidence and mortality in Arizona's low populous counties. METHODS: To measure county-level cancer capacity, clinical organizations operating within low populous areas of Arizona were surveyed to assess on-site breast cancer services provided (screening, diagnosis and treatment) and number of healthcare providers were pulled from Centers for Medicare and Medicaid Services National Provider Identifier database. The number of clinical sites and healthcare providers were converted to county-level per capita rates. Rural-Urban Continuum codes were used to designate rural or urban county status. Age-adjusted county-level breast cancer incidence and death rates from 2010 to 2016 were obtained from the Arizona Department of Health Services, Arizona Cancer Registry. Descriptive statistics were used to summarize the results. Multivariate regression was used to evaluate the association between cancer service capacity and incidence and mortality in 13 out of Arizona's 15 counties. RESULTS: Rural counties had more per capita clinical sites (20.4) than urban counties (8.9) (p=0.02). Urban counties had more per capita pathologists (1.0) than rural counties (0) (p≤0.01). In addition to zero pathologists, rural counties had zero medical oncologists. Rural county status was associated with a decrease in breast cancer incidence (β=-20.1, 95% confidence interval: -37.2-3.1). CONCLUSION: While Arizona's sparsely populated rural counties may have more physical infrastructure per capita, these services are dispersed over vast geographic areas. They lack specialists providing cancer services. Non-physician clinical providers may be more prevalent in rural areas and represent opportunities for improving access to cancer preventive services and care. Compared to urban counties, rural county status was associated with lower detected breast cancer incidence rates although there were no statistically significant differences in breast cancer mortality. Other factors may contribute to rural-urban differences in breast cancer incidence. Future research should explore these factors and the association between cancer capacity and local resources because the use of county-level data represents a challenge in Arizona, where counties average over 19 425 km2 (7500 square miles).

Associations of Aspirin and Non-Aspirin Non-Steroidal Anti-Inflammatory Drugs With Colorectal Cancer Mortality After Diagnosis.

BACKGROUND: Aspirin use reduces colorectal cancer (CRC) incidence, but there is limited evidence regarding associations of aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) with CRC-specific survival. METHODS: This prospective analysis includes women and men from the Cancer Prevention Study-II Nutrition Cohort who were cancer free at baseline (1992 or 1993) and diagnosed with CRC during incidence follow-up through 2015. Detailed information on aspirin and non-aspirin NSAID use was self-reported on questionnaires at baseline, in 1997, and every 2 years thereafter. Pre- and postdiagnosis data were available for 2686 and 1931 participants without distant metastases, respectively, among whom 512 and 251 died from CRC during mortality follow-up through 2016. Secondary analyses examined associations between prediagnosis aspirin use and stage at diagnosis (distant metastatic vs localized or regional). All statistical tests were 2-sided. RESULTS: Long-term regular use of aspirin (>15 times per month) before diagnosis was associated with lower CRC-specific mortality (multivariable-adjusted hazard ratio [HR] = 0.69, 95% confidence interval [CI] = 0.52 to 0.92). Postdiagnosis regular aspirin use was not statistically significantly associated with risk of CRC-specific mortality overall (HR = 0.82, 95% CI = 0.62 to 1.09), although participants who began regular aspirin use only after their diagnosis were at lower risk than participants who did not use aspirin at both the pre- and postdiagnosis periods (HR = 0.60, 95% CI = 0.36 to 0.98). Long-term aspirin use before diagnosis was also associated with lower odds of diagnosis with distant metastases (multivariable-adjusted odds ratio = 0.73, 95% CI = 0.53 to 0.99). CONCLUSIONS: Our results suggest that long-term aspirin use before a diagnosis of nonmetastatic colorectal cancer may be associated with lower CRC-specific mortality after diagnosis, consistent with possible inhibition of micrometastases before diagnosis.

Blueprint for cancer research: Critical gaps and opportunities.

We are experiencing a revolution in cancer. Advances in screening, targeted and immune therapies, big data, computational methodologies, and significant new knowledge of cancer biology are transforming the ways in which we prevent, detect, diagnose, treat, and survive cancer. These advances are enabling durable progress in the goal to achieve personalized cancer care. Despite these gains, more work is needed to develop better tools and strategies to limit cancer as a major health concern. One persistent gap is the inconsistent coordination among researchers and caregivers to implement evidence-based programs that rely on a fuller understanding of the molecular, cellular, and systems biology mechanisms underpinning different types of cancer. Here, the authors integrate conversations with over 90 leading cancer experts to highlight current challenges, encourage a robust and diverse national research portfolio, and capture timely opportunities to advance evidence-based approaches for all patients with cancer and for all communities.

Impact of COVID-19 Pandemic on Cancer Research.

The COVID-19 pandemic is profoundly changing cancer researchers and cancer research. Leaders from different fields and at different career stages share their perspectives.

Surgeon-Authored Virtual Laparoscopic Adrenalectomy Module Is Judged Effective and Preferred Over Traditional Teaching Tools.

OBJECTIVE: The study assesses user acceptance and effectiveness of a surgeon-authored virtual reality (VR) training module authored by surgeons using the Toolkit for Illustration of Procedures in Surgery (TIPS). METHODS: Laparoscopic adrenalectomy was selected to test the TIPS framework on an unusual and complex procedure. No commercial simulation module exists to teach this procedure. A specialist surgeon authored the module, including force-feedback interactive simulation, and designed a quiz to test knowledge of the key procedural steps. Five practicing surgeons, with 15 to 24 years of experience, peer reviewed and tested the module. In all, 14 residents and 9 fellows trained with the module and answered the quiz, preuse and postuse. Participants received an overview during Surgical Grand Rounds session and a 20-minute one-on-one tutorial followed by 30 minutes of instruction in addition to a force-feedback interactive simulation session. Additionally, in answering questionnaires, the trainees reflected on their learning experience and their experience with the TIPS framework. RESULTS: Correct quiz response rates on procedural steps improved significantly postuse over preuse. In the questionnaire, 96% of the respondents stated that the TIPS module prepares them well or very well for the adrenalectomy, and 87% indicated that the module successfully teaches the steps of the procedure. All participants indicated that they preferred the module compared to training using purely physical props, one-on-one teaching, medical atlases, and video recordings. CONCLUSIONS: Improved quiz scores and endorsement by the participants of the TIPS adrenalectomy module establish the viability of surgeons authoring VR training.

Oncogenic Receptor Tyrosine Kinases Directly Phosphorylate Focal Adhesion Kinase (FAK) as a Resistance Mechanism to FAK-Kinase Inhibitors.

Focal adhesion kinase (FAK) is a major drug target in cancer and current inhibitors targeted to the ATP-binding pocket of the kinase domain have entered clinical trials. However, preliminary results have shown limited single-agent efficacy in patients. Despite these unfavorable data, the molecular mechanisms that drive intrinsic and acquired resistance to FAK-kinase inhibitors are largely unknown. We have demonstrated that receptor tyrosine kinases (RTK) can directly bypass FAK-kinase inhibition in cancer cells through phosphorylation of FAK's critical tyrosine 397 (Y397). We also showed that HER2 forms a direct protein-protein interaction with the FAK-FERM-F1 lobe, promoting direct phosphorylation of Y397. In addition, FAK-kinase inhibition induced two forms of compensatory RTK reprogramming: (i) the rapid phosphorylation and activation of RTK signaling pathways in RTKHigh cells and (ii) the long-term acquisition of RTKs novel to the parental cell line in RTKLow cells. Finally, HER2 +: cancer cells displayed resistance to FAK-kinase inhibition in 3D growth assays using a HER2 isogenic system and HER2+ cancer cell lines. Our data indicate a novel drug resistance mechanism to FAK-kinase inhibitors whereby HER2 and other RTKs can rescue and maintain FAK activation (pY397) even in the presence of FAK-kinase inhibition. These data may have important ramifications for existing clinical trials of FAK inhibitors and suggest that individual tumor stratification by RTK expression would be important to predict patient response to FAK-kinase inhibitors. Mol Cancer Ther; 15(12); 3028-39. ©2016 AACR.

Synthesis and bioactivity of a Goralatide analog with antileukemic activity.

Natural tetrapeptide Goralatide (AcSDKP) is a selective inhibitor of primitive haematopoietic cell proliferation. It is not stable in vivo and decomposes within 4.5min when applied to live cells. In this work we developed an analog of Goralatide that exhibits cytotoxicity towards human myeloid HL-60, HEL, Nalm-6 leukemia cells, endothelial HUVEC, glioblastoma U251 and transformed kidney 293T cells. The Goralatide analog showed significant stability in organic solution with no tendency to degrade oxidatively.

Down-regulation of ALDH1A3, CD44 or MDR1 sensitizes resistant cancer cells to FAK autophosphorylation inhibitor Y15.

PURPOSE: Focal adhesion kinase is an important survival signal in cancer. Recently, we demonstrated that the autophosphorylation inhibitor of FAK, Y15, effectively inhibited cancer cell growth. We detected many cancer cell lines sensitive to Y15 and also detected several cell lines such as colon cancer Lovo-1 and thyroid K1 more resistant to Y15. We sought to determine the main players responsible for the resistance. METHODS: To reveal the signaling pathways responsible for the increased resistance of these cancer cells to the inhibitor of FAK, we performed a microarray gene profile study in both sensitive and resistant cells treated with Y15 inhibitor to compare with the more sensitive cells. RESULTS: Among unique genes up-regulated by Y15 in Lovo-1 and K1 resistant cells, a stem cell marker-ALDH1A3-was detected to be up-regulated >twofold. The resistant Lovo-1 and thyroid K1 cells overexpressed ALDH1A3 and CD44 versus sensitive cells. Treatment with ALDH1A3 siRNAs or ALDH inhibitor, DEAB sensitized resistant Lovo-1 and K1 cells to Y15 inhibitor, decreased viability and caused G1 cell cycle arrest more effectively than each agent alone. In addition, down-regulation of CD44 that was overexpressed in resistant Lovo-1 cells with CD44 siRNA effectively decreased the viability of cells in combination with Y15. In addition, down-regulation of overexpressed MDR1 with specific inhibitor, PSC-833, also sensitized resistant colon cancer cells to Y15. CONCLUSIONS: This report clearly demonstrates the mechanism of resistance to FAK autophosphorylation inhibitor and the mechanism to overcome it that is important for developing FAK-targeted therapy approaches.

The use of modified four-dimensional computed tomography in patients with primary hyperparathyroidism: an argument for the abandonment of routine sestamibi single-positron emission computed tomography (SPECT).

BACKGROUND: Four-dimensional computed tomography (4D CT) has emerged as an extremely sensitive preoperative imaging modality for primary hyperparathyroidism compared with the historical use of sestamibi and ultrasound (US). Specialized volume rendering and technical modifications further enhance this technique for operative guidance while reducing radiation exposure. METHODS: Patients undergoing parathyroidectomy for primary hyperparathyroidism from December 2010 to September 2013, carried out by two surgeons at a tertiary cancer center, were evaluated. Comparison was made between the three imaging modalities (4D CT, sestamibi, and US) for preoperative localization rate and accuracy. Biochemical parameters and radiation exposure were also analyzed. RESULTS: A total of 202 patients were identified from the database and 200 patients were included in the analysis. All patients underwent 4D CT (100 %), 185 sestamibi (92.5 %) and 186 US (93 %). In patients with single-gland disease (n = 153), 4D CT, sestamibi, and US were positive in 96 %, 65.4 % and 57.7 % of patients, respectively and, when positive, were accurately localized in 97.2 %, 93.4 % and 96.3 % of patients, respectively. In patients with multigland disease (MGD) [n = 47], 4D CT, sestamibi, and US predicted MGD in 32 %, 0 %, and 13.6 % of patients, respectively. With our technique modification, radiation exposure from 4D CT approached that of sestamibi. CONCLUSIONS: Low-dose, modified 4D CT with volume rendering when compared with sestamibi has a statistically significant higher positivity rate, improved accuracy rate, provides excellent images, superior surgical planning, and has a comparable radiation exposure risk profile. Consideration should be made for the abandonment of routine sestamibi single-positron emission computed tomography (SPECT), with 4D CT as the preoperative imaging modality of choice.

Inhibition of FAK and VEGFR-3 binding decreases tumorigenicity in neuroblastoma.

Neuroblastoma is the most common extracranial solid tumor of childhood and is responsible for over 15% of pediatric cancer deaths. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumor development and progression. Vascular endothelial growth factor receptor-3 (VEGFR-3), another tyrosine kinase, has also been found to be important in the development of many human tumors including neuroblastoma. Recent reports have found that FAK and VEGFR-3 interact, and we have previously shown that both of these kinases interact in neuroblastoma. We have hypothesized that interruption of the FAK-VEGFR-3 interaction would lead to decreased neuroblastoma cell survival. In the current study, we examined the effects of a small molecule, chloropyramine hydrochloride (C4), designed to disrupt the FAK-VEGFR-3 interaction, upon cellular attachment, migration, and survival in two human neuroblastoma cell lines. We also utilized a murine xenograft model to study the impact of C4 upon tumor growth. In these studies, we showed that disruption of the FAK-VEGFR-3 interaction led to decreased cellular attachment, migration, and survival in vitro. In addition, treatment of murine xenografts with chloropyramine hydrochloride decreased neuroblastoma xenograft growth. Further, this molecule acted synergistically with standard chemotherapy to further decrease neuroblastoma xenograft growth. The findings from this current study help to further our understanding of the regulation of neuroblastoma tumorigenesis, and may provide novel therapeutic strategies and targets for neuroblastoma and other solid tumors of childhood.

In vivo toxicity, metabolism and pharmacokinetic properties of FAK inhibitor 14 or Y15 (1, 2, 4, 5-benzenetetramine tetrahydrochloride).

Y15 or inhibitor 14 (1,2,4,5-benzenetetramine tetrahydrochloride) is a potent and specific inhibitor of focal adhesion kinase that inhibits its autophosphorylation activity, decreases the viability of cancer cells, and blocks tumor growth. In this preclinical study, we analyzed the pharmacokinetics of Y15 in mice plasma, its metabolic stability in mouse and human liver microsomes and toxicity in mice. The pharmacokinetics study in mice demonstrated that, following intraperitoneal administration at 30 mg/kg dose, Y15 was very rapidly absorbed in mice, reaching maximum plasma concentration in 4.8 min. Y15 rapidly metabolized in mouse and human liver microsomes with half-life t1/2 of 6.9 and 11.6 min, respectively. The maximal tolerated dose of single-dose administration of Y15 by oral administration was 200 mg/kg, and the multiple maximum tolerated dose of Y15 was 100 mg/kg by PO during 7 day study. Y15 did not cause any mortality or statistically significant differences in the body weight at 30 mg/kg by IP during 28-day study, and at 100 mg/kg by PO during the 7-day study. There were no clinical chemical, hematological, or histopathological changes in different mice organs at 30 mg/kg by IP during 28 days and at 100 mg/kg dose by PO during 7 days. Thus, this is the first preclinical toxicity, pharmacokinetics, and metabolic stability study of Y15 inhibitor. Further development of Y15 will provide a basis for new therapeutic and future clinical studies.

A FAK scaffold inhibitor disrupts FAK and VEGFR-3 signaling and blocks melanoma growth by targeting both tumor and endothelial cells.

Melanoma has the highest mortality rate of all skin cancers and a major cause of treatment failure is drug resistance. Tumors heterogeneity requires novel therapeutic strategies and new drugs targeting multiple pathways. One of the new approaches is targeting the scaffolding function of tumor related proteins such as focal adhesion kinase (FAK). FAK is overexpressed in most solid tumors and is involved in multiple protein-protein interactions critical for tumor cell survival, tumor neovascularization, progression and metastasis. In this study, we investigated the anticancer activity of the FAK scaffold inhibitor C4, targeted to the FAK-VEGFR-3 complex, against melanomas. We compared C4 inhibitory effects in BRAF mutant vs BRAF wild type melanomas. C4 effectively caused melanoma tumor regression in vivo, when administered alone and sensitized tumors to chemotherapy. The most dramatic effect of C4 was related to reduction of vasculature of both BRAF wild type and V600E mutant xenograft tumors. The in vivo effects of C4 were assessed in xenograft models using non-invasive multimodality imaging in conjunction with histologic and molecular biology methods. C4 inhibited cell viability, adhesion and motility of melanoma and endothelial cells, specifically blocked phosphorylation of VEGFR-3 and FAK and disrupted their complexes. Specificity of in vivo effects for C4 were confirmed by a decrease in tumor FAK and VEGFR-3 phosphorylation, reduction of vasculogenesis and reduced blood flow. Our collective observations provide evidence that a small molecule inhibitor targeted to the FAK protein-protein interaction site successfully inhibits melanoma growth through dual targeting of tumor and endothelial cells and is effective against both BRAF wild type and mutant melanomas.