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Background: Practice patterns and potential quality differences among surgical oncology fellowship graduates relative to years of independent practice have not been defined., Methods: Medicare claims were used to identify patients who underwent esophagectomy, pancreatectomy, hepatectomy, or rectal resection for cancer between 2016 and 2021. Surgical oncology fellowship graduates were identified, and the association between years of independent practice, serious complications, and 90-day mortality was examined., Results: Overall, 11,746 cancer operations (pancreatectomy [61.2%], hepatectomy [19.5%], rectal resection [13.7%], esophagectomy [5.6%]) were performed by 676 surgical oncology fellowship graduates (females: 17.7%). The operations were performed for 4147 patients (35.3%) by early-career surgeons (1-7 years), for 4104 patients (34.9%) by mid-career surgeons (8-14 years), and for 3495 patients (29.8%) by late-career surgeons (>15 years). The patients who had surgery by early-career surgeons were treated more frequently at a Midwestern (24.9% vs. 14.2%) than at a Northeastern institution (20.6% vs. 26.9%) compared with individuals treated by late-career surgeons (p < 0.05). Surgical oncologists had comparable risk-adjusted serious complications and 90-day mortality rates irrespective of career stage (early career [13.0% and 7.2%], mid-career [12.6% and 6.3%], late career [12.8% and 6.5%], respectively; all p > 0.05). Surgeon case-specific volume independently predicted serious complications across all career stages (high vs. low volume: early career [odds ratio {OR}, 0.80; 95% confidence interval {CI}, 0.65-0.98]; mid-career [OR, 0.81; 95% CI, 0.66-0.99]; late career [OR, 0.78; 95% CI, 0.62-0.97])., Conclusion: Among surgical oncology fellowship graduates performing complex cancer surgery, rates of serious complications and 90-day mortality were comparable between the early-career and mid/late-career stages. Individual surgeon case-specific volume was strongly associated with postoperative outcomes irrespective of years of independent practice or career stage., (© 2024. The Author(s).)

Background: The association of hospital market competition, financial costs, and quality of oncologic care has not been well-defined. This study sought to evaluate variations in patient outcomes and financial expenditures after complex cancer surgery across high- and low-competition markets., Methods: Medicare 100% Standard Analytic Files were used to identify patients with lung, esophageal, gastric, hepatopancreaticobiliary, or colorectal cancer who underwent surgical resection between 2018 and 2021. Data were merged with the annual hospital survey database, and the hospital market Herfindahl-Hirschman index was used to categorize hospitals into low- and high-concentration markets. Multi-level, multivariable regression models adjusting for patient characteristics (i.e., age, sex, comorbidities, and social vulnerability), year of procedure, and hospital factors (i.e., case volume, nurse-bed ratio, and teaching status) were used to assess the association between hospital market competition and outcomes., Results: Among 117,641 beneficiaries who underwent complex oncologic surgery, the mean age was 73.8 ± 6.1 years, and approximately one-half of the cohort was male (n = 56,243, 47.8%). Overall, 63.8% (n = 75,041) of the patients underwent care within a high-competition market. Notably, there was marked geographic variation relative to market competition. High versus low market-competition hospitals were more likely to be in high social vulnerability areas (35.1 vs 27.5%; p < 0.001), as well as care for racial/ethnic minority individuals (13.8 vs 7.7%; p < 0.001), and patients with more comorbidities (≥ 2 Elixhauser comorbidities: 63.1 vs 61.1%; p < 0.001). In the multivariable analysis, treatment at hospitals in high- versus low-competition markets was associated with lower odds of achieving a textbook outcome (odds ratio, 0.95; 95% confidence interval, 0.91-0.99; p = 0.009). Patients at high-competition hospitals had greater mean index hospitalization costs ($19,462.2 [16211.9] vs $18,844.7 [14994.7]) and 90-day post-discharge costs ($7807.8 [15431.3] vs $7332.8 [14038.2]) (both p < 0.001) than individuals at low-competition hospitals., Conclusions: Hospital market competition was associated with poor achievement of an optimal postoperative outcome and greater hospitalization costs., (© 2024. The Author(s).)

Aim: Patients with cancer experience various forms of psychological distress, including depressive symptoms, which can impact quality of life, elevate morbidity risk, and increase medical costs. Psychotherapy and pharmacotherapy are effective for reducing depressive symptoms among patients with cancer, but most patients prefer psychotherapy. This study aimed to develop an efficient and effective smartphone psychotherapy component to address depressive symptom., Methods: This was a decentralized, parallel-group, multicenter, open, individually randomized, fully factorial trial. Patients aged ≥20 years with cancer were randomized by the presence/absence of three cognitive-behavioral therapy (CBT) skills (behavioral activation [BA], assertiveness training [AT], and problem-solving [PS]) on a smartphone app. All participants received psychoeducation (PE). The primary outcome was change in the patient health questionnaire-9 (PHQ-9) total score between baseline and week 8. Secondary outcomes included anxiety., Results: In total, 359 participants were randomized. Primary outcome data at week 8 were obtained for 355 participants (99%). The week 8 PHQ-9 total score was significantly reduced from baseline for all participants by -1.41 points (95% confidence interval [CI] -1.89, -0.92), but between-group differences in change scores were not significant (BA: -0.04, 95% CI -0.75, 0.67; AT: -0.16, 95% CI -0.87, 0.55; PS: -0.19, 95% CI -0.90, 0.52)., Conclusion: As the presence of any of the three intervention components did not contribute to a significant additive reduction of depressive symptoms, we cannot make evidence-based recommendations regarding the use of specific smartphone psychotherapy., (© 2024 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Introduction: Cannabis usage is increasing in the United States, especially among patients with cancer. We sought to evaluate whether cannabis use disorder (CUD) was associated with higher morbidity and mortality among patients undergoing complex cancer surgery., Methods: Patients who underwent complex cancer surgery between January 2016 and December 2019 were identified in the National Inpatient Sample database. CUD was defined according to ICD-10 codes. Propensity score matching was performed to create a 1:1 matched cohort that was well balanced with respect to covariates, which included patient comorbidities, sociodemographic factors, and procedure type. The primary composite outcome was in-hospital mortality and seven major perioperative complications (myocardial ischemia, acute kidney injury, stroke, respiratory failure, venous thromboembolism, hospital-acquired infection, and surgical procedure-related complications)., Results: Among 15 014 patients who underwent a high-risk surgical procedure, a cohort of 7507 patients with CUD (median age; 43 years [IQR: 30-56 years]; n = 3078 [41.0%] female) were matched with 7507 patients who were not cannabis users (median age; 44 years [IQR: 30-58 years); n = 2997 [39.9%] female). CUD was associated with slight increased risk relative to postoperative kidney injury (CUD, 7.8% vs. no CUD, 6.1%); however, in-hospital mortality was slightly lower (CUD, 0.9% vs. no CUD, 1.6%) (both p < 0.001). On multivariable analysis, after controlling for other risk factors, CUD was not associated with higher morbidity and mortality (adjusted odds ratio: 1.06, 95% CI: 0.98-1.15; p = 0.158)., Conclusion: CUD was not associated with a higher risk of postoperative morbidity and mortality following complex cancer surgery., (© 2024 Wiley Periodicals LLC.)

Background: The COVID-19 pandemic disrupted health care delivery, including cancer screening practices. This study sought to determine the impact of the COVID-19 pandemic lockdown on colorectal cancer (CRC) screening relative to social vulnerability., Methods: Using the Medicare Standard Analytic File, individuals 65 years old or older who were eligible for guideline-concordant CRC screening between 2019 and 2021 were identified. These data were merged with the Center for Disease Control Social Vulnerability Index (SVI) dataset. Changes in county-level monthly screening volumes relative to the start of the COVID-19 pandemic (March 2020) and easing of restrictions (March 2021) were assessed relative to SVI., Results: Among 10,503,180 individuals continuously enrolled in Medicare with no prior diagnosis of CRC, 1,362,457 (12.97%) underwent CRC screening between 2019 and 2021. With the COVID-19 pandemic, CRC screening decreased markedly across the United States (median monthly screening: pre-pandemic [n = 76,444] vs pandemic era [n = 60,826]; median Δn = 15,618; p < 0.001). The 1-year post-pandemic overall CRC screening utilization generally rebounded to pre-COVID-19 levels (monthly median screening volumes: pandemic era [n = 60,826] vs post-pandemic [n = 74,170]; median Δn = 13,344; p < 0.001). Individuals residing in counties with the highest SVI experienced a larger decline in CRC screening odds than individuals residing in low-SVI counties (reference, low SVI: pre-pandemic high SVI [OR, 0.85] vs pandemic high SVI [OR, 0.81] vs post-pandemic high SVI [OR, 0.85]; all p < 0.001)., Conclusions: The COVID-19 pandemic was associated with a decrease in CRC screening volumes. Patients who resided in high social vulnerability areas experienced the greatest pandemic-related decline., (© 2024. The Author(s).)

Introduction: We sought to define the individual contributions of patient characteristics (PCs), hospital characteristics (HCs), case volume (CV), and social determinants of health (SDoH) on in-hospital mortality (IHM) after complex cancer surgery., Methods: The California Department of Health Care Access and Information database identified patients who underwent esophagectomy (ES), pneumonectomy (PN), pancreatectomy (PD), or proctectomy (PR) for a malignant diagnosis between 2010 and 2020. Multi-level multivariable regression was performed to assess the proportion of variance explained by PCs, HCs, CV and SDoH on IHM., Results: A total of 52,838 patients underwent cancer surgery (ES: n = 2,700, 5.1%; PN: n = 30,822, 58.3%; PD: n = 7530, 14.3%; PR: n = 11,786, 22.3%) across 294 hospitals. The IHM for the overall cohort was 1.7% and varied from 4.4% for ES to 0.8% for PR. On multivariable regression, PCs contributed the most to the variance in IHM (overall: 32.0%; ES: 21.6%; PN: 28.0%; PD: 20.3%; PR: 39.9%). Among the overall cohort, CV contributed 2.4%, HCs contributed 1.3%, and SDoH contributed 1.2% to the variation in IHM. CV was the second highest contributor to IHM among ES (5.3%), PN (5.3%), and PD (5.9%); however, HCs were a more important contributor among patients who underwent PR (8.0%). The unexplained variance in IHM was highest among ES (72.4%), followed by the PD (67.5%) and PN (64.6%) patient groups., Conclusions: PCs are the greatest underlying contributor to variations in IHM following cancer surgery. These data highlight the need to focus on optimizing patients and exploring unexplained sources of IHM to improve quality of surgical care., (© 2024. The Author(s).)

Background: Behavioral health disorders (BHDs) can often be exacerbated in the setting of cancer. We sought to define the prevalence of BHD among cancer patients and characterize the association of BHD with surgical outcomes., Study Design: Patients diagnosed with lung, esophageal, gastric, liver, pancreatic, and colorectal cancer between 2018 and 2021 were identified within Medicare Standard Analytic Files. Data on BHD defined as substance abuse, eating disorder, or sleep disorder were obtained. Postoperative textbook outcomes (ie no complications, prolonged length of stay, 90-day readmission, or 90-day mortality), as well as in-hospital expenditures and overall survival were assessed., Results: Among 694,836 cancer patients, 46,719 (6.7%) patients had at least 1 BHD. Patients with BHD were less likely to undergo resection (no BHD: 23.4% vs BHD: 20.3%; p < 0.001). Among surgical patients, individuals with BHD had higher odds of a complication (odds ratio [OR] 1.32 [1.26 to 1.39]), prolonged length of stay (OR 1.36 [1.29 to 1.43]), and 90-day readmission (OR 1.57 [1.50 to 1.65]) independent of social vulnerability or hospital-volume status resulting in lower odds to achieve a TO (OR 0.66 [0.63 to 0.69]). Surgical patients with BHD also had higher in-hospital expenditures (no BHD: $16,159 vs BHD: $17,432; p < 0.001). Of note, patients with BHD had worse long-term postoperative survival (median, no BHD: 46.6 [45.9 to 46.7] vs BHD: 37.1 [35.6 to 38.7] months) even after controlling for other clinical factors (hazard ratio 1.26 [1.22 to 1.31], p < 0.001)., Conclusions: BHD was associated with lower likelihood to achieve a postoperative textbook outcome, higher expenditures, as well as worse prognosis. Initiatives to target BHD are needed to improve outcomes of cancer patients undergoing surgery., (Copyright © 2024 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: Sex concordance may impact the therapeutic relationship and provider-patient interactions. We sought to define the association of surgeon-patient sex concordance on postoperative patient outcomes following complex cancer surgery., Methods: Patients who underwent surgery for lung, breast, hepato-pancreato-biliary, or colorectal cancer between 2014 and 2020 were identified from the Medicare Standard Analytic Files. The impact of surgeon-patient sex concordance or discordance on achieving an optimal postoperative textbook outcome (TO) was assessed using multivariable logistic regression., Results: Among 495 628 patients, 241 938 (48.8%) patients were sex concordant with their surgeon while 253 690 (51.2%) patients were sex discordant. Sex discordance between surgeon and patient was associated with a decreased likelihood to achieve a postoperative TO (odds ratio [OR]: 0.95, 95% CI: 0.93-0.97; p < 0.001). Sex discordance was associated with a higher risk of complications (OR: 1.05, 95% CI: 1.03-1.07; p < 0.001) and 90-day mortality (OR: 1.05, 95% CI: 1.01-1.09; p = 0.011). Of note, male patients treated by female surgeons (OR: 0.96, 95% CI: 0.93-0.99; p = 0.017) had a similar lower likelihood to achieve a TO as female patients treated by male surgeons (OR: 0.90, 95% CI: 0.86-0.93; p < 0.001)., Conclusions: Sex discordance was associated with a reduced likelihood of achieving an "optimal" postoperative course following complex cancer surgery., (© 2023 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Background: Previous studies have shown conflicting evidence regarding the incidence of cancer in patients with systemic lupus erythematosus (SLE) compared with that in healthy individuals. Calcineurin inhibitors (CNIs) such as cyclosporine and tacrolimus have been widely used to treat SLE; however, their effects on cancer risk remain unclear. We aimed to investigate the incidence of cancer in patients with SLE and determine the potential association between CNI use and cancer risk., Methods: The standardized incidence ratio (SIR) of cancer among patients with lupus in the Lupus Registry of Nationwide Institutions (LUNA) was calculated based on the age-standardized incidence rate of cancer reported by Japan's Ministry of Health, Labour and Welfare. We also examined the association between CNI exposure and cancer risk, while considering potential confounding factors. The analysis accounted for confounding variables such as age, sex, smoking history, maximum glucocorticoid dose, treatment history with cyclophosphamide, ongoing hydroxychloroquine, Systemic Lupus International Collaboration Clinics/American College of Rheumatology Damage Index (SDI) value (excluding cancer occurrence), comorbidity of diabetes mellitus, and smoking history., Results: The study included 704 patients with SLE (625 females; 88.8%) with a median age of 44 years [interquartile range (IQR) = 34-55] years. The median past maximum glucocorticoid dose was 40 mg/day [IQR = 30-60 mg/day], and the SDI at registration was 1 [IQR = 0-2]. Among the patients, 246 (35.1%) had smoking histories, and 38 (5.4%) experienced cancer complications. Gynecological malignancies accounted for 63.2% of all cancers. The SIR of cancer in the LUNA cohort was 1.08 (95% confidence interval [CI] = 0.74-1.43). No statistically significant risks of cancer were found in relation to CNI treatment history; the odds ratio using multiple logistic regression was 1.12 (95% CI = 0.42-3.00), the risk ratio using standardization was 1.18 (95% CI = 0.47-2.16), and the risk ratio using inverse probability weighting was 1.8 (95% CI = 0.41-4.66)., Conclusions: The incidence of cancer in patients with SLE in the LUNA cohort did not significantly differ from that in the general population. These findings suggest that CNI treatment in this cohort did not pose a risk factor for cancer development., (© 2024. The Author(s).)

Objective: We sought to define the impact of community privilege on variations in travel patterns and access to care at high-volume hospitals for complex surgical procedures., Background: With increased emphasis on centralization of high-risk surgery, social determinants of health play a critical role in preventing equitable access to care. Privilege is a right, benefit, advantage, or opportunity that positively impacts all social determinants of health., Methods: The California Office of State-wide Health Planning Database identified patients who underwent esophagectomy (ES), pneumonectomy (PN), pancreatectomy (PA), or proctectomy (PR) for a malignant diagnosis between 2012 and 2016 and was merged using ZIP codes with the Index of Concentration of Extremes, a validated metric of both spatial polarization and privilege obtained from the American Community Survey. Clustered multivariable regression was performed to assess the probability of undergoing care at a high-volume center, bypassing the nearest and high-volume center, and total real driving time and travel distance., Results: Among 25,070 patients who underwent a complex oncologic operation (ES: n=1216, 4.9%; PN: n=13,247, 52.8%; PD: n=3559, 14.2%; PR: n=7048, 28.1%), 5019 (20.0%) individuals resided in areas with the highest privilege (i.e., White, high-income homogeneity), whereas 4994 (19.9%) individuals resided in areas of the lowest privilege (i.e., Black, low-income homogeneity). Median travel distance was 33.1 miles (interquartile range 14.4-72.2). Roughly, three-quarters of patients (overall: 74.8%, ES: 35.0%; PN: 74.3%; PD: 75.2%; PR: 82.2%) sought surgical care at a high-volume center. On multivariable regression, patients residing in the least advantaged communities were less likely to undergo surgery at a high-volume hospital (overall: odds ratio 0.65, 95% CI 0.52-0.81). Of note, individuals in the least privileged areas had longer travel distances (28.5 miles, 95% CI 21.2-35.8) to reach the destination facility, as well as over 70% greater odds of bypassing a high-volume hospital to undergo surgical care at a low-volume center (odds ratio 1.74, 95% CI 1.29-2.34) versus individuals living in the highest privileged areas., Conclusions and Relevance: Privilege had a marked effect on access to complex oncologic surgical care at high-volume centers. These data highlight the need to focus on privilege as a key social determinant of health that influences patient access to and utilization of health care resources., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Malnutrition has been linked to the development of hepatopancreatobiliary (HPB) cancer. We sought to examine the association between food swamps and food deserts on surgical outcomes of patients with HPB cancer., Methods: Patients who underwent surgery for HPB cancer between 2014 and 2020 were identified from the Medicare Standard Analytic Files. Patient-level data were linked to the United States Department of Agriculture data on food swamps and deserts. Multivariable regression was performed to examine the association between the food environment and outcomes., Results: Among 53,426 patients, patients from the worse food environment were more likely to be Black, have a higher Charlson Comorbidity Index, and reside in areas with high social vulnerability. Following surgery, the overall incidence of textbook outcome (TO) was 41.6% (n = 22,220). Patients residing in the worse food environments less often achieved a TO versus individuals residing in the healthiest food environments (food swamp: 39.4% vs. 43.9%; food desert: 38.5% vs 42.2%; p < 0.05). On multivariable analysis, individuals residing in the poorest food environments were associated with lower odds of achieving TO compared with individuals living in healthiest food environments (food swamp: OR 0.83, 95%CI 0.75-0.92, food desert: OR 0.86, 95%CI 0.76-0.97; both p < 0.05)., Conclusion: The surrounding food environment of patients may serve as a modifiable socio-demographic risk factor that contributes to disparities in surgical outcomes of HPB cancer., (© 2023. The Society for Surgery of the Alimentary Tract.)

Introduction: Regionalization of complex surgical procedures may improve healthcare quality. We sought to define the impact of regionalization on access to high-volume hospitals for complex oncologic procedures in the state of California., Methods: The California Department of Health Care Access and Information Database (2012-2016) identified patients who underwent esophagectomy (ES), pneumonectomy (PN), pancreatectomy (PA), or proctectomy (PR). Geospatial analysis was conducted to determine travel patterns. Clustered multivariable regression was performed to assess the probability of receiving care at a high-volume center., Results: Among 25,070 patients (ES: n = 1216, 4.9%; PN: n = 13,247, 52.8%; PD: n = 3559, 14.2%; PR: n = 7048, 28.1%), 6575 (26.2%) individuals resided within 30 min, 11,046 (44.1%) resided within 30-60 min, 7125 (28.4%) resided within 60-90 min, and 324 (1.3%) resided beyond a 90-min travel window from a high-volume center. Median travel distance was 13.4 miles (interquartile range [IQR] 6.0-28.7). On multivariable regression, patients residing further away were more likely to bypass a low-volume center to undergo care at a high-volume hospital (odds ratio 1.32, 95% confidence interval 1.12-1.55) versus individuals residing closer to high-volume centers. Approximately one-third (29.7%) of patients lived beyond a 1-h travel window to the nearest high-volume hospital, of whom 5% traveled over 90 min. While hospital mortality rates across different travel time windows did not differ, surgery at a high-volume center was associated with an overall 1.2% decrease in in-hospital mortality., Conclusions: Regionalization of complex cancer surgery may be associated with a significant travel burden for a large subset of patients with complex cancer., (© 2023. Society of Surgical Oncology.)

Background and Objectives: Minimally invasive surgery (MIS) has been successfully adopted in hepatopancreatobiliary (HPB) cancer, and has been associated with improved perioperative and comparable oncological outcomes. We sought to define the impact of county-level duration of poverty on access to MIS and clinical outcomes among patients with HPB cancer undergoing surgical treatment., Materials and Methods: Data on patients diagnosed with HPB cancer were obtained from the Surveillance, Epidemiology, and End Results (SEER)-Medicare data (2010-2016). County-level poverty data were obtained from the American Community Survey and the U.S. Department of Agriculture, and categorized into three groups: never high poverty (NHP), intermittent high poverty (IHP), and persistent poverty (PP). Multivariable regression was used to assess the relationship between PP and MIS., Results: Among 8098 patients, 82% (n = 664) resided in regions with NHP, 13.6% (n = 1104) resided in regions with IHP, and 4.4% (n = 350) resided in regions with PP. Median age at the diagnosis was 71 years (interquartile range [IQR]: 67-77). Patients from IHP and PP counties had lower odds of undergoing MIS (IHP/PP vs. NHP, odds ratio [OR]: 0.59, 95% confidence interval [CI]: 0.36-0.96, p = 0.034) and being discharged home (IHP/PP vs. NHP, OR: 0.64, 95% CI: 0.43-0.99, p = 0.043), as well as a higher risk of 1-year mortality (IHP/PP vs. NHP, HR: 1.51, 95% CI: 1.036-2.209, p = 0.032) compared with patients residing in NHP counties., Conclusions: Duration of county-level poverty was associated with lower receipt of MIS and unfavorable clinical and survival outcomes among patients with HPB cancer. There is a need to improve access to modern surgical treatment options among vulnerable, PP populations., (© 2023 Wiley Periodicals LLC.)

Tumor-specific CD8+ T cells play a pivotal role in antitumor immunity and are a key target of immunotherapeutic approaches. Intratumoral CD8+ T cells are heterogeneous; Tcf1+ stemlike CD8+ T cells give rise to their cytotoxic progeny-Tim-3+ terminally differentiated CD8+ T cells. However, where and how this differentiation process occurs has not been elucidated. We herein show that terminally differentiated CD8+ T cells can be generated within tumor-draining lymph nodes (TDLN) and that CD69 expression on tumor-specific CD8+ T cells controls its differentiation process through regulating the expression of the transcription factor TOX. In TDLNs, CD69 deficiency diminished TOX expression in tumor-specific CD8+ T cells, and consequently promoted generation of functional terminally differentiated CD8+ T cells. Anti-CD69 administration promoted the generation of terminally differentiated CD8+ T cells, and the combined use of anti-CD69 and anti-programmed cell death protein 1 (PD-1) showed an efficient antitumor effect. Thus, CD69 is an attractive target for cancer immunotherapy that synergizes with immune checkpoint blockade., (©2023 American Association for Cancer Research.)

Background: Structural racism within the U.S. health care system contributes to disparities in oncologic care. This study sought to examine the socioeconomic factors that underlie the impact of racial segregation on hepatopancreaticobiliary (HPB) cancer inequities., Methods: Both Black and White patients who presented with HPB cancer were identified from the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database (2005-2015) and 2010 Census data. The Index of Dissimilarity (IoD), a validated measure of segregation, was examined relative to cancer stage at diagnosis, surgical resection, and overall mortality. Principal component analysis and structural equation modeling were used to determine the mediating effect of socioeconomic factors., Results: Among 39,063 patients, 86.4 % (n = 33,749) were White and 13.6 % (n = 5314) were Black. Black patients were more likely to reside in segregated areas than White patients (IoD, 0.62 vs. 0.52; p < 0.05). Black patients in highly segregated areas were less likely to present with early-stage disease (relative risk [RR], 0.89; 95 % confidence interval [CI] 0.82-0.95) or undergo surgery for localized disease (RR, 0.81; 95% CI 0.70-0.91), and had greater mortality hazards (hazard ratio 1.12, 95% CI 1.06-1.17) than White patients in low segregation areas (all p < 0.05). Mediation analysis identified poverty, lack of insurance, education level, crowded living conditions, commute time, and supportive income as contributing to 25 % of the disparities in early-stage presentation. Average income, house price, and income mobility explained 17 % of the disparities in surgical resection. Notably, average income, house price, and income mobility mediated 59 % of the effect that racial segregation had on long-term survival., Conclusion: Racial segregation, mediated through underlying socioeconomic factors, accounted for marked disparities in access to surgical care and outcomes for patients with HPB cancer., (© 2023. Society of Surgical Oncology.)

Background: Socioeconomic status can often dictate access to timely surgical care and postoperative outcomes. We sought to analyze the impact of county-level poverty duration on hepatopancreaticobiliary cancer outcomes., Methods: Patients diagnosed with hepatopancreaticobiliary cancer were identified from the Surveillance, Epidemiology, and End Results-Medicare 2010 to 2015 database linked with county-level poverty from the American Community Survey and the US Department of Agriculture between 1980 to 2010. Counties were categorized as never high-poverty, intermittent high-poverty, and persistent poverty. Hierarchical generalized linear models and accelerated failure time models with Weibull distribution were used to assess diagnosis, treatment, textbook outcomes, and survival., Results: Among 41,077 patients, 1,758 (4.3%) lived in persistent poverty. Counties exposed to greater durations of poverty had increased proportions of non-Hispanic Black patients (never high-poverty: 7.6%, intermittent high-poverty: 20.4%, persistent poverty: 23.2%), uninsured patients (never high-poverty: 0.5%, intermittent high-poverty: 0.5%, persistent poverty: 0.9%), and patients with a rural residence (never high-poverty: 0.6%, intermittent high-poverty: 2.4%, persistent poverty: 11.5%). Individuals residing in persistent poverty had lower odds of undergoing resection (odds ratio 0.82, 95% confidence interval 0.66-0.98), achieving textbook outcomes (odds ratio 0.54, 95% confidence interval 0.34-0.84), and increased cancer-specific mortality (hazard ratio 1.07, 95% CI 1.00-1.15) (all P < .05). Non-Hispanic Black patients were less likely to present with early-stage disease (odds ratio 0.86, 95% confidence interval 0.79-0.95) and undergo surgical treatment (odds ratio 0.58, 95% confidence interval 0.52-0.66) compared to non-Hispanic White patients (both P < .01). Notably, non-Hispanic White patients in persistent poverty were more likely to present with early-stage disease (odds ratio 1.30, 95% confidence interval 1.12-1.52) and undergo surgery for localized disease (odds ratio 1.36, 95% confidence interval 1.06-1.74) compared to non-Hispanic Black patients in never high-poverty (both P < .05)., Conclusion: Duration of poverty was associated with lower odds of receipt of surgical treatment, achievement of textbook outcomes, and worse cancer-specific survival. Non-Hispanic Black patients were at particular risk of suboptimal outcomes, highlighting the impact of structural racism independent of socioeconomic status., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Laparoscopic liver resection (LLR) is possible in many patients, but pure LLR is sometimes difficult to complete, and unplanned intraoperative hand-assisted laparoscopic surgery (HALS) or open conversion is sometimes necessary. However, appropriate indications and timing for conversion are unclear. This study aimed to clarify the indications for HALS and open conversion from pure LLR., Methods: We collected data from 208 patients who underwent LLR from January 2010 to February 2021 in our department. We retrospectively examined these data between cases of unplanned intraoperative HALS conversion, open conversion, and pure LLR, and clarified risk factors and indications for HALS or open conversion., Results: There were 191 pure LLRs, nine HALS conversions, and eight open conversions. In the HALS conversion group versus pure LLR group, body mass index (BMI) (27.0 vs. 23.7 kg/m 2 , p = 0.047), proportions of patients with history of upper abdominal surgery (78% vs. 33%; p = 0.006), repeat hepatectomy (56% vs. 15%; p = 0.002), S7 or S8 tumor location (67% vs. 35%; p = 0.049), and difficulty score (DS) ≥ 7 (56% vs. 19%; p = 0.008) were significantly higher, and surgical time (339 vs. 239 min; p = 0.031) was significantly longer. However, postoperative states were not significantly different between the two groups. The BMI cutoff value for risk of unplanned intraoperative conversion determined by receiver operating characteristic curve analysis was 25 kg/m 2 , and the proportion of patients with BMI ≥ 25 kg/m 2 (89% vs. 31%, p < 0.001) was significantly higher in the HALS conversion versus pure LLR group. In the open conversion group, although there were no significant differences compared to the HALS group in clinicopathological factors except for sex, blood loss was greater (1425 vs. 367 mL; p < 0.001)., Conclusion: Risk factors for considering HALS during LLR were patients with a history of upper abdominal surgery including repeat hepatectomy, BMI ≥ 25 kg/m 2 , S7 or S8 tumor location, DS ≥ 7, and prolonged surgical time. Furthermore, uncontrollable intraoperative bleeding was an indication for open conversion., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Overexpression of satellite RNAs in heterochromatin induces chromosomal instability (CIN) through the DNA damage response and cell cycle checkpoint activation. Although satellite RNAs may be therapeutic targets, the associated mechanisms underlying drug sensitivity are unknown. Here, we determined whether satellite RNAs reflect drug sensitivity to the topoisomerase I inhibitor camptothecin (CPT) via CIN induction. We constructed retroviral vectors expressing major satellite and control viruses, infected microsatellite stable mouse colon cancer cells (CT26) and MC38 cells harboring microsatellite instability, and assessed drug sensitivity after 48 h. Cells overexpressing satellite RNAs showed clear features of abnormal segregation, including micronuclei and anaphase bridging, and elevated levels of the DNA damage marker γH2AX relative to controls. Additionally, overexpression of satellite RNAs enhanced MC38 cell susceptibility to CPT [half-maximal inhibitory concentration: 0.814 μM (control) vs. 0.332 μM (MC38 cells with a major satellite), p = 0.003] but not that of CT26. These findings imply that MC38 cells, which are unlikely to harbor CIN, are more susceptible to CIN-induced CPT sensitivity than CT26 cells, which are characterized by CIN. Furthermore, CPT administration upregulated p53 levels but not those of p21, indicating that overexpression of major satellite transcripts likely induces CPT-responsive cell death rather than cellular senescence., (© 2022. The Author(s).)

Purpose: This study aimed to determine interstitial lung disease (ILD) incidences in patients receiving cancer drug therapies with or without bevacizumab treatment., Methods: Systematic searches of PubMed, Embase, and Cochrane Library were conducted in January 2021. The main inclusion criteria were randomized clinical trials that compared bevacizumab with standard treatment in patients with solid tumors. Cochrane Collaboration's Tool was used for assessing risk-of-bias., Results: Thirteen records involving 7201 patients were included in the meta-analysis. There were 42 ILD events in bevacizumab groups and 72 in control groups. In bevacizumab groups, the odds ratio for ILD was 0.62 (95% CI 0.42-0.92; p = 0.02), which was a significantly lower incidence than the control. This tendency was shown in targeted therapy groups but not in the cytotoxic agent groups., Conclusion: Our data suggest that bevacizumab may reduce the incidence of ILD., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Cancer cachexia and the associated skeletal muscle wasting are considered poor prognostic factors, although effective treatment has not yet been established. Recent studies have indicated that the pathogenesis of skeletal muscle loss may involve dysbiosis of the gut microbiota and the accompanying chronic inflammation or altered metabolism. In this study, we evaluated the possible effects of modifying the gut microenvironment with partially hydrolyzed guar gum (PHGG), a soluble dietary fiber, on cancer-related muscle wasting and its mechanism using a colon-26 murine cachexia model. Compared with a fiber-free (FF) diet, PHGG contained fiber-rich (FR) diet-attenuated skeletal muscle loss in cachectic mice by suppressing the elevation of the major muscle-specific ubiquitin ligases Atrogin-1 and MuRF1, as well as the autophagy markers LC3 and Bnip3. Although tight-junction markers were partially reduced in both FR and FF diet-fed cachectic mice, the abundance of Bifidobacterium, Akkermansia, and unclassified S24-7 family increased by FR diet, contributing to the retention of the colonic mucus layer. The reinforcement of the gut barrier function resulted in the controlled entry of pathogens into the host system and reduced circulating levels of lipopolysaccharide-binding protein (LBP) and IL-6, which in turn led to the suppression of proteolysis by downregulating the ubiquitin-proteasome system and autophagy pathway. These results suggest that dietary fiber may have the potential to alleviate skeletal muscle loss in cancer cachexia, providing new insights for developing effective strategies in the future., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

HER1-and HER2-targeted drugs are effective in cancer therapy, especially against lung, breast and colon malignancies; however, resistance of cancer cells to HER1-and HER2-targeted therapies is becoming a serious problem. The avidity/affinity constant (K A ) and growth inhibitory effect of anti-HER3 rat monoclonal antibodies (mAb, Ab1∼Ab6) in the presence of therapeutic mAb or low-molecular-weight inhibitors against HER family proteins were analyzed by flow cytometry-based Scatchard plots (Splot) and cell proliferation assay. The K A of Ab3 and Ab6, but not Ab1 or Ab4, split into dual (high and low) modes of K A , and Ab6 exhibited greater anti-proliferative effects against LS-174T colon cancer cells in the presence of Pertuzumab (anti-HER2 mAb). A high K A by Ab6 and Ab6-mediated increased growth inhibition were observed against NCI-H1838 lung or BT474 breast cancer cells, respectively, in the presence of Panitumumab (anti-HER1 mAb) or Perutuzumab. A high K A by Ab6 and Ab6-mediated increased anti-proliferative effects against NCI-H1838 or BT474 were also respectively observed in the presence of Erlotinib (HER1 inhibitor) or Lapatinib (HER1/HER2 inhibitor). In HER1-knockout (KO) NCI-H1838, the reactivity and K A of Ab4 increased compared with in parent NCI-H1838. In HER1-KO or HER3-KO SW1116 colon cancer cells, dual modes of K A with Pertuzumab were noted, and the combination Ab6 and Pertuzumab promoted growth inhibition of HER1-KO, but not of parent SW1116., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Takashi Masuko reports financial support was provided by Healios KK., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Conventionally, a disassembly and reassembly method has been used for encapsulation of drug molecules in ferritin protein nano-cages. However, clinical applications of ferritin have been greatly restricted by its limited drug-loading capacity and process complexity. Here, we establish a simple high yield process for preparing high drug-loaded ferritin nanomedicine for industrial production. A complex of ferritin and a target drug was obtained by incubating the mixture at an appropriate pH. An electrostatic charge potential and small ferritin cavity facilitates the passage of drug molecules through the pores, traversing the ferritin shell and enabling deposition of the drug in the ferritin cavity. Compared to the disassembly/reassembly method, the loading capacity of a doxorubicin-loaded ferritin heavy chain (DOX-FTH), constructed by our novel method, was over 3-fold higher, while doxorubicin recovery was 10-fold higher. Results of transmission electron microscopy, size exclusion chromatography, dynamic light scattering, and zeta potential indicate that DOX-FTH exhibits the same physicochemical characteristics of natural apo-ferritin. Moreover, DOX-FTH can be taken up and induce apoptosis of cancer cells overexpressing TfR1. Here, we have demonstrated the successful introduction of more than ten drug molecule types into ferritin nano-cages using a novel method. These results demonstrate that this one-step method is a powerful production process to construct a drug-loading ferritin drug delivery system carrier.

DNA aneuploidy, the altered DNA content of a cell, is a common feature of canine tumors. However, it is unclear whether aneuploid DNA in canine tumor cells show centrosome amplification (CA), which contributes to numerical and structural chromosome aberrations that result in DNA aneuploidy. Here, we evaluated whether DNA aneuploidy and CA occur concurrently in canine tumor cell lines. Centrosome numbers were evaluated in 18 canine tumor cell lines by immunocytochemistry with anti-γ-tubulin antibody, and DNA content was evaluated by flow cytometry using propidium iodide. A total of 15 cell lines showed DNA aneuploidy, and CA was observed in 5 of these 15 cell lines. Together, our results suggest that DNA aneuploidy in canine tumor cells might be explained at least in part by CA. In addition, cell lines with CA may be useful tools to examine the detailed relationship between CA and DNA aneuploidy and the molecular mechanism of CA in canine tumor., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

In vivo experimental models are still essential for advancing our understanding of cancer and developing novel therapeutic strategies, despite rapid and remarkable developments in cellular and molecular technologies. Multiple patient-derived tumor xenograft (PDX) models, in which primary cancer tissues or cells are transplanted into immunodeficient mice, have been developed. PDX models are widely used in the field of precision cancer medicine. The purpose of this chapter is to introduce the chick embryo xenograft model, which has a longer history than the athymic nude mouse model., (© 2019 Elsevier Inc. All rights reserved.)

An artificial receptor for proMMP-9 was created by fusing tissue inhibitor of MMP-1 (TIMP-1) with type II transmembrane mosaic serine protease (MSP-T1). Expression of MSP-T1 in 293T cells induced binding of proMMP-9, which was processed by MMP-2 activated by membrane type 1 MMP (MT1-MMP). HT1080 cells transfected with the MSP-T1 gene produced activated MMP-9 in collagen gel, and addition of proMMP-2 to the culture augmented it, which resulted in intensive collagen digestion. These cells metastasized into chick embryonic liver more than control cells. Treatment of HT1080 cells with concanavalin A in the presence of exogenous proMMP-2 induced activation of not only proMMP-2 but also proMMP-9. Knockdown of MT1-MMP or TIMP-2 expression with siRNA suppressed activation of both proMMP-2 and proMMP-9. Transfection of TIMP-1 siRNA suppressed cell binding and activation of proMMP-9, but not proMMP-2 activation. Knockdown of a disintegrin and metalloproteinase 10 (ADAM10) expression reduced cell binding and processing of proMMP-9. These results suggest that proMMP-9, which binds to a receptor complex containing TIMP-1 and ADAM10, is activated by the MT1-MMP/MMP-2 axis, and MMP-9 thus activated stimulates cellular proteolysis and metastasis., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: We previously demonstrated that hsa-miR-520d-5p can convert cancer cells into induced pluripotent stem cells (iPSCs) or mesenchymal stem cells (MSCs) via a demethylation process and p53 upregulation in vivo. Additionally, we have reported the non-tumorigenic effect of miR-520d-5p on normal human cells, including fibroblasts., Methods: We used atelocollagen-conjugated miR-520d-5p (520d/atelocollagen) to confirm the possibility of a therapeutic effect on cancer cells. We traced the size and signal intensity of GFP-expressing tumors in mice each week, beginning 4 weeks after subcutaneous inoculation., Results: 520d/atelocollagen treatment suppressed tumor growth by greater than 80 % each week relative to controls and resulted in an approximately 30 % disappearance of tumors. In mice whose tumors disappeared, the existence of human genomic material at the injection site was examined by quantitative Alu-PCR, and we confirmed the co-existence of both species-derived cells. In every site where a tumor disappeared in immunodeficient mice, GFP protein was expressed in the connective tissues, and approximately 0.1 % of the extracted DNA contained human genomic material. We could not identify any adverse effects in vivo., Conclusions: This is the first report to confirm an inhibitory effect of 520d/atelocollagen on cancer cells in vivo. The development of optimized modifications of this carrier is expected to enhance the efficiency of entry into tumor cells and the induction of its inhibitory effect.

Aims: Many studies of human subjects have demonstrated the utility of assessing serum levels of endothelin-1 (ET-1) and big ET-1 as clinical biomarkers in cardiopulmonary and neoplastic diseases. In this study we explored the feasibility of using serum big ET-1 as a reliable veterinary marker in dogs with various cardiopulmonary and neoplastic diseases., Main Methods: Serum big ET-1 levels were measured by ELISA in dogs with cardiopulmonary (n=21) and neoplastic diseases (n=57). Dogs exhibiting cardiopulmonary disease were divided into two groups based on the velocity of tricuspid valve regurgitation (3.0>m/s) measured by ultrasound: without and with pulmonary hypertension. Big ET-1 levels for the dogs with the diseases were compared with levels in normal healthy dogs (n=17)., Key Findings: Dogs with cardiopulmonary disease (4.6±4.6 pmol/l) showed a significantly (P<0.01) higher level of big ET-1 than healthy control dogs (1.1±0.53 pmol/l). Serum levels in the dogs with pulmonary hypertension (6.2±5.3 pmol/l) were significantly (P<0.01) higher than those without pulmonary hypertension (2.0±0.6 pmol/l). Dogs with hemangiosarcoma (5.6±2.2 pmol/l), adenocarcinoma (2.0±1.8 pmol/l), histiocytic sarcoma (3.3±1.9 pmol/l), chondrosarcoma or osteosarcoma (3.0±1.6 pmol/l) and hepatocellular carcinoma (2.7±1.8 pmol/l) showed significantly (P<0.05) higher levels than healthy control dogs., Significance: These findings point to the potential of serum big ET-1 as a clinical marker for cardiopulmonary and neoplastic diseases in dogs., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Nimustine (ACNU) is an alkylating agent of the nitrosourea and can be an antineoplastic agent in dogs. But, there has been no report on its dose-limiting toxicity (DLT) in dogs. This study was a phase I dose-escalation clinical trial to determine the maximum tolerated dose (MTD) and DLT of ACNU in tumor-bearing dogs. The starting dosage was 25 mg/m(2), and subsequent dosages were administered in increments of 5 mg/m(2) in cohort of 3 dogs. Eight dogs were included, the MTD was determined to be 25 mg/m(2), DLT was neutropenia, and the optimal interval was considered to be 21 days. The data herein provide a basis for the subsequent phase II trial of ACNU in dogs.

Background: Cadmium, a ubiquitous environmental pollutant, is classified as a carcinogenic substance. Several laboratory and epidemiologic studies of workers and subjects in polluted areas have suggested a positive association between cadmium exposure and risk of several cancers. However, data from general populations are sparse. We prospectively examined the association between cadmium exposure and incidence of cancer in a Japanese population with a relatively high dietary intake of cadmium., Methods: We conducted a population-based prospective study in 90,383 Japanese men and women 45-74 years of age. Participants responded to a validated questionnaire that included 138 food items. We estimated dietary cadmium intake from 6 food groups, based on the questionnaire data. During 9 years of follow-up, 5849 cancer cases were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer were calculated by Cox proportional hazards modeling., Results: There was no evidence of an association of cadmium consumption and total cancer, with HRs in the highest versus lowest cadmium intake group of 0.94 (95% CI = 0.82 to 1.08; test for trend, P = 0.46) for men and 0.96 (0.81 to 1.15; 0.60) for women. No site-specific cancers were associated with cadmium intake in men or women., Conclusion: We found no associations of cancer with cadmium, at least at the exposure levels observed in a general population in Japan.

Changes in an individual's immune status are considered major contributing factors towards the morbidity of cancer and mortality of aging. To evaluate age-related changes in the immune status of dogs, the immunophenotypes (CD3, CD4, CD8 and CD21) of peripheral blood lymphocytes were measured in 160 healthy dogs aged from 1 to 17 years, and in 365 dogs with various tumors and at various stages. In healthy dogs, the absolute numbers of white blood cells, lymphocytes, and CD3(+), CD4(+) and CD21(+) lymphocytes decreased significantly with age. The relative percentages of lymphocytes and CD4(+) cells decreased significantly, while CD8(+) cells increased significantly with age. The CD4:CD8 ratio showed a significant age-related decrease. In contrast, dogs with tumors possessed significantly lower absolute numbers and relative percentages of all lymphocyte phenotypes, while the CD4:CD8 ratio was significantly higher than in age-matched controls. The relative percentages of CD3(+) and CD8(+) lymphocytes were significantly lower in dogs with distant metastases compared with dogs without metastases, and the CD4:CD8 ratio increased with advanced stage. These observations illustrate the significant changes in immune status with age and the presence of marked immunological defects in a large-scale study of dogs with advanced tumors., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Chick embryos have been used as alternative experimental animals in various research fields, including virology, immunology, toxicology, oncology, and embryology. Until now, there have been no in vivo models using chick embryo to evaluate radiosensitizing activity. Here, the in vivo radiosensitizing activity of etanidazole, a well-known hypoxic cell radiosensitizer, was evaluated using tumor-bearing chick embryo. On the basis of tumor growth, drug administration and X-ray irradiation were performed on day 15 chick embryo, with the endpoint being day 18 chick embryo. In day 15 chick embryo, an X-ray irradiation dose of equal or less than 10 Gy did not cause significant tumor growth suppression. Intravenous administration of equal or less than 1.0 mg of etanidazole did not cause tumor growth suppression. Neither doses of equal or less than 8 Gy of irradiation nor 1.0 mg of etanidazole caused fatality of the chick embryo. On the basis of these results, we evaluated the radiosensitizing effect of a combination treatment with 8 Gy of irradiation and 1.0 mg of etanidazole. As noted above, 1.0 mg of etanidazole alone and 8 Gy of irradiation alone did not show tumor growth suppression. In contrast, a combination treatment with 8 Gy of irradiation and 1.0 mg of etanidazole showed 35% of significant tumor growth suppression. Thus, we succeeded in evaluating the in vivo radiosensitizing activity of etanidazole using tumor-bearing chick embryo. These results suggest that the use of tumor-bearing chick embryo may be part of a promising system for evaluating radiosensitizing activity.

Dendritic cells (DCs) are the most potent antigen-presenting cells and acquire cellular antigens and danger signals from dying cells to initiate antitumor immune responses via direct cell-to-cell interaction and cytokine production. The optimal forms of tumor cell death for priming DCs for the release of danger signals are not fully understood. OBP-301 (Telomelysin) is a telomerase-specific replication-competent adenovirus that induces selective E1 expression and exclusively kills human cancer cells. Here, we show that OBP-301 replication produced the endogenous danger signaling molecule, uric acid, in infected human tumor cells, which in turn stimulated DCs to produce interferon-gamma (IFN-gamma) and interleukin 12 (IL-12). Subsequently, IFN-gamma release upregulated the endogenous expression of the proteasome activator PA28 in tumor cells and resulted in the induction of cytotoxic T-lymphocytes. Our data suggest that virus-mediated oncolysis might be the effective stimulus for immature DCs to induce specific activity against human cancer cells.

Somatic mutation of PIGA in hematopoietic stem cells causes deficiency of glycosyl phosphatidylinositol-anchored proteins in paroxysmal nocturnal hemoglobinuria (PNH) that underlies the intravascular hemolysis but does not account for expansion of the PNH clone. Immune mechanisms may mediate clonal selection but appear insufficient to account for the clonal dominance necessary for PNH to become clinically apparent. Herein, we report 2 patients with PNH whose PIGA-mutant cells had a concurrent, acquired rearrangement of chromosome 12. In both cases, der(12) had a break within the 3' untranslated region of HMGA2, the architectural transcription factor gene deregulated in many benign mesenchymal tumors, that caused ectopic expression of HMGA2 in the bone marrow. These observations suggest that aberrant HMGA2 expression, in concert with mutant PIGA, accounts for clonal hematopoiesis in these 2 patients and suggest the concept of PNH as a benign tumor of the bone marrow.

Cancer invasion and metastasis are highly complex processes and a serine protease urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor system has been postulated to play a central role in the mediation of cancer progression. Of note, malignant tumor urokinase-type plasminogen activator and urokinase-type plasminogen activator receptor levels have been found to vary considerably, and to be related to patient prognosis. In mouse models, the urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor system has been studied extensively as a target for anticancer therapy using a variety of approaches. In this review, we discuss the advances in the various modalities that have been used to target the urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor system, including protein-based and peptide-based drugs, antisense therapy, and RNA interference technology. In particular, preclinical mouse model studies that used human tumor xenografts are reviewed.

Oncolytic adenoviruses are being developed as novel anticancer therapeutics and currently undergoing clinical trials. We previously demonstrated that telomerase-specific replication-competent adenovirus (Telomelysin: OBP-301), in which the human telomerase reverse transcriptase (hTERT) promoter regulates viral replication, efficiently killed human tumor cells. We further constructed OBP-401 (Telomelysin-GFP) that expresses the green fluorescent protein (GFP) reporter gene under the control of the cytomegalovirus promoter in the E3 region to monitor viral distribution. Here, we examined the feasibility of a single-agent therapy with OBP-401 as well as of combining OBP-401 with chemotherapeutic agents. Infection of OBP-401 alone or followed by the treatment of a chemotherapeutic drug, docetaxel (Taxotere), resulted in a profound in vitro cytotoxicity and GFP expression in various human cancer cell lines originating from different organs (lung, colon, esophagus, stomach, liver and prostate), although the magnitude of antitumor effect varied among the cell types. Other chemotherapeutic drugs such as vinorelbine (Navelbine) and SN38 (the potent active metabolite of irinotecan) combined with OBP-401 also inhibited the growth of human cancer cells. Quantitative real-time PCR analysis demonstrated that docetaxel did not affect viral replication. For in vivo evaluation, nu/nu mice xenografted with H1299 human lung tumor received intratumoral injection of OBP-401 and intraperitoneal administration of docetaxel. Analysis of growth of implanted tumors showed a significant, therapeutic synergism, although OBP-401 alone and docetaxel alone showed modest inhibition of tumor growth. Thus, OBP-401 in combination with docetaxel efficiently enhances the antitumor efficacy both in vitro and in vivo, and the outcome has important implications for tumor-specific oncolytic chemovirotherapies for human cancers., (2006 Wiley-Liss, Inc.)

Study of 125 terminal patients with malignancies who received our SECOM Home Medical Service revealed that the duration of at-home treatment was positively correlated with pain control, absence of ascites and the good performance status scale, but not with the patients wish to be treated at home, information of the malignancy or the medical treatment modalities. These results suggest that terminal patients could be encouraged to return home for at-home treatment as soon as the symptoms are controlled even if not perfectly.

Uncontrolled expression of matrix metalloproteinases 2, 3 and 9 (MMP-2, -3 and -9) is believed to be a critical part of the invasive potential of tumor cells because of their ability to degrade type IV collagen, a major structural component of basement membranes. Availability of proteolytic activity in the vicinity of the cell surface is further affected by a local balance between the enzymes and their inhibitors produced by the cell. To determine how frequently deregulated expression of the MMPs and tissue inhibitors of metalloproteinases (TIMPs) is associated with tumor cells, 26 human tumor cell lines were examined by Northern blotting. Transcripts for MMP-2 and MMP-9 were more frequently expressed in mesenchymal tumor cells (9/9 for MMP-2 and 6/9 for MMP-9) than in epithelial tumor cells (4/17 for MMP-2 and 2/17 for MMP-9). Although expression of MMP-2 mRNA was clearly cell type-specific, MMP-9 mRNA expression in mesenchymal cells correlated well with the reported tumorigenicity of the cells. Enhanced expression of MMP-9 mRNA was also associated with the tumorigenic transformation of cells by an activated c-H-ras gene in human embryonic fibroblasts. Only 3 of the 26 tumor cells expressed MMP-3 mRNA, and 2 of the 3 were epithelial tumor cells which coordinately expressed MMP-9 and TIMP-1 mRNAs. TIMP-1 mRNA was almost undetectable in 50% of the tumor cells, but TIMP-2 mRNA was expressed in the majority of the cells. These findings provide comprehensive information about mRNA expression of the MMPs and TIMPs in tumor cells, the deregulation of which is thought to be an integral part of the invasive potential of tumor cells.

An enzyme-linked immunosorbent assay (ELISA) has been developed for human manganese-superoxide dismutase (Mn-SOD), using a specific monoclonal antibody raised against the purified enzyme. The Mn-SOD molecule comprises four identical sub-units and this permitted the development of a symmetrical assay, using the same monoclonal antibody as both capture and detector. The assay offers a specific, sensitive and convenient means of measuring immunoreactive Mn-SOD in human sera. Under optimum conditions, the sensitivity of the assay permits the detection of 2-200 ng of purified Mn-SOD from human liver. The mean serum Mn-SOD levels of normal healthy males and females were 99.8 +/- 24.8 (mean +/- SD) and 88.8 +/- 20.8 (mean +/- SD), respectively. A high level of the enzyme was found in the sera of patients with acute myocardial infarction as well as malignant diseases such as acute myeloid leukemia, primary hepatoma and gastric cancer. This is the first report of an ELISA using a monoclonal antibody specific for a distinct epitope of Mn-SOD.