Lower Cancer-related Mortality Research Articles

Associations of Flavonoid Intakes with Mortality among Populations with Hypertension: A Prospective Cohort Study.

The effect of flavonoid consumption on all-cause and special-cause mortality remains unclear among populations with hypertension. A total of 6110 people with hypertension from three NHANES survey cycles (2007-2008, 2009-2010, and 2017-2018) were enrolled in this study. Cox proportional hazard models were conducted to estimate the association between the intake of total flavonoids and flavonoid subclasses and all-cause, cancer-related, and cardiovascular disease (CVD)-related mortality. Nonlinear relationships were identified using restricted cubic splines (RCS). During 43,977 person-years of follow-up, 1155 participants died from any cause, 282 participants died from CVD, and 265 participants died from cancer. After adjusting for relevant confounders, including demographic, lifestyle, and dietary intake, a higher intake of total flavonoids was significantly associated with lower all-cause mortality but not CVD-related and cancer-related mortality among the population with hypertension. Compared with extreme quartiles, the hazard ratio (HR) and 95% confidence interval (CI) were 0.74 (0.56-0.97) for all-cause mortality, 0.77 (0.40-1.46) for CVD-related mortality, and 0.62 (0.35-1.08) for cancer-related mortality. In terms of all-cause mortality, this inverse association was optimized at total flavonoid consumption of approximately 375 mg/day. In addition, the negative association between total flavonoid consumption and all-cause mortality was more pronounced in non-obese (BMI < 30 kg/m2) compared to obese (BMI ≥ 30 kg/m2) populations. Higher intakes of anthocyanidin, flavan-3-ol, flavonol, and isoflavone were significantly associated with lower all-cause mortality (HR (95%CI): 0.70 (0.55-0.89); 0.76 (0.59-0.96); 0.66 (0.46-0.94); 0.79 (0.67-0.93), respectively). Higher intakes of anthocyanidin, flavan-3-ol, and flavonol were significantly associated with lower cancer-related mortality (HR (95%CI): 0.55 (0.32-0.93); 0.51 (0.31-0.82); 0.52 (0.28-0.96), respectively). This study suggests that a heightened consumption of total flavonoids and some flavonoid subclasses was linked to lower mortality, which supports the proposal of increasing flavonoid intake as part of healthy diets in patients with hypertension.

Hepatocellular carcinoma surveillance in the telehealth era: A single-centre review.

Real-world hepatocellular carcinoma (HCC) surveillance uptake remains suboptimal, despite evidence that surveillance is associated with lower cancer-related mortality in patients with cirrhosis and chronic hepatitis B. We aimed to examine the impact of telehealth consultations on HCC surveillance rates within a specialist liver clinic. We conducted a retrospective observational study within an Australian outreach liver clinic within a culturally diverse community, comparing standard consultations before the COVID-19 pandemic to telehealth consultations during the pandemic. The primary outcome was surveillance uptake defined as the percentage of time up-to-date with surveillance (PTUDS) with the 6-month interval following each scan considered up-to-date. Over 18 months of follow-up for each cohort, the median PTUDS was 86.5% in the standard consultation cohort and 85.5% in the telehealth consultation cohort (p = 0.12). HCC diagnoses did not differ between groups and hospitalisation and mortality rates were low. Using multivariate regression, increasing age, the need for an interpreter and being born in South-East Asia independently predicted PTUDS in the standard consultation cohort, whereas being born in Australia or New Zealand was predictive of a lower PTUDS. Current alcohol use and distance from the clinic predicted a lower PTUDS in the telehealth consultation cohort. In both groups, missed clinic attendances were strongly predictive of a lower PTUDS. Telehealth hepatology consultations effectively coordinate HCC surveillance and are associated with similar outcomes to standard consultations. Its implementation should be widely considered given its advantages with regards to accessibility for patients.

Population Screening for Ovarian Cancer Does Not Lower Cancer-Related Mortality

Although ovarian cancer is much less deadly if it is diagnosed early, there is no evidence that screening for ovarian cancer prevents cancer-related

Sick leave absence and the relationship between intra-generational social mobility and mortality: health selection in Sweden

BackgroundPoor health could influence how individuals are sorted into occupational classes. Health selection has therefore been considered a potential modifier to the mortality class gradient through differences in social mobility. Direct health selection in particular may operate in the short-term as poor health may lead to reduced work hours or achievement, downward social mobility, unemployment or restricted upward mobility, and death. In this study, the relationship between social mobility and mortality (all-cause, cancer-related, cardiovascular disease-related (CVD), and suicide) is explored when the relationship is adjusted for poor health.MethodsUsing Swedish register data (1996–2012) and discrete time event-history analysis, odds ratios and average marginal effects (AME) of social mobility and unemployment on mortality are observed before and after accounting for sickness absence in the previous year.ResultsAfter adjusting for sickness absence, all-cause mortality remained lower for men after upward mobility in comparison to not being mobile (OR 0.82, AME -0.0003, CI − 0.0003 to − 0.0002). Similarly, upward mobility continued to be associated with lower cancer-related mortality for men (OR 0.85, AME -0.00008, CI − 0.00002 to − 0.0002), CVD-related mortality for men (OR 0.76, AME -0.0001, CI − 0.00006 to − 0.0002) and suicide for women (OR 0.67, AME -0.00002, CI − 0.000002 to − 0.00003). The relationship between unemployment and mortality also persisted across most causes of death for both men and women after controlling for previous sickness absence. In contrast, adjusting for sickness absence renders the relationship between downward mobility and cancer-related mortality not statistically different from the non-mobile.ConclusionsHealth selection plays a role in how downward mobility is linked to cancer related deaths. It additionally accounts for a portion of why upward mobility is associated with lower mortality. That health selection plays a role in how social mobility and mortality are related may be unexpected in a context with strong job protection. Job protection does not, however, equalize opportunities for upward mobility, which may be limited for those who have been ill. Because intra-generational upward mobility and mortality remained related after adjusting for sickness absence, other important mechanisms such as indirect selection or social causation should be explored.

Metformin Induces p53-Dependent Mitochondrial Stress in Therapy-Sensitive and -Resistant Lymphoma Pre-Clinical Model and Primary Patients Sample with B-Cell Non-Hodgkin Lymphoma (NHL)

Introduction: Metformin, a guanidine originally derived for Galega officinalis (French lilac), has been widely prescribed to type II diabetics since 1950 and well known for its safety toxicity profile. Recently, metformin use was associated with a decrease in risk cancer development and lower cancer-related mortality among breast, colorectal, prostrate, lung, hepatic and ovarian cancer patients. Our group previously reported that the use of metformin during front-line chemo-immunotherapy (i.e. R+CHOP) improved the clinical outcome of diffuse large B-cell lymphoma (DLBCL). The mechanism(s) of action underlying the antitumor effect of metformin remains not to be fully elucidated. Previous research done in our laboratory revealed that metformin inhibited cell proliferation through repressing PCNA and p21 proteins. Here, we report that metformin activates tumor suppressor p53 by suppressing MDMX in pre-clinical lymphoma models.Methods: A panel of rituximab-sensitive (RSCL), rituximab-resistant (RRCL) cell lines and primary tumor cells isolated from B-cell lymphoma patients were exposed to escalating doses of metformin (0-64mM). Changes in cell viability were determined by Presto Blue (Sigma) assay in cell lines and Titer Glo in patient samples. Changes in MDMX, MDM2 and p53 expression levels were determined by western blotting after exposure cells to metformin. MDMX-MDM2-p53 interactions and p53 ubiquitination following in vitro exposure to metformin were determined by immunoprecipitation of p53 and probing for MDMX, MDM2, ubiquitin and p53 in RSCL and RRCLs. Loss of Dψm or induction of apoptosis following metformin exposure were assessed by DiOC6 or Annexin V/PI staining and flow cytometry. Oxidative stress induced by metformin was measured by flow cytometry using dihydrorhodamine-123 (DHR-123) dye.Result: Metformin induced a dose-and time- dependent cell death in cell lines and primary patient tumor cells. In vitro exposure of lymphoma cell to metformin resulted in a decrease in MDMX levels. Immunoprecipitation studies demonstrated that following exposure to metformin, MDMX bound less to p53 leading to less p53 ubiquitination. In vitro exposure of RSCL or RRCL to metformin resulted in the expression of p53 regulated BH3 single domain proteins (Noxa and Puma). Moreover, metformin repressed mitochondrial potential, induced reactive oxidative species (ROS) generation and triggered apoptosis.Conclusion: Our data suggests that metformin had anti-tumor activity against RSCL, RRCL and primary tumor cells isolated from lymphoma patients. The down-regulation of MDMX and re-activation p53 function following metformin exposure may contribute to the disruption in the mitochondria potential, generation of ROS and induction of apoptosis observed in our models RSCL and RRCL. Our finding highlights a potential role for metformin in the treatment of B-cell malignancies. (Research, in part, supported by a NIH grant R01 CA136907-01A1 awarded to Roswell Park Cancer Institute and The Eugene and Connie Corasanti Lymphoma Research Funds) DisclosuresCzuczman:MorphoSys: Consultancy; Boehringer-Ingelheim: Other: Advisory Board; Celgene: Employment; Immunogen: Other: Advisory board.

Surveillance endoscopy is associated with improved outcomes of oesophageal adenocarcinoma detected in patients with Barrett's oesophagus

BackgroundThe effectiveness of surveillance endoscopy in patients with Barrett's oesophagus (BE) for reducing oesophageal adenocarcinoma (EAC)-related mortality in patients with BE is unclear.MethodsThis is a cohort study of patients with...

46LBA 15-years follow-up results of the randomized Dutch D1D2 Trial: lower cancer-related mortality after D2

Phosphagen kinases (PKs) play a major role in the regulation of energy metabolism in animals. Creatine kinase (CK) is the sole PK in vertebrates, whereas several PKs are present in invertebrates. Here, we report the enzymatic properties and gene structure of PK in the trematode Schistosoma japonicum (Sj). SjPK has a unique contiguous dimeric structure comprising domain 1 (D1) and domain 2 (D2). The three states of the recombinant SjPK (D1, D2, and D1D2) show a specific activity for the substrate taurocyamine. The comparison of the two domains of SjPK revealed that D1 had a high turnover rate (kcat = 52.91) and D2 exhibited a high affinity for taurocyamine (KmTauro = 0.53 ± 0.06). The full-length protein exhibited higher affinity for taurocyamine (KmTauro = 0.47 ± 0.03) than the truncated domains (D1 = 1.30 ± 0.10, D2 = 0.53 ± 0.06). D1D2 also exhibited higher catalytic efficiency (kcat/KmTauro = 82.98) than D1 (40.70) and D2 (29.04). These results demonstrated that both domains of SjTKD1D2 interacted efficiently and remained functional. The three-dimensional structure of SjPKD1 was constructed by the homology modeling based on the transition state analog complex state of Limulus AK. This protein model of SjPKD1 suggests that the overall structure is almost conserve between SjPKD1 and Limulus AK except for the flexible loops, that is, particularly guanidino-specificity (GS) region, which is associated with the recognition of the corresponding guanidino substrate. The constructed NJ tree and the comparison of exon/intron organization suggest that SjTK has evolved from an arginine kinase (AK) gene. SjTK has potential as a novel antihelminthic drug target as it is absent in mammals and its strong activity may imply a significant role for this protein in the energy metabolism of the parasite.

The Antidiabetic Biguanide Metformin Induces Growth Arrest in Multiple Myeloma Cells in Vitro, overcoming the Effect of Stromal Cells

Obesity and insulin resistance are associated with increased risk for several malignancies, including multiple myeloma (MM), possibly due to hyperinsulinemia and the resulting increased circulating free IGF-I levels that can have a growth-promoting and anti-apoptotic effect on MM cells. It has been proposed that improving insulin sensitivity, with a low-fat diet or with the use of the biguanide metformin, could suppress circulating insulin and free IGF-I levels and lower cancer risk. Metformin has been widely used as an antidiabetic agent since the 1950s and has an excellent safety profile. Interestingly, epidemiologic studies have suggested that patients with type 2 diabetes mellitus who are treated with metformin have lower cancer incidence and lower cancer-related mortality than diabetics who receive sulfonylurea monotherapy or insulin. Even more intriguing is the recent finding that metformin can have direct anticancer activity in vitro against prostate and breast carcinoma cell lines. In breast carcinoma cells, metformin inhibits mammalian target of rapamycin (mTOR) activity and suppresses translation initiation and global protein synthesis, via an AMP-activated protein kinase (AMPK)-dependent pathway. We investigated the direct effects of metformin in vitro in a panel of 17 MM cell lines and sublines using MTT, flow cytometry, annexin V-PI, as well as compartment-specific bioluminescence (CS-BLI) assays in the absence or presence of bone marrow stromal cells (BMSCs). We found that metformin suppressed the growth of all MM cell lines and sublines, including those that are resistant to conventional and several investigational anti-MM agents. The anti-MM activity of metformin was achieved with clinically relevant sub-mM or low mM levels, and was in the same order of magnitude or stronger than its activity reported in solid tumor cell line models. The anti-MM activity of metformin did not involve apoptotic/necrotic cell death, but inhibition of proliferation (G0/G1 arrest). Western blot analyses showed that metformin treatment of RPMI-8226/S MM cells led to increased phosphorylation of AMPK; suppression of p70S6K phosphorylation; and decreased cyclin D1 levels. These results are consistent with the known effect of metformin in triggering AMPK activity and thereby suppressing the function of its downstream targets mTOR and p70S6K. Co-culture with BMSCs did not abrogate the anti-MM effect of metformin, but further sensitized MM cell to this agent, at concentrations which did not affect BMSC viability. This sensitization was more prominent in MM cell lines that respond to BMSCs with increased proliferation/survival (e.g. MM-1S, MM-1R, KMS-11, L363) than in cell lines independent/unresponsive to stromal stimulation (e.g. OPM-2). To further probe the mechanistic basis for this stroma-induced sensitization to metformin, we studied the transcriptional signature of genes suppressed by mTOR inhibition, a downstream effect of metformin, in MM cells cultured alone vs. co-cultured with BMSCs. We observed that stroma triggers a significant increase in the average expression of mTOR-responsive genes in stroma responsive MM cell lines, but not in stroma unresponsive lines, in which this transcriptional signature is constitutively upregulated. This observation suggests that the increased metformin sensitivity of MM cells co-cultured with BMSCs may reflect the ability of metformin to counteract the upregulation of p70S6K/mTOR pathway activity triggered by stroma. Our studies demonstrate a direct, growth-suppressive effect of metformin in MM cells in vitro, which can be potentiated by interactions with the bone marrow microenvironment. Taken together with the beneficial effect of this antidiabetic agent on circulating insulin and free IGF-I levels and its favorable safety profile, these data support the clinical evaluation of metformin in patients with MM.

Survival benefits and trends in use of adjuvant therapy among elderly stage II and III rectal cancer patients in the general population

This study examined elderly stage II and III rectal cancer patients' adjuvant chemoradiation therapy adherence, trends in adherence over time, and the relation of levels of adherence to mortality. The authors studied 2886 stage II and III rectal cancer patients who had surgical resection and who appeared in 1992-1999 linked SEER-Medicare claims data. The authors compared measures of adjuvant radiation and chemotherapy receipt and completion between stage II and III patients. Adjusted risk of cancer-related 5-year mortality was calculated by multivariate logistic regression for different levels of chemoradiation adherence among stage II and III patients. Of the 2886 patients, 45.4% received both adjuvant radiation and chemotherapy. Stage III patients were more likely to receive chemoradiation than stage II patients. The receipt of chemoradiation by stage II patients increased significantly from 1992 to 1999. Stage III patients were more likely to complete radiation therapy (96.6%), chemotherapy (68.2%), and both modalities (67.5%) than stage II patients (91.5%, 49.8%, 47.6%, respectively). Only a complete course of both radiation and chemotherapy for both stage II (relative risk [RR] 0.74; 95% CI, 0.54, 0.97) and III (RR 0.80; 95% CI, 0.65, 0.96) decreased the adjusted 5-year cancer mortality risk compared with counterparts with no adjuvant therapy. Even though stage II rectal cancer patients were less likely than stage III patients to receive and complete adjuvant chemoradiation, both patient groups in the general population had lower cancer-related mortality if they completed chemoradiation. These patients deserve support and encouragement to complete treatment.

5043 POSTER 10-year-survival data for 138 patients with endometrial carcinoma treated with postoperative vaginal vault brachytherapy: excellent therapeutic ratio for intermediate risk-group and lower cancer-related mortality than from further malignancies

5043 POSTER 10-year-survival data for 138 patients with endometrial carcinoma treated with postoperative vaginal vault brachytherapy: excellent therapeutic ratio for intermediate risk-group and lower cancer-related mortality than from further malignancies

Melanoma Outcomes for Medicare Patients

To determine whether a difference in melanoma outcomes exists in the United States between tumors detected by dermatologists vs those detected by nondermatologists. Retrospective analysis of linked data from the Medicare enrollment and claims files from the Centers for Medicare and Medicaid Services and the National Cancer Institute's Surveillance, Epidemiology, and End Results program database from 1991 to 1996. The registries are from 12 US sites. A study sample comprised of 2020 subjects. Tumor characteristics (Breslow thickness and histologic ulceration), stage at diagnosis, and survival and mortality rates. Tumor detection by a dermatologist vs nondermatologist was associated with an earlier stage melanoma (stage 0, stage I, and stage II vs stage III and stage IV; chi(2) test, P<.01) and a thinner tumor (Breslow thickness, 0.86 mm vs 1.00 mm; P<.05). At all time points (6 months, 2 years, and 5 years), patients whose melanoma was detected by dermatologists had better survival rates (98%, 87%, and 74%, respectively, for those whose melanoma was detected by dermatologists vs 95%, 79%, and 69%, respectively, for nondermatologists; P<.05). Non-cancer-related mortality was similar for the 2 groups, but the patients whose tumors were detected by dermatologists had lower cancer-related mortality (13% vs 21%; P<.01) and overall mortality (29% vs 37%; P<.01). Multivariate analysis showed that age, sex, stage at diagnosis, and melanoma detection by a dermatologist were all significantly predictive of survival. Earlier stage melanoma and improved survival are associated with detection by a dermatologist rather than by a nondermatologist. Increasing access to dermatologists, particularly for older patients, may represent one approach to improving melanoma-related health outcomes.