Intermediate Risk Factors Research Articles

Long-Term Adiposity and Midlife Carotid Intima-Media Thickness Are Linked Partly Through Intermediate Risk Factors.

This study aims to determine quantitatively the mediation effects of multiple cardiovascular risk factors on the associations of childhood body mass index (BMI) and its cumulative burden with adult carotid intima-media thickness (cIMT). The longitudinal cohort consisted of 1391 adults who had been examined for BMI 4-15 times over 35.0 years on average since childhood and had data on adult cIMT, systolic blood pressure, low-density lipoprotein cholesterol, atherogenic index of plasma, and serum glucose. The area under the curve was used as a measure of cumulative burden of BMI. After adjusting for covariates, the total effects (standardized regression coefficient) of childhood BMI (0.138), adult BMI (0.111), and area under the curve of BMI (0.150) on cIMT were all significant (P<0.001) without mediators included in the model. The mediation effects of adult systolic blood pressure, glucose, atherogenic index of plasma and low-density lipoprotein cholesterol were 8.0%, 4.3%, 3.6%, and 0.0%, respectively, in the model with childhood BMI as the predictor, 23.4%, 15.3%, 12.6%, and 7.2%, respectively, with adult BMI as the predictor, and 14.7%, 8.7%, 6.0%, and 2.0%, respectively, with area under the curve of BMI as the predictor. The direct effects on cIMT were 0.117 (P<0.001) for childhood BMI, 0.046 (P=0.224) for adult BMI, and 0.103 (P<0.001) for area under the curve of BMI after removing the mediation effects. The long-term deleterious impact of adiposity on subclinical changes in vascular structure begins early in life and is accumulated over lifetime. Excess adiposity and higher cIMT are linked partly through other cardiovascular risk factors in later life, especially elevated blood pressure and glucose.

CtHPVDNA and Recurrence Risk in MC1675, a Secondary Analysis of a Phase III Evaluation of De-Escalated Adjuvant Radiation Therapy (DART) vs. Standard Adjuvant Treatment for HPV Associated Oropharyngeal Squamous Cell Carcinoma

<h3>Purpose/Objective(s)</h3> We previously reported the results of a phase III clinical trial (MC1675) evaluating 30-36 Gy of adjuvant radiation therapy (RT) with weekly docetaxel (DART) vs standard of care (SOC) adjuvant (chemo)RT. We analyzed prospectively collected patient plasma specimens for circulating tumor tissue modified viral (TTMV)-HPV DNA as a marker of molecular residual disease (MRD) and its association with outcomes. <h3>Materials/Methods</h3> The DART regimen consists of transoral surgery (TOS) & neck dissection for a margin negative resection. Patients (pts) with intermediate risk factors received 30 Gy/1.5 Gy b.i.d. + docetaxel 15 mg/m² days 1 & 8, while pts with extranodal extension (ENE) received a simultaneous boost to 36 Gy/1.8 Gy b.i.d. to ENE+ nodal levels. Pts randomized to SOC received 60 Gy +/- cisplatin. Pts could optionally consent to plasma collection prior to surgery, post operatively, and 3 months after completion of RT. 2mL samples were de-identified and analyzed for TTMV-HPV DNA for HPV subtypes using a commercial test in a blinded fashion. A TTMV Score of >/= 5 normalized TTMV-HPV DNA fragments (frgs)/mL plasma was prespecified as MRD. Descriptive rates are reported along with Kaplan Meier (KM) estimates for progression free survival (PFS) by traditional risk factors and TTMV-HPV DNA. KM estimates were planned for patients treated per protocol. <h3>Results</h3> Of the 194 patients (DART: 130, SOC: 64), 150 had plasma available for analysis at any timepoint. Of 44 pts with pre-surgery plasma available, 37 (84%) had detectable TTMV-HPV DNA, with a median value of 250 frgs/mL (range 5-31092). Post-op, 137 pts had plasma available (median 21 days post-op), of which 16 (11%) had detectable post op TTMV-HPV DNA, median 10 frgs/mL. Three months after completion of RT, 114 pts had plasma available, of which 8 pts (7%) had detectable TTMV-HPV DNA median 43 frgs/mL. At 18 months, PFS was 73.1% for patients with post-op detectable MRD compared to 95.8% of patients with no MRD (p<0.01). Similarly, MRD at 3 months post treatment was associated with a PFS of only 25% at 18 months compared to 97.2% PFS in patients without MRD (p<0.0001). For pts receiving DART with ENE and pN1 disease, 18-month PFS was 66.7% in the setting of MRD compared to 88.8% for no MRD (p=0.08). <h3>Conclusion</h3> This secondary analysis of MC1675 validates post-op detectable TTMV-HPV DNA as a risk factor for recurrence and demonstrates 3-month post treatment TTMV-HPV DNA as an additional highly significant MRD timepoint identifying at least 50% of all recurrences. Assay standardization is paramount to future studies as well as pre-op collection on all patients. For patients with clinical risk factors such as ENE, our data support the hypothesis that post-op TTMV-HPV DNA could aid in patient selection for de-escalation.

Patient Reported Outcomes (PROs) in MC1675, De-Escalated Adjuvant Radiation Therapy (DART) vs. Standard of Care Adjuvant Radiation Therapy (SOC) for HPV Associated Oropharyngeal Squamous Cell Carcinoma

<h3>Purpose/Objective(s)</h3> We previously reported the results of a phase III clinical trial (MC1675) evaluating 30-36 Gy of adjuvant radiation therapy (RT) with weekly docetaxel (DART) vs standard of care (SOC) adjuvant (chemo)RT. Here we report patient reported outcomes (PROs) of this randomized study. <h3>Materials/Methods</h3> The DART regimen consists of transoral robotic-assisted surgery (TORS) & neck dissection for a margin negative resection. Patients (pts) with intermediate risk factors received 30 Gy/1.5 Gy b.i.d. + docetaxel 15 mg/m² days 1 & 8, while pts with extranodal extension (ENE) received a simultaneous boost to 36 Gy/1.8 Gy b.i.d. to ENE+ nodal levels. Pts randomized to SOC received 60 Gy/2.0 Gy qd +/- cisplatin. Pts completed PROs consisting of the FACT-HN, EQ5D, XEQOLS, and EORTC HN-35 post operatively (prior to adjuvant RT), immediately post RT, and at 1-, 3-, 12-, and 24-months post treatment. Mixed models with contrast statements were utilized to test the effect of treatment arm over time and their interaction by analyzing mean difference change from baseline. <h3>Results</h3> Of the 194 patients (DART: 130, SOC: 64) 189 patients completed post-op PROs, 179 immediately post RT, 175 at 1-month, 166 at 3-months, 140 at 12-months, and 74 at 24-months, with no differences in completion rate by study arm (p=.9). Compared to post-op, PROs revealed significant symptom burden post RT and improvement over time, with the DART arm having significantly fewer symptoms in multiple domains of the PROs: FACT-HN Total (p=0.004), FACT-HN Trial Outcome Index (p<0.001, <b>Table 1</b>), and XEQOLS Total Score (p<0.001). Additional significant differences (all favoring DART, all p<0.02) were the EQ5D Index Score, EORTC scales of pain, swallow, speech, social eating, social contact, sex score, dry mouth, open mouth, sticky saliva, felt ill score, and coughing score. Measures of clinically meaningful change and correlation to objective measures of modified barium swallow will be presented. <h3>Conclusion</h3> DART was associated with significantly fewer patient reported symptoms compared to SOC as evidenced by PROs across multiple domains. PROs normalized as expected over time, yet evidence of decreased symptom burden with DART compared to SOC persisted at 12 to 24 months by patient report. If deemed oncologically equivalent for lower risk patients, DART should be considered based on this superiority in PROs and previously reported objective swallowing measures.

A novel Silva pattern-based model for precisely predicting recurrence in intermediate-risk cervical adenocarcinoma patients

BackgroundConsidering the unique biological behavior of cervical adenocarcinoma (AC) compared to squamous cell carcinoma, we now lack a distinct method to assess prognosis for AC patients, especially for intermediate-risk patients. Thus, we sought to establish a Silva-based model to predict recurrence specific for the intermediate-risk AC patients and guide adjuvant therapy.Methods345 AC patients were classified according to Silva pattern, their clinicopathological data and survival outcomes were assessed. Among them, 254 patients with only intermediate-risk factors were identified. The significant cutoff values of four factors (tumor size, lymphovascular space invasion (LVSI), depth of stromal invasion (DSI) and Silva pattern) were determined by univariate and multivariate Cox analyses. Subsequently, a series of four-, three- and two-factor Silva-based models were developed via various combinations of the above factors.Results(1) We confirmed the prognostic value of Silva pattern using a cohort of 345 AC patients. (2) We established Silva-based models with potential recurrence prediction value in 254 intermediate-risk AC patients, including 12 four-factor models, 30 three-factor models and 16 two-factor models. (3) Notably, the four-factor model, which includes any three of four intermediate-risk factors (Silva C, ≥ 3 cm, DSI > 2/3, and > mild LVSI), exhibited the best recurrence prediction performance and surpassed the Sedlis criteria.ConclusionsOur study established a Silva-based four-factor model specific for intermediate-risk AC patients, which has superior recurrence prediction performance than Sedlis criteria and may better guide postoperative adjuvant therapy.

Amide proton transfer weighted imaging combined with dynamic contrast-enhanced MRI in predicting lymphovascular space invasion and deep stromal invasion of IB1-IIA1 cervical cancer.

ObjectivesTo investigate the value of amide proton transfer weighted (APTw) imaging combined with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in predicting intermediate-risk factors of deep stromal invasion (DSI) and lymphovascular vascular space invasion (LVSI) in cervical cancer.MethodsSeventy patients with cervical cancer who underwent MRI before operation from July 2019 to February 2022 were retrospectively included in this study. Clinical information including age, histologic subtype etc. were recorded for patients. ATPw imaging parameter APTmean and DCE-MRI parameters Ktrans, Kep and Ve were measured and analyzed. The independent-sample t-test, Mann-Whitney U test, or Chi-square test was used to compare the differences of parameters between DSI/LVSI positive and negative groups. Logistic analysis was used to develop a combined predictive model. The receiver operating characteristic curve was for predictive performance. ANOVA and Kruskal-Wallis test were used to compare the differences of consecutive parameters among multiple groups.ResultsKtrans and SCC-Ag were independent factors in predicting DSI; Ktrans+SCC-Ag had the highest AUC 0.819 with sensitivity and specificity of 71.74% and 91.67%, respectively. APTmean and Ktrans were independent factors in predicting LVSI; APTmean+Ktrans had the highest AUC 0.874 with sensitivity and specificity of 92.86% and 75.00%, respectively. Ktrans and Ve could discriminate coexistence of DSI and LVSI from presence of single one, APTmean could discriminate the presence of DSI or LVSI from no risk factor presence.ConclusionThe combination of APTw and DCE-MRI is valuable in predicting intermediate-risk factors of DSI and LVSI in cervical cancer.

Socioeconomic and Behavioral Disparities Among Diabetics in Saudi Arabia: A Nation-Wide Descriptive Study.

PurposeThis study aims to explore sociodemographic, behavioral and clinical factors in adult participants with Diabetes in Saudi Arabia.MethodsA population-based cross-sectional study of 20492 potential participants conducted in quarters 1 and 2 in 2021 from all 13 administrative regions of Saudi Arabia. A backward maximum likelihood logistic regression model, including all variables, was used to identify variables associated with participants living with Diabetes.ResultsA total of 14007 participants, aged ≥18 years, completed the interview, with a response rate of 68.3% and successful quota sampling. Fifty percent were male, the mean age was 36.7 (SD 13.7; range: 18–90). Of the total sample, 1633, 11.7% had Diabetes. Seven percent only of diabetic patients (124 participants) had an acceptable level of fruit and vegetable intake. In addition, only (274, 16.8%) had an acceptable level of physical activity, compared to (2389, 19.3%) in the non-diabetic group. Daily smokers were slightly higher in the diabetic group compared to the non-diabetic group (13.2% vs 11.7%). Hypertension was reported mostly by the diabetic group (45.1% vs 8%). Overweight and Obesity were more prevalent in patients with Diabetes (72.50% vs 51.62%). The results of the logistic regression have shown that several sociodemographic, behavioral and intermediate risk factors were significantly associated with Diabetes.ConclusionThe study found that the prevalence of Diabetes in Saudi Arabia is around 12%, which is lower than the previously reported prevalence of Diabetes in Saudi Arabia. Moreover, Diabetes was found to be associated with lower educational level, smoking, obesity and overweight, hypercholesterolemia and hypertension. These factors are essential to be identified and screened in the community at regular interval; furthermore, controlling these factors may improve their disease management and quality of life. Additionally, knowing these factors will assist policymakers to shape an effective practical approach to combat diabetes widespread.

Nordic dietary patterns and cardiometabolic outcomes: a systematic review and meta-analysis of prospective cohort studies and randomised controlled trials

Aims/hypothesisNordic dietary patterns that are high in healthy traditional Nordic foods may have a role in the prevention and management of diabetes. To inform the update of the EASD clinical practice guidelines for nutrition therapy, we conducted a systematic review and meta-analysis of Nordic dietary patterns and cardiometabolic outcomes.MethodsWe searched MEDLINE, EMBASE and The Cochrane Library from inception to 9 March 2021. We included prospective cohort studies and RCTs with a follow-up of ≥1 year and ≥3 weeks, respectively. Two independent reviewers extracted relevant data and assessed the risk of bias (Newcastle–Ottawa Scale and Cochrane risk of bias tool). The primary outcome was total CVD incidence in the prospective cohort studies and LDL-cholesterol in the RCTs. Secondary outcomes in the prospective cohort studies were CVD mortality, CHD incidence and mortality, stroke incidence and mortality, and type 2 diabetes incidence; in the RCTs, secondary outcomes were other established lipid targets (non-HDL-cholesterol, apolipoprotein B, HDL-cholesterol, triglycerides), markers of glycaemic control (HbA1c, fasting glucose, fasting insulin), adiposity (body weight, BMI, waist circumference) and inflammation (C-reactive protein), and blood pressure (systolic and diastolic blood pressure). The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of the evidence.ResultsWe included 15 unique prospective cohort studies (n=1,057,176, with 41,708 cardiovascular events and 13,121 diabetes cases) of people with diabetes for the assessment of cardiovascular outcomes or people without diabetes for the assessment of diabetes incidence, and six RCTs (n=717) in people with one or more risk factor for diabetes. In the prospective cohort studies, higher adherence to Nordic dietary patterns was associated with ‘small important’ reductions in the primary outcome, total CVD incidence (RR for highest vs lowest adherence: 0.93 [95% CI 0.88, 0.99], p=0.01; substantial heterogeneity: I2=88%, pQ<0.001), and similar or greater reductions in the secondary outcomes of CVD mortality and incidence of CHD, stroke and type 2 diabetes (p<0.05). Inverse dose–response gradients were seen for total CVD incidence, CVD mortality and incidence of CHD, stroke and type 2 diabetes (p<0.05). No studies assessed CHD or stroke mortality. In the RCTs, there were small important reductions in LDL-cholesterol (mean difference [MD] −0.26 mmol/l [95% CI −0.52, −0.00], pMD=0.05; substantial heterogeneity: I2=89%, pQ<0.01), and ‘small important’ or greater reductions in the secondary outcomes of non-HDL-cholesterol, apolipoprotein B, insulin, body weight, BMI and systolic blood pressure (p<0.05). For the other outcomes there were ‘trivial’ reductions or no effect. The certainty of the evidence was low for total CVD incidence and LDL-cholesterol; moderate to high for CVD mortality, established lipid targets, adiposity markers, glycaemic control, blood pressure and inflammation; and low for all other outcomes, with evidence being downgraded mainly because of imprecision and inconsistency.Conclusions/interpretationAdherence to Nordic dietary patterns is associated with generally small important reductions in the risk of major CVD outcomes and diabetes, which are supported by similar reductions in LDL-cholesterol and other intermediate cardiometabolic risk factors. The available evidence provides a generally good indication of the likely benefits of Nordic dietary patterns in people with or at risk for diabetes.RegistrationClinicalTrials.gov NCT04094194.FundingDiabetes and Nutrition Study Group of the EASD Clinical Practice.Graphical abstract

The effect of adjuvant radiotherapy on oncological outcomes in patients with early-stage cervical carcinoma with only intermediate-risk factors: a propensity score matching analysis

We aimed to evaluate whether adjuvant radiotherapy had a survival benefit for patients with early-stage cervical carcinoma with intermediate-risk factors. This study included patients who underwent radical hysterectomy and lymphadenectomy according to Wertheim–Okabayashi for stage IB1-IIA2 cervical carcinoma. Each patient had at least one intermediate-risk factor including tumour diameter ≥4 cm, deep stromal invasion, and positive lymphovascular space invasion (LVSI). Patients with lymph node metastasis, parametrial invasion, and positive surgical margins according to the final paraffin section were excluded. In total, 183 patients were included. Seventy-three (39.9%) patients had one, 85 (46.4%) had two, and 25 (13.7%) had three intermediate risk factors. Sixty-seven (36.6%) patients received adjuvant radiotherapy. There was a statistically significant difference in terms of stage, LVSI, and endometrial/uterine invasion between the groups that did and did not receive adjuvant radiotherapy (p = .024, p = .018, and p = .001, respectively). These two groups were homogenised by performing propensity score matching (PSM) analysis. In the new matched cohort (n = 134), 5-year disease-free survival (DFS) was 89.5% in the group that received adjuvant radiotherapy and 82% in the group that did not (HR: 0.484, 95% CI: [0.171–1.369]; p = .171). Also, receiving adjuvant radiotherapy was not associated with an improvement in oncologic outcomes in patients with one, two, or more intermediate risk factors. In univariate analysis, none of the risk factors was associated with DFS. In conclusion, adjuvant radiotherapy had no favourable effect on survival outcomes in patients with early-stage cervical carcinoma with only intermediate risk factors. IMPACT STATEMENT What is already known on this subject? Radiotherapy after radical hysterectomy in cervical carcinoma is accepted as the standard of care when high-risk factors – positive surgical margins, lymph node metastasis, and parametrial involvement – are found in the surgical specimen. However, the necessity of adjuvant radiotherapy in patients with intermediate-risk factors – deep stromal invasion, positive LVSI, tumour diameter ≥4 cm – is controversial. What do the results of this study add? We compared patients who received adjuvant radiotherapy and those who did not. No significant difference was found between the two groups in terms of oncologic outcomes. There was no difference between the two groups in terms of pelvic and extrapelvic recurrence rates. The number of positive intermediate-risk factors did not affect survival. Moreover, age, tumour type, stage, number of removed lymph nodes, grade, bilateral salpingo-oophorectomy, and endometrial/uterine invasion were not associated with DFS among patients with stage IB–IIA cervical carcinoma with only intermediate-risk factors. What are the implications of these findings for clinical practice and/or further research? Debate remains over the prognostic factors and the adjuvant treatment options in patients with early-stage cervical carcinoma who possess intermediate-risk factors. Adjuvant radiotherapy can be ignored if initial adequate surgery has been performed in this patient group.

Prognostic factors of 2018 FIGO stage IB-IIA cervical cancer with absence of high/ intermediate surgical-pathological risk factors.

This retrospective analysis of a real-world database of open radical hysterectomy in Japan aimed to reveal the clinicopathological findings and clinical outcomes of low-risk patients with stage IB-IIA cervical cancer. A total of 1143 stage IB1, IB2 and IIA1 (reclassified by FIGO 2018 staging system) patients with cervical cancer who underwent radical hysterectomy between January 2004 and December 2008 from the Japanese Gynecologic Oncology Group database were analyzed. Low-risk patients were defined as those without a tumor size exceeding 4cm, parametrial tumor involvement, deep (outer half) stromal invasion, lymphovascular space invasion or lymph nodal metastasis. 61.2% (772/1262) patients with stage IB1, 32.1% (229/932) with stage IB2 and 16.9% (72/294) of stage IIA1 were classified into the low-risk group. The 5-year overall survival and disease-free survival rates were 98.4 and 93.7%, respectively. Histological classification did not affect the survival rates, but stage IIA cases had significantly lower overall survival and disease-free survival (83.5 and 93.8%, respectively) than stage IB cases. The independent prognostic factors for disease-free survival were older age (≧50), histology, clinical stage and clinical stage as independent prognostic factors for overall survival. Regarding recurrence, older age, non-SCC and stage IIA1 were independent risk factors for local recurrence, but stage IIA1 was the only independent risk factor for distant metastasis. We found that stage IIA1 was the strongest risk factor for survival and recurrence of low-risk uterine cervical cancer (FIGO, 2018). In low-risk cases, stage IIA1 should be considered separately from stage IB.

Correction to: Risk assessment in the patients with uterine cervical cancer harboring intermediate risk factors after radical hysterectomy: a multicenter, retrospective analysis by the Japanese Gynecologic Oncology Group

Correction to: Risk assessment in the patients with uterine cervical cancer harboring intermediate risk factors after radical hysterectomy: a multicenter, retrospective analysis by the Japanese Gynecologic Oncology Group

Risk assessment in the patients with uterine cervical cancer harboring intermediate risk factors after radical hysterectomy: a multicenter, retrospective analysis by the Japanese Gynecologic Oncology Group.

Adjuvant therapy is usually considered for surgically treated patients with uterine cervical cancer harboring intermediate risk (IR) factors such as large tumor diameter, stromal invasion to the outer half, and lymphovascular space invasion (LVSI). However, the indications and types of adjuvant therapy for the IR group remain controversial. This study aimed to analyze the differences in patient outcomes in the IR group to provide novel insights for tailoring adjuvant therapy. Data from 6192 patients with cervical cancer who underwent radical hysterectomy at 116 institutions belonging to the Japanese Gynecologic Oncology Group were reviewed. In total, 1688 patients were classified into the IR group, of whom 37.3% did not receive adjuvant therapy. Conversely, approximately equal proportions of the remaining patients received adjuvant radiotherapy, concurrent chemoradiotherapy, and chemotherapy. Patients with all three risk factors showed worse overall survival than those with one or two risk factors. In addition to LVSI, non-squamous cell carcinoma histology, and vaginal invasion were identified as independent risk factors for both recurrence and mortality in multivariate analyses. Tumor diameter greater than 40mm and surgical center volume were identified as independent risk factors for recurrence. Stromal invasion to the outer half and ovarian metastasis were identified as independent risk factors for mortality. This study revealed the significant differences in prognosis in the IR group. The indications for adjuvant therapy should be further studied, focusing on conventional risk factors and other pathological findings.

Mendelian randomization analysis of 37 clinical factors and coronary artery disease in East Asian and European populations

BackgroundCoronary artery disease (CAD) remains the leading cause of mortality worldwide despite enormous efforts devoted to its prevention and treatment. While many genetic loci have been identified to associate with CAD, the intermediate causal risk factors and etiology have not been fully understood. This study assesses the causal effects of 37 heritable clinical factors on CAD in East Asian and European populations.MethodsWe collected genome-wide association summary statistics of 37 clinical factors from the Biobank Japan (42,793 to 191,764 participants) and the UK Biobank (314,658 to 442,817 participants), paired with summary statistics of CAD from East Asians (29,319 cases and 183,134 controls) and Europeans (91,753 cases and 311,344 controls). These clinical factors covered 12 cardiometabolic traits, 13 hematological indices, 7 hepatological and 3 renal function indices, and 2 serum electrolyte indices. We performed univariable and multivariable Mendelian randomization (MR) analyses in East Asians and Europeans separately, followed by meta-analysis.ResultsUnivariable MR analyses identified reliable causal evidence (P < 0.05/37) of 10 cardiometabolic traits (height, body mass index [BMI], blood pressure, glycemic and lipid traits) and 4 other clinical factors related to red blood cells (red blood cell count [RBC], hemoglobin, hematocrit) and uric acid (UA). Interestingly, while generally consistent, we identified population heterogeneity in the causal effects of BMI and UA, with higher effect sizes in East Asians than those in Europeans. After adjusting for cardiometabolic factors in multivariable MR analysis, red blood cell traits (RBC, meta-analysis odds ratio 1.07 per standard deviation increase, 95% confidence interval 1.02–1.13; hemoglobin, 1.10, 1.03–1.16; hematocrit, 1.10, 1.04–1.17) remained significant (P < 0.05), while UA showed an independent causal effect in East Asians only (1.12, 1.06–1.19, P = 3.26×10−5).ConclusionsWe confirmed the causal effects of 10 cardiometabolic traits on CAD and identified causal risk effects of RBC, hemoglobin, hematocrit, and UA independent of traditional cardiometabolic factors. We found no causal effects for 23 clinical factors, despite their reported epidemiological associations. Our findings suggest the physiology of red blood cells and the level of UA as potential intervention targets for the prevention of CAD.

Long-Term Toxic Effects, Swallow Function, and Quality of Life on MC1273: A Phase 2 Study of Dose De-escalation for Adjuvant Chemoradiation in Human Papillomavirus-Positive Oropharyngeal Cancer

Patients with human papillomavirus oropharyngeal cancer are highly curable but risk significant long-term toxic effects with standard therapy. This study investigated a de-escalation strategy of decreased adjuvant radiation therapy and chemotherapy after transoral robotic surgery, and reports on long-term functional and quality of life (QOL) outcomes. Eligible patients had a p16-positive oropharyngeal cancer and ≤10 pack-year smoking history and underwent surgery followed by treatment with either 30 Gy delivered in 1.5-Gy fractions twice per day over 2 weeks with weekly docetaxel (15 mg/m2) if they had intermediate pathologic risk factors or 36 Gy in 1.8-Gy fractions twice per day over 2 weeks with the same chemotherapy if they had extranodal extension. Toxic effects, swallow function, and QOL were measured longitudinally. Seventy-nine patients (89.9% male) were treated and eligible for toxic effect and functional evaluation. Dry mouth was the most common grade 1 toxic effect at 1 year (55.6%), 2 years (53.3%), and 3 years (49.2%). The cumulative rates of grade 2 toxic effects at 1, 2, and 3 years were 1.4%, 6.7%, and 6.8%, respectively. There were only 2 grade 3 toxic effects at ≥1 year, including a grade 3 fatigue at 2.5 years, and a grade 3 superficial soft tissue fibrosis at 4 years. There were no grade 4 to 5 toxic effects. No patients were percutaneous endoscopic gastrostomy-dependent. Swallow function improved by 12 months posttreatment. QOL improved over time by all measurement tools and most patients returned to baseline level of function and QOL. De-escalated adjuvant therapy for select patients with human papillomavirus oropharyngeal cancer resulted in low rates of long-term toxic effects, excellent swallow outcomes, and preservation of global and xerostomia-related QOL.

A novel predictor for the use of concurrent chemotherapy in early-stage cervical cancer with intermediate-risk factors.

e17521 Background: For early-stage cervical cancer patients experiencing radical surgery, postoperative radiotherapy was recommended for patients with a combination of intermediate-risk factors. However, there was no consensus on whether to administer concurrent chemotherapy. The aim of the study was to confirm the clinical value of the controlling nutritional status (COUNT) score in guiding the use of concurrent chemotherapy in patients with early-stage cervical cancers during postoperative radiotherapy. Methods: A total of 945 patients with FIGO stage IB-IIA (2009) cervical cancer were retrospectively analyzed in the study from 2009 to 2018. There were 503 patents receiving concurrent chemoradiotherapy, while another 442 patents undergone radiotherapy lonely. Radiotherapy was performed by conformal radiotherapy or intensity-modulated radiotherapy. The concurrent chemotherapy regimen included either cisplatin or paclitaxel. Pre-treatment CONUT score were calculated within 1 weeks before curative resection. Low CONUT group and high CONUT group were defined based on the cutoff value of CONUT score which was determined by the receiver operating characteristic analysis. Kaplan-Meier survival analysis was performed to compare disease-free survival (DFS) and cancer-specific survival (CSS) rates between different group. A Cox proportional hazards regression test was used to conduct multivariate analyses of DFS, local recurrence-free survival and distant metastasis-free survival (DMFS). Results: The median follow-up was 54.6 months (range: 4.8-147.5 months). The optimal cutoff value of CONUT was 3 in the study. For the patients included in the high CONUT group (≥3), the addition of concurrent chemotherapy significantly improved treatment outcomes, and had better 5-year DFS (90.37% vs 70.69%, P &lt; 0.001) and CSS (95.02% vs 78.74%, P = 0.005) than those without it. Meanwhile, the patients with concurrent chemotherapy had less rate of distant metastasis (6.5% vs 28.1%, P &lt; 0.001). For the patients included in low CONUT group (&lt; 3), there was no difference in prognosis between patients receiving concurrent chemotherapy and not receiving. In the high CONUT group, the multivariate analysis showed that concurrent chemotherapy was detected to be a factor significantly associated with DFS (HR 3.077; 95% CI: 1.295-6.679, P = 0.011) and DMFS (HR 3.435; 95% CI: 1.506-7.014, P = 0.006). Conclusions: Pre-treatment CONUT score may be a predictive factor for the use of concurrent chemotherapy in early-stage cervical cancer patients with intermediate-risk factors during postoperative radiotherapy, and it can be helpful to determine the adjuvant treatment scheme.

Pathway-specific population attributable fractions.

A population attributable fraction represents the relative change in disease prevalence that one might expect if a particular exposure was absent from the population. Often, one might be interested in what percentage of this effect acts through particular pathways. For instance, the effect of a sedentary lifestyle on stroke risk may be mediated by blood pressure, body mass index and several other intermediate risk factors. We define a new metric, the pathway-specific population attributable fraction (PS-PAF), for mediating pathways of interest. PS-PAFs can be informally defined as the relative change in disease prevalence from an intervention that shifts the distribution of the mediator to its expected distribution if the risk factor were eliminated, and sometimes more simply as the relative change in disease prevalence if the mediating pathway were disabled. A potential outcomes framework is used for formal definitions and associated estimands are derived via relevant identifiability conditions. Computationally efficient estimators for PS-PAFs are derived based on these identifiability conditions. Calculations are demonstrated using INTERSTROKE-an international case-control study designed to quantify disease burden attributable to a number of known causal risk factors. The applied results suggest that mediating pathways from physical activity through blood pressure, blood lipids and body size explain comparable proportions of stroke disease burden, but a large proportion of the disease burden due to physical inactivity may be explained by alternative pathways. PS-PAFs measure disease burden attributable to differing mediating pathways and can generate insights into the dominant mechanisms by which a risk factor affects disease at a population level.

A real-world retrospective study of the use of Ki-67 testing and treatment patterns in patients with HR+, HER2− early breast cancer in the United States

BackgroundThe National Comprehensive Cancer Network recommends that patients with hormone receptor-positive early breast cancer be considered for adjuvant endocrine therapy (ET) after primary treatment like surgical excision. Adjuvant chemotherapy (CT) use primarily depends on risk of recurrence. Biomarkers such as Ki-67 potentially have most value in patients with intermediate risk factors, such as involvement of 1–3 positive nodes. This study evaluated the use of Ki-67 testing and treatment patterns in patients with HR+, human epidermal growth factor receptor 2-negative early breast cancer.MethodsThis was an observational retrospective cohort study of patients with electronic medical records from January 2010 to August 2018 treated for HR+, HER2− early breast cancer at Sarah Cannon sites in the United States (US). Overall, 567 patients were randomly selected after using the eligibility criteria: female or male ≥18 years, without distant metastases, and with available physician and pathology reports. Multivariable logistic regression was used to investigate factors predicting Ki-67 testing and test results. Descriptive analyses were applied to treatment patterns.ResultsMultivariable logistic regression analyses found no clinical or pathological factors that predicted whether Ki-67 testing had been ordered by physicians. Of all tested patients (N = 130), having Grade-2 tumors (OR, 7.95 [95% CI: 2.05, 30.9]; p = 0.0027) or Grade-3 tumors (OR, 95.3 [95% CI, 11.9, 760.7]; p < 0.001) at initial diagnosis was a predictor of high Ki-67 expression (≥20%). Ki-67 expression was tested in 23.6% (61/258) of patients with 1–3 positive nodes; 54.1% of them (33/61) had high Ki-67 expression (≥20%). While having a higher grade tumor predicted high Ki-67 (≥20%), 28.6% of patients with Grade-1 tumors also had high Ki-67 expression. Neo-adjuvant therapy was received by 16.0% of patients (91/567), most of whom (66/91; 72.5%) received CT alone. Adjuvant therapy, either endocrine and/or chemotherapy, was received by 92.6% (525/567) of patients and by 67.0% (61/91) of those who received neo-adjuvant therapy. Most (428/525, 81.5%) received ET in the adjuvant treatment setting.ConclusionsHigh grade tumors predicted high Ki-67 (≥20%) expression, but Ki-67 testing was not widely used in these US patients. Most HR+, HER2− early breast cancers were treated with adjuvant ET, with or without CT.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12885-022-09557-6.

High-dose radiotherapy and risk-adapted androgen deprivation in localised prostate cancer (DART 01/05): 10-year results of a phase 3 randomised, controlled trial

The optimal duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains controversial. The DART 01/05 trial was designed to determine whether long-term androgen deprivation is superior to short-term androgen deprivation when combined with high-dose radiotherapy. The 5-year results showed that 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy significantly improved biochemical control, metastasis, and overall survival, especially in patients with high-risk disease. In this report, we present the 10-year final results of the trial. This open-label, phase 3, randomised, controlled trial was done in ten hospitals in Spain. The eligibility criteria included patients aged 18 years or older with histologically confirmed T1c to T3, N0, and M0 adenocarcinoma of the prostate, according to the 2002 classification of the American Joint Committee on Cancer, with intermediate-risk and high-risk factors, prostate-specific antigen (PSA) less than 100 ng/mL, and a Karnofsky performance score of at least 70%. Patients were randomly assigned (1:1) to receive 4 months of neoadjuvant and concomitant short-term androgen deprivation (STAD) plus high-dose radiotherapy (minimum dose 76 Gy; median dose 78 Gy) or to receive the same treatment followed by 24 months of adjuvant long-term androgen deprivation (LTAD), via a randomisation scheduled generated by Statistical Analysis Software programme (version 9.1) and an interactive web response system. Patients assigned to the STAD group received 4 months of neoadjuvant and concomitant androgen deprivation (oral flutamide 750 mg per day or oral bicalutamide 50 mg per day) with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy was added during the first 2 months of treatment. Patients assigned to LTAD continued with goserelin every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival at 5 years. For this 10-year study we analysed overall survival, metastasis-free survival, biochemical disease-free survival, and cause-specific survival. Analysis was by intention to treat. This trial is closed and is registered at ClinicalTrials.gov (NCT02175212) and in the EU Clinical Trials Register (EudraCT 2005-000417-36). Between Nov 7, 2005, and Dec 20, 2010, 355 patients were enrolled. One patient in the STAD group withdrew from the trial, hence 354 participants were randomly assigned to STAD (n=177) or LTAD (n=177). The median follow-up was 119·4 months (IQR 100·6-124·3). The 10-year biochemical disease-free survival for LTAD was 70·2% (95% CI 63·1-77·3) and for STAD was 62·3% (54·9-69·7; hazard ratio [HR] 0·84; 95% CI 0·50-1·43; p=0·52). At 10 years, overall survival was 78·4% (72·1-84·8) for LTAD and 73·3% (66·6-80·0) for STAD (HR 0·84; 95% CI 0·55-1·27; p=0·40), and metastasis-free survival was 76·0% (69·4-82·7) for LTAD and 70·9% (64·0-77·8) for STAD (HR 0·90; 95% CI, 0·37-2·19; p=0·81). For the subgroup of high-risk patients, the 10-year biochemical disease-free survival was 67·2% (57·2-77·2) for LTAD and 53·7% (43·3-64·1) for STAD (HR 0·90; 95% CI 0·49-1·64; p=0·73), the 10-year overall survival was 78·5% (69·6-87·3) for LTAD and 67·0% (57·3-76·7) for STAD (HR 0·58; 95% CI 0·33-1·01; p=0·054), and the 10-year metastasis-free survival was 76·6% (95% CI 67·6-85·6) for LTAD and 65·0% (55·1-74·8) for STAD (HR 0·89; 95% CI 0·33-2·43; p=0·82). Only 11 (3%) of 354 patients died from prostate cancer, all of them in the high-risk subgroup (five in the LTAD group and six in the STAD group). 76 (21%) patients died from other causes (mainly second malignancies in 31 [9%] and cardiovascular disease in 21 [6%]). No treatment-related deaths were observed. After an extended 10-year follow-up, we were unable to support the significant benefit of LTAD reported at 5 years. However, the magnitude of the benefit was clinically relevant in high-risk patients. Intermediate-risk patients treated with high-dose radiotherapy do not benefit from LTAD. A biological characterisation with the inclusion of genomic testing is needed in the decision-making process. Grupo de Investigación en Oncología Radioterápica and Sociedad Española de Oncología Radioterápica, the National Health Investigation Fund, and AstraZeneca.

Acute Side-effects of Different Radiotherapy Treatment Schedules in Early Prostate Cancer.

Optimal radiation therapy (RT) fractionation in early prostate cancer in elderly patients is controversial. We compared acute toxicities of fractionation schedules: 78/2 Gy, 60/3 Gy and 36.25/7.25 Gy, in this single-centre study. We also evaluated the effect of the rectal immobilization system Rectafix on quality of life (QoL). Seventy-three patients with one or two intermediate prostate cancer risk factors according to National Comprehensive Cancer Network criteria were recruited. Twenty-one patients were treated with 78/2 Gy and 60/3 Gy, and 31 patients with 36.25/7.25 Gy. Their QoL data were assessed with regard to genitourinary, gastrointestinal and sexual wellbeing at the beginning and end of RT and at 3 months after treatment. Rectafix was used in the 78/2 Gy and 60/3 Gy groups. There were no statistically significant QoL differences in between the treatment groups 3 months after RT. The 78/2 Gy group had significantly increased bowel movements between baseline and 3 months after RT (p=0.036). At 3 months after RT, this group also had significantly more erectile dysfunction than the 60/3 Gy group (p=0.025). At the end of RT, the 78/2 Gy group had more symptoms than the 36.25/7.25 Gy group. Rectafix did not reduce acute toxicities in the 78/2 Gy or 60/3 Gy groups. Treatment with the 78/2 Gy schedule is no longer to be recommended due to its increased acute toxicity compared to treatments of 60/3 Gy and 36.25/7.25 Gy. The shortest schedule of 36.25 Gy in five fractions seems to be a convenient treatment option with tolerable acute toxicity.

Non-Inferiority Margin and Nodal Analysis of De-Escalated Adjuvant Radiation Therapy (DART) for HPV-Related Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Preplanned Pooled Analysis of MC1273 & MC1675

<h3>Purpose/Objective(s)</h3> We previously reported the results of phase II/III trials (MC1273 & MC1675) evaluating 30-36 Gy of adjuvant radiation therapy for patients with HPV+ OPSCC. Herein we report the results of a pre-planned pooled analysis of MC1273/MC1675 designed to test whether the pooled PFS was statistically non-inferior to the PFS target of NRG HN005. <h3>Materials/Methods</h3> Pts who received DART on MC1675, or pts on MC1273 who fit MC1675 criteria were included in this analysis. All pts underwent margin clearing surgery and neck dissection. Pts with pT4 disease or required >2 attempts to clear margins were excluded. Pts with intermediate risk factors received 30 Gy/1.5 Gy b.i.d. + docetaxel 15 mg/m2 days 1 & 8, while pts with extranodal extension (ENE) simultaneously received 36 Gy/1.8 Gy b.i.d. to ENE+ nodal levels. A pooled analysis was performed on LRC, PFS, and OS using survivorship methodology, including Kaplan-Meier estimation. Pooled 2-yr PFS for the total cohort and subgroups were compared with the PFS non-inferiority margin for HN005 (86.9-92.3%). Cox proportional hazards regression analysis was performed to evaluate the effect of nodal and ENE status on survival outcomes. OS, PFS and LRC were evaluated using Chi-square tests. <h3>Results</h3> Accrual at Mayo Clinic Rochester and Arizona was from 2013 – 2020: MC1273: 72 pts, MC1675/DART: 130 pts, 202 total.) Median follow-up as of 10/21 was 36.6 months. 2 year estimates and 95% CI of OS, LRC, PFS for de-escalated pts can be found in Table 1. The hazard ratios (HR) for ENE status was OS 2.07 (p=0.39); LRC undefined (p=0.99); PFS 3.95 (p=0.015). HR for AJCC 8 pN2 was OS 5.78 (p=0.014), LRC 2.29 (p=0.23), PFS 4.11 (p=0.001). <h3>Conclusion</h3> Pooled PFS for MC1273/1675 (91.1%) was non-inferior to the target PFS for HN005 (92.3%, p = 0.29), and was also significantly above the HN005 acceptable PFS threshold of 86.9% (p=0.043). All ENE/pN subgroups also had PFS significantly above the 86.9% threshold except for the ENE+/pN2 cohort. On multivariate analysis, nodal status was a stronger predictor of OS than ENE. Analyses for extent of ENE and AJCC 7 N stage will be available for the meeting.

Overweight, Obesity, and CVD Risk: a Focus on Visceral/Ectopic Fat.

Despite its prevalence and well-documented impact on population health, obesity has not emerged as a strong independent risk factor for cardiovascular disease after control for intermediate risk factors. The purpose of this brief narrative review is to highlight results from imaging studies that have not only documented the remarkable heterogeneity of body fat topography but also the importance of visceral adiposity as a key body fat depot associated with cardiovascular disease risk and type 2 diabetes. Simple tools are also discussed in order to refine cardiometabolic risk assessment in persons with overweight/obesity. It is proposed that four lifestyle vital signs should be considered in clinical practice to improve discrimination of health risk in individuals with overweight/obesity: waist circumference as a simple marker of abdominal adiposity, cardiorespiratory fitness, overall diet quality, and level of reported physical activity. Heterogeneity of obesity is proposed as an example of a condition that would benefit from a precision lifestyle medicine approach.