What Are the Health Risks of Eating Red Meat, and How Should We Assess Them?

This paper discusses possible mechanisms that might lead to misinterpretations of collected data and makes new evidence-based medicine (EBM) recommendations to oppose the previously accepted preventive measures, or treatment options. It is focused on the danger of the "red meat" consumption, and the question whether eating pungent food is good or bad for our health and finally whether the "bad luck" concept of getting several cancer types is valid or not. These three topics got and still have significant media attention. Several mechanisms are proposed as possible causes of these apparent conflicts. Some of them have already been recognized but sadly remained less known to medical readers and also to the general population. Also see the video abstract here https://youtu.be/owjoRXrNShA.

The Will Rogers phenomenon, breast cancer and race.

BACKGROUND: The Will Rogers phenomenon [WRP] describes an apparent improvement in outcome for patients' group due to tumor grade reclassification. Staging of cancers is important to select appropriate treatment and to estimate prognosis. The WRP has been described as one of the most important biases limiting the use of historical cohorts when comparing survival or treatment. The main purpose of this study is to assess whether the WRP exists with the move from the AJCC 7th to AJCC 8th edition in breast cancer [BC] staging, and if racial differences are manifested in the expression of the WRP. METHODS: This is a retrospective analysis of 300 BC women (2007-2017) at an academic medical center. Overall survival [OS] and disease-free survival [DFS] was estimated by Kaplan-Meier analysis. Bi and multi-variate Cox regression analyses was used to identify racial factors associated with outcomes. RESULTS: Our patient cohort included 30.3% Caucasians [Whites] and 69.7% African-Americans [Blacks]. Stages I, II, III, and IV were 46.2, 26.3, 23.1, and 4.4% of Whites; 28.7, 43.1, 24.4, and 3.8% of Blacks respectively, in anatomic staging (p = 0.043). In prognostic staging, 52.8, 18.7, 23, and 5.5% were Whites while 35, 17.2, 43.5, and 4.3% were Blacks, respectively (p = 0.011). A total of Whites (45.05% vs. 47.85%) Blacks, upstaged. Whites (16.49% vs. 14.35%) Blacks, downstaged. The remaining, 38.46 and 37.79% patients had their stages unchanged. With a median follow-up of 54 months, the Black patients showed better stage-by-stage 5-year OS rates using 8th edition compared to the 7th edition (p = 0.000). Among the Whites, those who were stage IIIA in the 7th but became stage IB in the 8th had a better prognosis than stages IIA and IIB in the 8th (p = 0.000). The 8th showed complex results (p = 0.176) compared to DFS estimated using the 7th edition (p = 0.004). CONCLUSION: The WRP exists with significant variability in the move from the AJCC 7th to the 8th edition in BC staging (both White and Black patients). We suggest that caution needs to be exercised when results are compared across staging systems to account for the WRP in the interpretation of the data.

A simple method for correcting for the Will Rogers phenomenon with biometrical applications.

In its basic form, the Will Rogers phenomenon takes place when an increase in the average value of each of two sets is achieved by moving an element from one set to another. This leads to the conclusion that there has been an improvement, when in fact essentially nothing has changed. Extended versions of this phenomenon can occur in epidemiological studies, rendering their results unreliable. After describing epidemiological and clinical studies that have been affected by the Will Rogers phenomenon, this paper presents a simple method to correct for it. The method involves introducing a transition matrix between the two sets and taking probability weighted expectations. Two real-world biometrical examples, based on migration economics and breast cancer epidemiology, are given and improvements against a naïve analysis are demonstrated. In the cancer epidemiology example, we take account of estimation uncertainty. We also discuss briefly some limitations associated with our method.

Pathologic staging changes in oral cavity squamous cell carcinoma: Stage migration and implications for adjuvant treatment.

BACKGROUND: The eighth edition of the AJCC Cancer Staging Manual (AJCC 8) incorporates depth of invasion (DOI) into the pathologic tumor (pT) classification and pathologic extranodal extension (pENE) into the pathologic nodal (pN) classification for oral cavity squamous cell carcinoma (OCSCC). This study evaluated the incidence and prognostic importance of stage migration as a result of these changes in the AJCC 8 staging system. METHODS: From the National Cancer Database, cohorts were identified from patients with OCSCC undergoing definitive surgery between 2004 and 2013 for pT (n = 7184), pN (n = 13,627), and pathologic stage (pStage) analysis (n = 5580). RESULTS: DOI and pENE were prognostic in all groups except for pN3 according to the seventh edition of the AJCC Cancer Staging Manual (AJCC 7). Upstaging was seen in 12.4% of patients for the pT classification, in 13.3% for the pN classification, and in 24.8% for the overall pStage grouping. Notably, upstaging led to similar or improved 5-year overall survival (OS) for every AJCC 8 pT/N classification except pStage IVB. Patients with AJCC 7 pT1 tumors that were upstaged to AJCC 8 pT3 tumors had improved OS in comparison with the remainder of the pT3 group (71.7% vs 43.7%; P < .0001). A multivariable analysis of upstaged pT3N0 patients demonstrated a reduced risk of death with the receipt of postoperative radiotherapy (PORT; hazard ratio, 0.56; 95% confidence interval, 0.33-0.95; P = .03). CONCLUSIONS: Upstaging is common in AJCC 8, and patients with upstaged tumors demonstrate improved survival; these factors should be kept in mind when one is interpreting data with the new staging system. PORT may reduce deaths among newly upstaged pT3N0 patients, and further study is needed in this area.

Targeted biopsy of the prostate: does this result in improvement in detection of high-grade cancer or the occurrence of the Will Rogers phenomenon?

OBJECTIVE: To investigate whether patients with Gleason 3 + 4 cancer on transrectal biopsy are upgraded after undergoing transperineal magnetic resonance imaging (MRI)-targeted biopsy and whether this has implications for current clinical practice. PATIENTS AND METHODS: In this retrospective analysis we examined 107 consecutive patients presenting at a single tertiary referral centre (July 2012 to July 2016) with prostate cancer of Gleason score 3 + 4 on transrectal ultrasonography (TRUS)-guided systematic non-targeted biopsy who then underwent a multiparametric MRI followed by MRI-targeted transperineal prostate biopsy for accurate risk stratification and localization. RESULTS: The patients' mean (sd) age was 67.0 (8.0) years, and they had a median (interquartile range) PSA concentration of 6.2 (4.7-9.6) ng/mL. Of the 107 patients, 84 (78.5%) had Gleason 3 + 4 on both transrectal systematic biopsy and transperineal MRI-targeted biopsy. Nineteen patients (17.8%) were upgraded to Gleason 4 + 3, three patients (3.0%) to Gleason 4 + 4 and one patient (1.0%) to Gleason 4 + 5. These differences were significant (P = 0.0006). Likewise, 23/107 patients (22%) had higher-risk disease based on their targeted biopsies. CONCLUSION: The use of targeted biopsy in men with impalpable cancer, ultimately upgraded one in five patients from favourable-intermediate- to unfavourable-intermediate-risk disease or worse. This has significant clinical implications for men considering active surveillance or radical treatment. Our risk calculators must now be validated using these data from targeted biopsy as the technique becomes widely adopted.

Downstage migration after neoadjuvant chemoradiotherapy for rectal cancer: the reverse of the Will Rogers phenomenon?

Downstaging after neoadjuvant treatment is increasingly used as a prognostic factor and surrogate endpoint in clinical trials. However, in recent trials of neoadjuvant 5-fluorouracil-based chemoradiotherapy for rectal cancer, downstaging did not translate into a benefit with regard to either disease-free survival (DFS) or overall survival. By analyzing the 10-year outcome data of the German CAO/ARO/AIO-94 phase 3 trial, the authors demonstrated that significantly fewer patients had poor prognostic features (eg, ypT3-4, ypN1-2) after preoperative 5-fluorouracil-based chemoradiotherapy. Nevertheless, these patients with International Union for Cancer Control stage II disease were found to be at a higher risk of developing distant metastases and had poorer DFS compared with patients with corresponding TNM tumor (sub)groups in the postoperative treatment arm, whereas patients with International Union for Cancer Control stage III disease demonstrated a nonsignificant trend toward a worse outcome after preoperative treatment. Overall, DFS remained identical in both treatment arms. Thus, "downstage migration" after neoadjuvant treatment resembles the reverse of the Will Rogers phenomenon and therefore may not be a reliable endpoint for long-term outcomes.

Potential causes of stage migration and their prognostic implications in colon cancer: a nationwide survey of specialist institutions in Japan.

OBJECTIVE: The actual status of stage migration in colon cancer that occurs in the procedure of preparing pathological specimens of lymph nodes has not been fully investigated. METHODS: A nationwide survey of specialist institutions for colon cancer treatment was conducted to clarify interinstitutional differences in processing surgical specimens. After categorizing 111 institutions on the basis of their practice of processing specimens, distribution of tumor stage and the recurrence status of 3294 colon cancer patients treated with the same level of lymphadenectomy were compared. RESULTS: Patients were diagnosed with lower tumor stages in non-teaching hospitals, in hospitals where lymph nodes were retrieved by less experienced clinicians and in hospitals in which lymph nodes were retrieved with procedures that preserved the planes of surgery around the primary tumor. However, the process of sectioning and embedding lymph nodes did not affect stage distribution. The average number of lymph nodes examined per case in each institute was 19.4. Institutional number of lymph nodes examined was not associated with node positivity but it did affect the substage in Stage III for number of lymph nodes examined ≥21. In contrast, none of the factors associated with stage migration caused interinstitutional differences in the recurrence status according to the tumor stage. CONCLUSIONS: Considerable variety in the processing of surgical specimens existed even within one country, which could be a cause of stage migration in colon cancer. Better awareness of the clinical impact of the lymph node retrieval process is needed; an international guideline to standardize the treatment of surgical specimens might increase the value of tumor staging.

Incidence and Dynamics of CRC Stage Migration: A Regional vs. a National Analysis.

BACKGROUND/OBJECTIVES: Due to an increased rate of surveillance colonoscopy, we aim to determine the impact of stage migration on the incidence and overall survival (OS) of patients who underwent pathological staging of colorectal cancer (CRC) at our Health Network System. METHODS: Two datasets were included: subjects from the tumor registry at a regional Comprehensive Cancer Center (n = 1385) and subjects from the Surveillance, Epidemiology, and End Results (SEER) national database (n = 202,391). RESULTS: A significant increase in the diagnosis of CRC Stage 1 and 4 was observed, with a decrease in stage 2, and no change in Stage 3 in the National datasets (p < 0.01). There was an increase in Stage 4 CRC diagnosis, with a concurrent decrease in stage 2, and no changes in stages 1 and 3 in the regional dataset (p < 0.05). OS followed the expected and progressive decrease in OS by stage (from 1 to 4, p < 0.01). CONCLUSIONS: The present findings confirmed CRC stage migration in our Health Network System, along with a national trend conducive to an increased OS for early CRC stages.

The impact of local staging of prostate cancer determined on MRI or DRE at time of radical prostatectomy on progression-free survival: A Will Rogers phenomenon.

INTRODUCTION: We aimed to test whether the current practice of using mpMRI stage might lead to a Will Rogers phenomenon with a stage migration compared to DRE in men undergoing radical prostatectomy. MATERIAL AND METHODS: A total of 572 consecutive patients who underwent radical prostatectomy at a single institution (2007-2017) were included. Clinical stage using digital rectal examination was determined on table by the operating surgeon; mpMRI and pathological stage were recorded after tumor board review. Progression-free survival (PFS) was defined as no rising PSA, no adjuvant/salvage treatment, and no metastases or mortality. PFS was compared between groups and a model incorporating mpMRI into the EAU risk groups was created. RESULTS: Median age was 63 years (IQR 58.5-67) and median PSA was 8.9 ng/ml (IQR 6.5-13.2). Using DRE stage, 20% were NCCN low risk, 43% were intermediate, and 37% high. Median follow-up was 48 months (IQR 22-73). Estimated PFS at 1, 3, and 5 years was 75%, 59%, and 54%, respectively. When comparing PFS between DRE and mpMRI stages, patients deemed T1 (P < 0.01) or T3 (P = 0.03) by mpMRI showed better outcomes than patients staged T1 or T3 by DRE. On univariable analysis lower risk for failure was seen for MRI T1 disease (HR 0.10 95%, CI 0.01-0.73, P = 0.02) or MRI T3 (HR 0.70, CI 0.51-0.97, P = 0.03). On multivariable analysis, only MRI T1 remained a significant predictor (HR 0.08, 95% CI 0.01-0.59, P = 0.01). The subsequent, modified EAU risk model using both DRE and mpMRI performed significantly better than the DRE model. CONCLUSION: PFS based on mpMRI is not the same as DRE staging. Current risk groups which use DRE should be used with caution in whom local stage is based on mpMRI. Our modified EAU-risk categories can provide greater accuracy.

The Will Rogers phenomenon in the staging of breast cancer - does it matter?

INTRODUCTION: Changes in the American Joint Commission on Cancer staging for breast cancer occurred when the 5th Edition was updated to the 6th Edition. OBJECTIVE: To investigate how these changes affected stage and survival. METHODS: 3127 cases of breast cancer were restaged. RESULTS: Late stages increased from 27.7% to 38.1%. The five-year survival improved in Stage 2 (82.9-86.1%) and Stage 3 (50.6-59%). DISCUSSION: Stage shift leads to an erroneous impression that women are presenting with later stages and stage-specific survival is improving. CONCLUSION: Standardizing cancer staging is important when reporting stage and survival in different time periods.

The diagnostic criteria for multiple sclerosis: From Charcot to McDonald.

The history of diagnostic criteria for multiple sclerosis (MS) from Charcot to McDonald is reviewed. Although the criteria have evolved positively with each revision we think there is still room for improvement. It is proposed that the 2010 revision to the McDonald criteria should be used for research or drug trials and comprise two categories: 'MS' and 'Not MS'. McDonald 2010 could be used optionally for routine clinical purposes. The categories 'probable' and 'possible' are permissible for everyday clinical activity, particularly where there is limited access to MRI, but they would not be appropriate for research or drug trials. Future updates should make it mandatory to perform MRI of the brain, and possibly spinal cord, and the definition of 'an attack' should be revised to include information from physical examination or MRI. Finally, we suggest that certain paroxysmal symptoms (e.g. Lhermitte phenomenon) should be incorporated in any further revision.