The use of statins was associated with a 47 percent relative reduction in the risk of colorectal cancer after adjustment for other known risk factors. Because the absolute risk reduction is likely low, further investigation of the overall benefits of statins in preventing colorectal cancer is warranted.
The phenotypic markers of colorectal carcinomas with microsatellite instability have been widely studied and include mucinous or poor differentiation, prominent host response, a circumscribed growth pattern, histologic heterogeneity, and right-sided location. As part of a population-based case-control study of colorectal cancer in northern Israel, we reviewed the pathology and microsatellite status of 528 consecutively diagnosed colorectal cancers. Phenotypic analysis was performed by one pathologist (J.K.G.) and included assessment of grade, mucinous histology (>50%, or focal), histologic heterogeneity, growth pattern, necrosis, and host response. Microsatellite status was determined on microdissected portions of formalin-fixed, paraffin-embedded tissue using a panel of 5 NCI consensus primers. Fifty-two of 528 colorectal carcinomas were microsatellite unstable (9.85%). Multivariate analysis found that >2 tumor infiltrating lymphocytes per high power field (p <0.0001), the lack of dirty necrosis (p = 0.0054), a Crohn's-like host response (p = 0.0064), right-sided location (p = 0.032), well or poor differentiation (p = 0.037), and any mucinous differentiation (p = 0.039) were independent predictors of microsatellite instability. Tumor infiltrating lymphocytes were the single best histologic predictor of microsatellite instability. The absence of dirty necrosis and the presence of well-differentiated tumors and tumors with only focal mucinous differentiation were also important markers for microsatellite instability that have not been emphasized previously. The combination of >2 tumor infiltrating lymphocytes per high power field and/or any mucinous differentiation and/or the absence of dirty necrosis identified all MSI-H tumors in this study.
IMPORTANCEThe efficacy and safety profile of SARS-CoV-2 vaccines have been acquired from phase 3 studies; however, patients with cancer were not represented in these trials. Owing to the recommendation to prioritize high-risk populations for vaccination, further data are warranted.OBJECTIVE To evaluate the use and safety of the BNT162b2 vaccine in patients undergoing treatment for cancer.
DESIGN, SETTING, AND PARTICIPANTSIn January 2021, mass SARS-CoV-2 vaccination of high-risk populations, including patients with cancer, was initiated in Israel. This cohort study prospectively enrolled and followed up patients with cancer and healthy participants between January 15 and March 14, 2021. The study was conducted at the Division of Oncology of Rambam Health Care Campus, the major tertiary (referral) medical center of northern Israel. Participants included 232 patients with cancer who were receiving active treatment after the first and second doses of the BNT162b2 vaccine and 261 healthy, age-matched health care workers who served as controls.EXPOSURES Serum samples were collected after each vaccine dose and in cases of seronegativity. Questionnaires regarding sociodemographic characteristics and adverse reactions were administered at serum collection. A regulatory agencies-approved assay was used to assess IgG at all time points. Patients' electronic medical records were reviewed for documentation of COVID-19 infection and results of blood cell counts, liver enzyme levels, and imaging studies.
MAIN OUTCOMES AND MEASURESSeroconversion rate after the first and second doses of the BNT162b2 vaccine and documented COVID-19 infection.
RESULTSOf the 232 patients undergoing treatment for cancer, 132 were men (57%); mean (SD) age was 66 (12.09) years. After the first dose of BNT162b2 vaccine, 29% (n = 25) patients were seropositive compared with 84% (n = 220) of the controls (P < .001). After the second dose, the seropositive rate reached 86% (n = 187) in the patients. Testing rate ratios per 1000 person-days after the first dose were 12.5 (95% CI, 3.4-45.7) for the patients and 48.5 (95% CI, 37.2-63.2) for the controls. Patients undergoing chemotherapy showed reduced immunogenicity (odds ratio, 0.41; 95% CI, 0.17-0.98). In seronegative patients, the rate of documented absolute leukopenia reached 39%. No COVID-19 cases were documented throughout the study period; however, 2 cases in the patient cohort were noted immediately after the first dose. Reported adverse events were similar to data in former trials comprising mostly healthy individuals.
CONCLUSIONS AND RELEVANCEIn this cohort study, the SARS-CoV-2 BNT162b2 vaccine appeared to be safe and achieve satisfactory serologic status in patients with cancer. There was a pronounced lag in antibody production compared with the rate in noncancer controls; however, seroconversion occurred in most patients after the second dose. Future real-world data are warranted to determine the long-term efficacy of the vaccine with regard to type of anticancer treatment.
SUMMARY BackgroundAdalimumab is an effective treatment for Crohn's disease (CD). Antiadalimumab antibodies (AAA) and low trough serum drug concentrations have been implicated as pre-disposing factors for treatment failure.
Glucocorticoid-initiated granulocytosis, excessive proliferation of granulocytes, persists after cortisol levels are lowered, suggesting the involvement of additional stress mediator(s). In this study, we report that the stress-induced acetylcholinesterase variant, AChE-R, and its cleavable, cell-penetrating C-terminal peptide, ARP, facilitate granulocytosis. In postdelivery patients, AChE-R-expressing granulocyte counts increased concomitantly with serum cortisol and AChE activity levels, yet persisted after cortisol had declined. Ex vivo, mononuclear cells of adult peripheral blood responded to synthetic ARP26 by overproduction of hemopoietically active proinflammatory cytokines (e.g., IL-6, IL-10, and TNF-α). Physiologically relevant ARP26 levels promoted AChE gene expression and induced the expansion of cultured CD34+ progenitors and granulocyte maturation more effectively than cortisol, suggesting autoregulatory prolongation of ARP effects. In vivo, transgenic mice overexpressing human AChE-R, unlike matched controls, showed enhanced expression of the myelopoietic transcription factor PU.1 and maintained a stable granulocytic state following bacterial LPS exposure. AChE-R accumulation and the consequent inflammatory consequences can thus modulate immune responses to stress stimuli.
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