ABSTRACT
Dysregulation of the innate immune system and inflammatory-related pathways has been implicated in hematopoietic defects in the bone marrow microenvironment and associated with aging, clonal hematopoiesis, myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). As the innate immune system and its pathway regulators have been implicated in the pathogenesis of MDS/AML, novel approaches targeting these pathways have shown promising results. Variability in expression of Toll like receptors (TLRs), abnormal levels of MyD88 and subsequent activation of NF-κß, dysregulated IL1-receptor associated kinases (IRAK), alterations in TGF-ß and SMAD signaling, high levels of S100A8/A9 have all been implicated in pathogenesis of MDS/AML. In this review we not only discuss the interplay of various innate immune pathways in MDS pathogenesis but also focus on potential therapeutic targets from recent clinical trials including the use of monoclonal antibodies and small molecule inhibitors against these pathways.
ABSTRACT
BACKGROUND: Anatomic extent of ductal carcinoma in situ (DCIS) may be uncertain in spite of clinical, pathologic, and imaging data. Consequently close/positive margins are common with lumpectomy for DCIS and often lead to a challenge in deciding whether to perform a re-excision or mastectomy. PATIENTS AND METHODS: From a single health system, we identified cases of lumpectomy for DCIS with close/positive margins who underwent re-excision for the purpose of constructing a nomogram. In total, 289 patients were available for analysis. The patients were randomly divided into two sets allocating 70% to the modeling and 30% to the validation set. A multivariable logistic regression model was used to estimate the probability of overall positive margin status using multiple clinicopathologic predictors. Nomogram validation included internal tenfold cross-validation, internal bootstrap validation, and external validation for which a concordance index was calculated to assess the external validity. RESULTS: Significant predictors of persistent positive margins from regression modeling included necrosis at diagnosis (non-comedo or comedo); DCIS not associated with calcifications on core biopsy; high-grade DCIS; progesterone receptor positivity; and number of positive margins at initial surgery. When subjected to internal validation, the nomogram achieved an uncorrected concordance index of 0.7332, a tenfold cross-validation concordance index of 0.6795, and a bootstrap-corrected concordance index of 0.6881. External validation yielded an estimated concordance index of 0.7095. CONCLUSION: Using clinical and pathologic variables from initial diagnosis and surgery for DCIS, this nomogram predicts persistent positive margins with margin re-excision, and may be a valuable tool in surgical decision-making.
Subject(s)
Breast Neoplasms , Carcinoma, Ductal, Breast , Carcinoma, Intraductal, Noninfiltrating , Breast Neoplasms/surgery , Carcinoma, Ductal, Breast/pathology , Carcinoma, Ductal, Breast/surgery , Carcinoma, Intraductal, Noninfiltrating/pathology , Carcinoma, Intraductal, Noninfiltrating/surgery , Female , Humans , Margins of Excision , Mastectomy , Mastectomy, Segmental , Neoplasm, Residual/surgery , Nomograms , Retrospective StudiesABSTRACT
AIMS: To characterize hypogonadism in male persons with diabetes mellitus. Patients and Methods. 184 consecutive male persons with diabetes were studied. Besides the usual care, total testosterone (TT), estradiol (E2), FSH, and LH were measured in the last appointment and in 40 patients, also in the next two appointments. Statistical analysis compared groups and explored factors for TT and LH levels. RESULTS: TT levels were stable and highly correlated (r > 0.750, p < 0.001) over a 6-12-month period. 20% of the patients presented secondary hypogonadism (SH) and 18% presented primary hypogonadism (PH). SH was inversely related to HbA1 (partial r (rp) = 0.229, p < 0.005), while PH was directly related to age (r = 0.356, p < 0.001). TT levels were reduced independently by metformin (364 ± 160 vs. 431 ± 242 ng/dL, t = 2.241, p < 0.05) and statins (359 ± 156 vs. 424 ± 230 ng/dl, t = 2.224, p < 0.05). TT levels were inversely related to microvascular disease (rp = -0.169, p < 0.05). Discussion. TT levels were stable over time and hypogonadism was common. SH, generally clinically, is related to the diabetic state, while PH, generally subclinically, is an age-dependent process unrelated to diabetes. Low TT levels were related to older age, poor metabolic control, metformin and statins use, and microvascular disease.
