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Fungal rhinosinusitis is a broad group of diseases that includes noninvasive and invasive forms with overlapping clinical presentations. While most cases of fungal rhinosinusitis follow an indolent clinical course, surgical pathologists play a crucial role in early identification of life-threating subtypes, specifically invasive fungal rhinosinusitis. This review describes fungal infections of the sinonasal tract and their histopathologic mimickers. Clinical, gross, and microscopic features that are important for diagnosis, as well as available ancillary studies, are discussed., Competing Interests: Disclosure The authors have no relevant conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants., Methods: The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages., Results: Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively., Conclusion: Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.

Purpose: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer., Methods: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years., Results: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer., Conclusion: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

Purpose: Pre-eclampsia is a multisystem disorder characterized by new-onset hypertension and proteinuria during pregnancy. Pre-eclampsia remains a major cause of maternal death in low-income countries. Vitamin D has a very diverse biological role in cardiovascular diseases. This study will evaluate the association of vitamin D levels and relevance to pre-eclampsia., Methods: We conducted a case-control study of women recruited from the GenPE (Genetics and Pre-eclampsia) Colombian registry. This is a multicenter case-control study conducted in eight Colombian cities. 25-Hydroxyvitamin D (25(OH)D) concentration was measured using liquid-chromatography-tandem mass spectrometry from 1013 women with pre-eclampsia and 1015 mothers without pre-eclampsia (controls)., Results: Fifty-two percent of women with pre-eclampsia were vitamin D deficient. The 25(OH)D concentrations were significantly lower in the pre-eclampsia (mean 29.99 ng/mL; 95% CI: 29.40-30.58 ng/mL) group compared to controls (mean 33.7 ng/mL; 95% CI: 33.20-34.30 ng/mL). In the unadjusted model, maternal vitamin D deficiency, defined by maternal 25(OH)D concentration <30 ng/mL, was associated with an increased probability of suffering from pre-eclampsia (OR 2.10; 95% CI, 1.75-2.51). After adjusting for covariates, a similarly increased probability of having pre-eclampsia was observed (OR 2.18; 95% CI, 1.80-2.64) among women with vitamin D deficiency, relative to controls., Conclusion: Although the results suggest that low maternal concentrations of 25(OH)D increase pre-eclampsia risk, this evidence may not be indicative of a causal association. Future studies are needed to confirm a definite causal relationship between concentrations of vitamin D and the risk of pre-eclampsia, by means of powered clinical trials., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Context: Physicians overestimate survival in patients with advanced cancer. Patient-reported outcomes could provide another way to estimate survival. We previously reported four prognostic groups based on Karnofsky Performance Status, Functional Assessment of Cancer Therapy physical well-being subscale, and Memorial Symptom Assessment Scale-Short Form physical symptom distress subscale scores., Objectives: To determine the validity of these four prognostic groups., Methods: We performed prospective surveys. Data from a total of 880 Veterans Affairs Medical Center patients, 417 in the First Cohort and 463 in the Validation Cohort, were analyzed. Both inpatients and outpatients were prospectively recruited in Institutional Review Board-approved studies from August 1999 to September 2009. Survival was measured from the date of entry until death or December 1, 2009. Patients completed self-assessments with the Functional Assessment of Cancer Therapy and Memorial Symptom Assessment Scale-Short Form. Analysis of variance was used to test differences between groups in continuous variables; a generalized Wilcoxon test was used for differences between groups for survival., Results: The average age in the Validation Cohort was 66.5 years and 98% were men. The majority of patients had metastatic cancer (90%), with lung (28%) and prostate (26%) cancers being predominant. The median Karnofsky Performance Status was 70. Median survival was 33, 46.5, 124, and 209.5 days for the four prognostic groups (P < 0.0001, all pair-wise comparisons P < 0.02)., Conclusion: The four prognostic groups remained distinct in the prospective cohort. Small differences in patient-reported physical well-being can halve survival estimates. Patient-reported outcomes can correct for physician overestimate of prognosis. This study provides a way to use patient-reported outcomes for prognosis in patients with advanced cancer, with important implications for assessment., (Published by Elsevier Inc.)

Dentin matrix protein 1 (DMP1) is a member of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family, a group of proteins initially described as mineralized extracellular matrices components. More recently, SIBLINGs have been implicated in several key steps of cancer progression, including angiogenesis. Although proangiogenic activities have been demonstrated for 2 SIBLINGs, the role of DMP1 in angiogenesis has not yet been addressed. We demonstrate that this extracellular matrix protein induced the expression of vascular endothelial cadherin (VE-cadherin), a key regulator of intercellular junctions and contact inhibition of growth of endothelial cells that is also known to modulate vascular endothelial growth factor receptor 2 (VEGFR-2) activity, the major high-affinity receptor for VEGF. DMP1 induced VE-cadherin and p27(Kip1) expression followed by cell-cycle arrest in human umbilical vein endothelial cells (HUVECs) in a CD44-dependent manner. VEGF-induced proliferation, migration, and tubulogenesis responses were specifically blocked on DMP1 pretreatment of HUVECs. Indeed, after VE-cadherin induction, DMP1 inhibited VEGFR-2 phosphorylation and Src-mediated signaling. However, DMP1 did not interfere with basic fibroblast growth factor-induced angiogenesis. In vivo, DMP1 significantly reduced laser-induced choroidal neovascularization lesions and tumor-associated angiogenesis. These data enable us to put DMP1 on the angiogenic chessboard for the first time and to identify this protein as a new specific inhibitor of VEGF-induced angiogenesis.

An adequate balance between serine proteases and their plasminogen activator inhibitor-1 (PAI-1) is critical for pathological angiogenesis. PAI-1 deficiency in mice is associated with impaired choroidal neovascularization (CNV) and tumoral angiogenesis. In the present work, we demonstrate unexpected differences in the contribution of bone marrow (BM)-derived cells in these two processes regulated by PAI-1. PAI-1(-/-) mice grafted with BM-derived from wild-type mice were able to support laser-induced CNV formation but not skin carcinoma vascularization. Engraftment of irradiated wild-type mice with PAI-1(-/-) BM prevented CNV formation, demonstrating the crucial role of PAI-1 delivered by BM-derived cells. In contrast, the transient infiltration of tumor transplants by local PAI-1-producing host cells rather than by BM cells was sufficient to rescue tumor growth and angiogenesis in PAI-1-deficient mice. These data identify PAI-1 as a molecular determinant of a local permissive soil for tumor angiogenesis. Altogether, the present study demonstrates that different cellular mechanisms contribute to PAI-1-regulated tumoral and CNV. PAI-1 contributes to BM-dependent choroidal vascularization and to BM-independent tumor growth and angiogenesis.

Cationic antimicrobial protein of 37 kd (CAP37), originally isolated from human neutrophils, is an important multifunctional inflammatory mediator. Here we describe its localization within the vascular endothelium associated with atherosclerotic plaques. Evidence from in vitro immunocytochemical, Northern blot, and reverse transcriptase-polymerase chain reaction analysis indicates that CAP37 is induced in endothelial cells in response to inflammatory mediators. Endothelial-derived CAP37 shows sequence identity with an extensive region of neutrophil-derived CAP37. This is the first demonstration of endogenous endothelial CAP37, confirmed by sequence analysis. We suggest that, because of its induction and location in the endothelium and its known monocyte- and endothelial-activating capabilities, CAP37 has potential to modulate monocyte/endothelial dynamics at the vessel wall in inflammation.

Cocaine N-demethylation to norcocaine was studied in human liver microsomes of different ages. Norcocaine was formed at a considerable rate in fetal (45.4+/-18.2 nmol/mg x hour, n = 8) and adult specimens (82.0+/-46.6 nmol/mg x hour, n = 15), p = 0.04 (Mann-Whitney). Furthermore, the apparent Km values in fetal specimens (0.57 and 0.48 mM, n = 2) showed a higher affinity compared with those of adults (mean value 2.7 (1.8-4.25) mM, n = 4). Estimated enzyme metabolic clearance with respect to P450 total content was higher in fetal than in adult liver microsomes (2.22 ml/nmol P450 x hour, and 0.18 (0.14-0.23) ml/nmol P450 x hour, respectively). Several drugs, known to be CYP3A substrates, were used as potential inhibitors of cocaine metabolism. Midazolam, ergotamine and erythromycin showed strong inhibition (approx. 70 %) when used at concentrations of 500 microM (midazolam, erythromycin) or 200 microM (ergotamine). The metabolism of 1 mM cocaine correlated strongly with immunodetected CYP3A protein determined by Western blotting in both fetal (r = 0.89, p = 0.19) and adult specimens (r = 0.82, p < 0.01) . These findings further support CYP3A as a major catalyst of norcocaine formation in human liver microsomes. These results are important given the potential risk of toxicity to the foetus of maternal cocaine abuse during pregnancy. Although the high Km values found in adult livers reduce the importance of this enzyme pathway in cocaine detoxication, this pathway would emerge as significant in circumstances of CYP3A induction and/or drug interactions leading to potential liver toxicity in chronic cocaine abusers.