Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. Conclusion This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
Coronary artery fistulas (CAFs) are rare and often asymptomatic, but severe complications can occur, resulting in heart failure and cardiac arrhythmia. They have been associated with iatrogenic or traumatic injuries as well as systemic inflammatory conditions. However, there have been very few documented cases of pregnancy associated CAFs. We observed a case of left circumflex to left atrium fistula in a 37-year-old female presenting with insidious onset of progressive dyspnea during pregnancy.
Glaucoma is the leading cause of blindness throughout the world (after cataracts); therefore, general physicians should be familiar with the diagnosis and management of affected patients. Glaucomas are usually categorized by the anatomy of the anterior chamber angle (open vs narrow/closed), rapidity of onset (acute vs chronic), and major etiology (primary vs secondary). Most glaucomas are primary (ie, without a contributing comorbidity); however, several coexisting ophthalmic conditions may serve as the underlying etiologies of secondary glaucomas. Chronic glaucoma occurs most commonly; thus, regular eye examinations should be performed in at-risk patients to prevent the insidious loss of vision that can develop before diagnosis. Glaucoma damages the optic nerve and retinal nerve fiber layer, leading to peripheral and central visual field defects. Elevated intraocular pressure (IOP), a crucial determinant of disease progression, remains the only modifiable risk factor; thus, all current treatments (medications, lasers, and operations) aim to reduce the IOP. Pharmacotherapy is the usual first-line therapy, but noncompliance, undesirable adverse effects, and cost limit effectiveness. Laser and surgical treatments may lower IOP significantly over long periods and may be more cost effective than pharmacotherapy, but they are plagued by greater procedural risks and frequent treatment failures. Traditional incisional procedures have recently been replaced by several novel, minimally invasive glaucoma surgeries with improved safety profiles and only minimal decreases in efficacy. Minimally invasive glaucoma surgeries have dramatically transformed the surgical management of glaucoma; nevertheless, large, randomized trials are required to assess their long-term efficacy.
- Bahaaldin Youssef
- Karina Hanna
- Andrew Bowman
- Aziza Nassar
Thyroid cancers exist in multiple forms. Papillary and follicular carcinomas of the thyroid are often referred to as well-differentiated thyroid cancers. Well-differentiated thyroid cancers rarely present as a distant metastatic cancer on initial diagnosis. Papillary thyroid cancer tends to have a good prognosis; however, if distant metastasis of PTC is present, there is usually a poor clinical outcome with a less favorable prognosis. In this study, we report a 90-year-old female who presented with right-sided abdominal discomfort. A renal ultrasound revealed bilateral upper pole renal masses. A percutaneous biopsy was ordered, and the microscopic examination revealed bilateral renal metastasis with a follicular variant of papillary thyroid carcinoma. The patient underwent thyroidectomy and sustained radiation therapy for her bilateral renal metastases. She died 6 years after her initial diagnosis, due to sepsis. This is the second study in literature to report bilateral renal metastasis of follicular variant of papillary thyroid cancer.
Introduction Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy projected to be the 2nd leading cause of cancer related death in the USA by 2030. This manuscript discusses current and evolving treatment approaches in patients with pancreatic cancer. Areas covered PDAC is classified as: a) resectable, b) borderline resectable, c) unresectable (locally advanced and metastatic). The standard of care for patients who present with resectable pancreatic adenocarcinoma is six months of adjuvant modified (m) FOLFIRINOX, gemcitabine plus capecitabine, or single agent gemcitabine. For many reasons, there has been a paradigm shift to employing neoadjuvant chemotherapy. For resectable and borderline resectable patients, we generally start with systemic therapy and re-evaluate resectability with subsequent scans specifically when the tumor is located in the head or body of the pancreas. Combined chemoradiation therapy can be employed in select patients. The standard of care for metastatic PDAC is FOLFIRINOX or gemcitabine and nab-paclitaxel. Germline and somatic genomic profiling should be obtained in all patients. Patients with a germline BRCA mutation can receive upfront gemcitabine and cisplatin. Expert opinion Thorough understanding of molecular pathogenesis in PDAC has opened various therapeutic avenues. We remain optimistic that future treatment modalities such as targeted therapies, cellular therapies and immunotherapy will further improve survival in PDAC.
PurposeBreast cancer risk is elevated in pathogenic germline BRCA 1/2 mutation carriers due to compromised DNA quality control. We hypothesized that if immunosurveillance promotes tumor suppression, then normal/benign breast lobules from BRCA carriers may demonstrate higher immune cell densities.Methods We assessed immune cell composition in normal/benign breast lobules from age-matched women with progressively increased breast cancer risk, including (1) low risk: 19 women who donated normal breast tissue to the Komen Tissue Bank (KTB) at Indiana University Simon Cancer Center, (2) intermediate risk: 15 women with biopsy-identified benign breast disease (BBD), and (3) high risk: 19 prophylactic mastectomies from women with germline mutations in BRCA1/2 genes. We performed immunohistochemical stains and analysis to quantitate immune cell densities from digital images in up to 10 representative lobules per sample. Median cell counts per mm2 were compared between groups using Wilcoxon rank-sum tests.ResultsNormal/benign breast lobules from BRCA carriers had significantly higher densities of immune cells/mm2 compared to KTB normal donors (all p < 0.001): CD8 + 354.4 vs 150.9; CD4 + 116.3 vs 17.7; CD68 + 237.5 vs 57.8; and CD11c + (3.5% vs 0.4% pixels positive). BBD tissues differed from BRCA carriers only in CD8 + cells but had higher densities of CD4 + , CD11c + , and CD68 + immune cells compared to KTB donors.Conclusions These preliminary analyses show that normal/benign breast lobules of BRCA mutation carriers contain increased immune cells compared with normal donor breast tissues, and BBD tissues appear overall more similar to BRCA carriers.
Lung adenocarcinoma (LUAD) is the most prevalent form of non–small cell lung cancer (NSCLC) and a leading cause of cancer death. Immune checkpoint inhibitors (ICIs) of programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) signaling induce tumor regressions in a subset of LUAD, but many LUAD tumors exhibit resistance to ICI therapy. Here, we identified Prkci as a major determinant of response to ICI in a syngeneic mouse model of oncogenic mutant Kras / Trp53 loss (KP)–driven LUAD. Protein kinase Cι (PKCι)–dependent KP tumors exhibited resistance to anti–PD-1 antibody therapy (α-PD-1), whereas KP tumors in which Prkci was genetically deleted (KPI tumors) were highly responsive. Prkci- dependent resistance to α-PD-1 was characterized by enhanced infiltration of myeloid-derived suppressor cells (MDSCs) and decreased infiltration of CD8 ⁺ T cells in response to α-PD-1. Mechanistically, Prkci regulated YAP1-dependent expression of Cxcl5 , which served to attract MDSCs to KP tumors. The PKCι inhibitor auranofin inhibited KP tumor growth and sensitized these tumors to α-PD-1, whereas expression of either Prkci or its downstream effector Cxcl5 in KPI tumors induced intratumoral infiltration of MDSCs and resistance to α-PD-1. PRKCI expression in tumors of patients with LUAD correlated with genomic signatures indicative of high YAP1-mediated transcription, elevated MDSC infiltration and low CD8 ⁺ T cell infiltration, and with elevated CXCL5 / 6 expression. Last, PKCι-YAP1 signaling was a biomarker associated with poor response to ICI in patients with LUAD. Our data indicate that immunosuppressive PKCι-YAP1-CXCL5 signaling is a key determinant of response to ICI, and pharmacologic inhibition of PKCι may improve therapeutic response to ICI in patients with LUAD.
Solid organ transplant recipients (SOTRs) are at increased risk for the development of skin cancer compared with the general population, which requires consistent monitoring and management from a multidisciplinary team. The aim of this review is to provide a comprehensive overview for nondermatologist clinicians, outlining skin cancer diagnosis, treatment pearls, and skin cancer prevention strategies as they relate to SOTRs. A comprehensive search of the literature was conducted through the MEDLINE database with search terms including organ transplantation, transplant recipient, skin cancer, cutaneous neoplasms, management, and therapies. The search was limited to the English language and dates ranging from January 1, 2011, to December 28, 2021. All studies were reviewed for inclusion. Skin cancer will develop in more than half of SOTRs at some point in their life, most often nonmelanoma skin cancer such as basal cell carcinoma or squamous cell carcinoma. Melanoma and rarer cutaneous malignant neoplasms, such as Merkel cell carcinoma and Kaposi sarcoma, are also more frequent among SOTRs. A multidisciplinary effort at skin cancer screening and patient education is invaluable to prevent skin cancer–related morbidity and mortality in this population of patients. Reduction in immunosuppressive medications and surgical intervention are effective therapeutic approaches, and more novel systemic therapies including G protein–coupled receptor inhibitors and immune checkpoint inhibitors are possible options when traditional treatment approaches are not feasible. Checkpoint inhibitor therapy, however, comes with the risk of allograft rejection. With a growing and aging SOTR population, it is essential that SOTRs have support from dermatologists and nondermatologists alike in skin cancer prevention and treatment.
Introduction Anaplastic thyroid cancer (ATC) is one of the most lethal diseases known to humans with a median survival of 5 months. The American Thyroid Association (ATA) recently published guidelines for the treatment of this dreadful thyroid malignancy. Areas covered This review presents the current therapeutic landscape of this challenging disease. We also present the results from trials published over the last five years and summarize currently active clinical trials. Expert opinion Recent attempts to improve the prognosis of these tumors are moving towards personalized medicine, basing the treatment decision on the specific genetic profile of the individual tumor. The positive results of dabrafenib and trametinib for ATC harboring the BRAF V600E mutation has provided a useful treatment option. For the other genetic profiles, different drugs are available and can be used to individualize the treatment, likely using drug combinations. Combinations of drugs act on different molecular pathways and achieve inhibition at separate areas. With new targeted therapies, average survival has improved considerably and death from local disease progression or airway compromise is less likely with improvement in quality of life. Unfortunately, the results remain poor in terms of survival.
Background: Despite multiple randomized trials, the role of perioperative chemotherapy in colorectal cancer liver metastasis (CRLM) is still under debate. In this systematic review and network meta-analysis (NMA), we aim to evaluate the efficacy of perioperative systemic therapies for patients with CRLM. Methods: We searched various databases for abstracts and full-text articles published from database inception through May 2021.We included randomized controlled trials (RCTs) comparing the addition of perioperative (post, pre, or both) systemic therapies to surgery alone in patients with CRLM. The outcomes were compared according to the chemotherapy regimen using a random effects model. Outcomes of interest included disease-free survival (DFS) and overall survival (OS). Results: Seven RCTs with a total of 1504 patients with CRLM were included. Six studies included post-operative treatment and one evaluated perioperative (pre- and postoperative) therapy. Fluoropyrimidine-based chemotherapy was the most used systemic therapy. NMA showed benefit of adding perioperative therapy to surgery in terms of DFS (HR 0.73, 95% CI 0.63 to 0.84). However, these findings did not translate into a statistically significant OS benefit (HR 0.88, 95% CI 0.74 to 1.05). NMA did not show any advantage of one regimen over another including oxaliplatin or irinotecan. Conclusions: This systematic review and NMA of 7 RCTs found that the addition of perioperative systemic treatment for resectable CRLM could improve disease-free survival but not overall survival. Based on the findings, addition of perioperative treatment in resectable CRLM should be individualized weighing the risks and benefits.
We investigated the clinicopathologic features of 5 follicular lymphomas (FL) that transformed to morphologic diffuse large B-cell lymphomas (DLBCL) and had a primary mediastinal large B-cell lymphoma (PMBL)-like gene expression profile (tFL-PMBLsig-pos). None of the tFL-PMBLsig-pos arose in the mediastinum, all cases tested had a germinal center B-cell phenotype, 20% were CD30+, 60% CD23+, 80% MAL+, 20% CD200+, and 0% CD273/PDL2+. Whole exome sequencing detected alterations in genes associated with both FL/DLBCL (CREBBP, KMT2C, KMT2D, ARID1A, HIST1 members, and TNFRSF14) and PMBL (JAK-STAT pathway genes, B2M, and CD58). Copy number (CN) analysis detected gains/amplification of REL and STAT6 in 60%, gains of SOCS1 in 40%, and gains of chromosome 16, including IL4R, in 40%. CN gains/amplification of BCL6 and MYC and loss of TNFRSF14 and TNFAIP3 were identified in 20%. 3/5 cases lacked a BCL2 rearrangement. Despite having some features that are less common in DLBCL (MAL and CD23 expression, JAK-STAT activation), these tFL-PMBLsig-pos cases lack the most characteristic CN alteration seen in PMBL (9p24.1 gain/amplification). This cohort expands the biologic heterogeneity of tFL, illustrating a subset with gene expression and some genetic features reminiscent of PMBL, with potential treatment implications that include the use of novel targeted therapies.
Background: Clinical picture and outcome of incidental pulmonary embolism (iPE) compared to symptomatic pulmonary embolism (sPE) remain unclear. Methods: Demographics, recurrent venous thromboembolism (VTE), mortality, major bleeding, and clinically relevant non-major bleeding (CRNMB) were compared between iPE and sPE patients who were followed prospectively at Mayo Thrombophilia Clinic (03/01/2013-08/01/2020). Results: Out of 3576 VTE patients, 1417 (39.6%) had PE: 562 (39.7%) iPE and 855 sPE. Patients with cancer were more likely to have iPE (400 iPD vs 314 sPE) compared to those without cancer (162 iPE vs 541 sPE). VTE recurrence rate (all per 100 person-years) was similar in all iPE and sPE patients (3.34 vs 3.68, p=0.50), with cancer (4.16 vs 4.89, p=0.370), and without cancer patients (0.89 vs 2.80, p=0.25). Higher mortality observed in all patients with iPE compared to sPE (46.45 vs 23.47, p<0.001) and with cancer (56.41 vs 45.77, p=0.03) became not significant after adjustment for age, antiplatelet therapy, metastases, and cancer location. Non-cancer iPE patients had higher mortality (15.95 vs 7.18, p=0.006) even after adjustment (p=0.05). The major bleeding rate was also higher in all patients iPE compared to sPE (7.10 vs 3.68, p=0.03), but not after adjustment (p=0.974); higher major bleeding rate in non-cancer patients (6.49 vs 1.25, p=0.007) remained significant after adjustment (0.02). CRNMB rate was similar iPE and sPE patients. Conclusion: iPE represents a more serious clinical condition compared to sPE as indicated by the higher mortality and major bleeding but these differences reflect underlying comorbidities rather than seriousness of embolic event.
Background We conducted a phase I, multicenter, open-label, dose-finding, and expansion study to determine the safety and preliminary efficacy of eprenetapopt (APR-246) combined with pembrolizumab in patients with advanced/metastatic solid tumors (ClinicalTrials.gov NCT04383938). Patients and methods For dose-finding, requirements were non-central nervous system primary solid tumor, intolerant to/progressed after ≥1 line of treatment, and eligible for pembrolizumab; for expansion: (i) gastric/gastroesophageal junction tumor, intolerant to/progressed after first-line treatment, and no prior anti-programmed cell death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy; (ii) bladder/urothelial tumor, intolerant to/progressed after first-line cisplatin-based chemotherapy, and no prior anti-PD-1/PD-L1 therapy; (iii) non-small-cell lung cancer (NSCLC) with previous anti-PD-1/PD-L1 therapy. Patients received eprenetapopt 4.5 g/day intravenously (IV) on days 1-4 with pembrolizumab 200 mg IV on day 3 in each 21-day cycle. Primary endpoints were dose-limiting toxicity (DLT), adverse events (AEs), and recommended phase II dose (RP2D) of eprenetapopt. Results Forty patients were enrolled (median age 66 years; range 27-85) and 37 received eprenetapopt plus pembrolizumab. No DLTs were reported and the RP2D for eprenetapopt in combination was 4.5 g/day IV on days 1-4. The most common eprenetapopt-related AEs were dizziness (35.1%), nausea (32.4%), and vomiting (29.7%). AEs leading to eprenetapopt discontinuation occurred in 2/37 patients (5.4%). In efficacy-assessable patients (n = 29), one achieved complete response (urothelial cancer), two achieved partial responses (NSCLC, urothelial cancer), and six patients had stable disease. Conclusions The eprenetapopt plus pembrolizumab combination was well tolerated with an acceptable safety profile and showed clinical activity in patients with solid tumors.
Context: The interleukin-3 receptor alpha chain (CD123), a cell-surface target, is aberrantly expressed on various myeloid neoplasms, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), and myelofibrosis (MF). Tagraxofusp (TAG, SL-401), a first-in-class CD123-targeted therapy, is the only treatment approved by the FDA and EMA for patients with BPDCN and is being investigated in AML, CMML, and MF. Objective: To report the aggregated safety data for TAG monotherapy from trials in BPDCN, AML, CMML, and MF. Design: An integrated safety analysis was performed for patients who received TAG monotherapy in three phase 1/2, multicenter clinical studies: Study 0114 (NCT02113982; BPDCN/AML), Study 0214 (NCT02270463; AML), and Study 0314 (NCT02268253; CMML/MF). Setting: Hospitals and medical research institutions. Patients: In total, 201 patients were included: BPDCN, n=86; AML, n=36; CMML, n=33; and MF, n=36. Intervention(s): Patients received the recommended phase 2 TAG dose of 12 mcg/kg intravenously on days 1-3 (MF and CMML) or days 1-5 (BPDCN and AML). Main outcome measure(s): Treatment-related adverse events (TRAEs), adverse events (AEs) of interest, and discontinuations. Results: As of July 2021, 11 (6%) patients discontinued TAG due to any-grade TRAEs. The most common any-grade TRAEs included hypoalbuminemia (41%), increased alanine (ALT; 40%) and aspartate (AST; 39%) aminotransferases, and thrombocytopenia (26%). The most common grade ≥3 TRAEs were thrombocytopenia (20%), increased AST (20%), and increased ALT (17%). Prolonged bone marrow suppression was not observed. Overall, 23% of patients experienced ≥1 serious TRAE. The onset of most TRAEs occurred in cycle 1 and was resolved by cycle 2. Capillary leak syndrome (CLS) occurred in 35 patients (17%), with onset usually within cycle 1. Most CLS events were non-severe (grade ≤2); 2 of 201 (1%) patients had a grade 5 event. Conclusions: This integrated analysis is the largest collation of safety data following treatment with TAG monotherapy. Most TRAEs were transient, and their frequency/severity decreased with increasing cycles. No myelosuppression or cumulative toxicity was reported following treatment over multiple cycles. These data confirm that the established and manageable safety profile of TAG monotherapy has been maintained in the 3 years following US approval.
Introduction: Health equity for all patients is an important characteristic of an effective healthcare system. Bias has the potential to create inequities. In this study, we examine emergency department (ED) throughput and care measures for sex-based differences, including metrics such as door-to-room (DTR) and door-to-healthcare practitioner (DTP) times to look for potential signs of systemic bias. Methods: We conducted an observational cohort study of all adult patients presenting to the ED between July 2015 and June 2017. We collected ED operational, throughput, clinical, and demographic data. Differences in the findings for male and female patients were assessed using Poisson regression and generalized estimating equations (GEEs). A priori, a clinically significant time difference was defined as 10 min. Results: A total of 106,011 adult visits to the ED were investigated. Female patients had 8-min longer median length-of-stay (LOS) than males (P < 0.01). Females had longer DTR (2-min median difference, P < 0.01), and longer DTP (5-min median difference, P < 0.01). Females had longer median door-to-over-the-counter analgesia time (84 vs. 80, P = 0.58), door-to-advanced analgesia (95 vs. 84, P < 0.01), door-to-PO (by mouth) ondansetron (70 vs. 62, P = 0.02), and door-to-intramuscular/intravenous antiemetic (76 vs. 69, P = 0.02) times compared with males. Conclusion: Numerous statistically significant differences were identified in throughput and care measures-mostly these differences favored male patients. Few of these comparisons met our criteria for clinical significance.
Objective To determine the frequency of new or enlarging T2-hyperintense or enhancing lesions outside of clinical attacks in myelin-oligodendrocyte-glycoprotein-antibody-associated-disease (MOGAD) versus multiple sclerosis (MS) and aquaporin-4 antibody-positive-neuromyelitis-optica-spectrum-disorder (AQP4+NMOSD). Design/Methods: We retrospectively included Mayo Clinic MOGAD patients with: 1) MOG-IgG positivity by live-cell-based-assay; 2) Fulfilling proposed MOGAD diagnostic criteria; 3) Baseline and follow-up paired MRIs without interval attacks. A neurologist and neuroradiologist reviewed MRIs (T2-FLAIR brain, T2 spine, and T1-post-gadolinium brain and spine) to identify new or enlarging lesions. A MOGAD subset was then compared to MS and AQP4+NMOSD patients, based on broadly similar inter-scan intervals. Results We included 105 MOGAD patients (median age, 31 years[range, 2-80]; 60% female) with 373 paired MRIs. In total, 10/105 (9.5%) patients and 13/373 (3%) scans had one or more new T2-lesions (brain, 12/213[6%]; spine, 1/160[0.6%]) and 8/367 (2%) had enhancing lesions. New brain lesions were less in MOGAD (1/25[4%]) than MS (14/26[54%], p<0.0001) but did not differ from AQP4+NMOSD (1/13[8%], p=1.0) in subgroup analysis. New spinal lesions were rare across groups (0-4%). Conclusions New or enlarging MRI lesions rarely develop outside of clinical attacks in MOGAD differing from MS. Surveillance MRIs in MOGAD have limited utility with implications for clinical practice and trial design.
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