Correlating Predicted Adjuvant Therapy Benefit and Risk of Recurrence Between Breast Cancer Index (BCI) and the 21-Gene Oncotype DX Recurrence Score (RS).

INTRODUCTION: Breast Cancer Index (BCI) is a genomic assay that evaluates the benefit of extending endocrine therapy (ET) from 5 to 10 years and predicts recurrence risk (RR). We evaluated the association between BCI and Oncotype DX (ODX). PATIENTS: Women with hormone receptor (HR)-positive early-stage breast cancer (EBC) who had BCI and ODX performed were included. METHODS: We performed a retrospective review of women with HR-positive EBC. BCI was categorized as predictive of extended ET versus not and ODX recurrence score (RS) as low (0-10), intermediate (11-25), and high (26-100). Univariate and multivariable logistic and linear regression models assessed the relationship between BCI and ODX, factors associated with each, and discordance between scores. RESULTS: We identified 153 women, 22% were premenopausal and 18% were lymph node positive. The univariate logistic and linear models revealed an association between BCI predictive score and ODX RS (OR 7.84, CI, 2.63-23.36, P < .001) and log of BCI RR (Beta 0.04, CI, 0.02-0.06, P < .001). Seventy-four percent of BCI predictive scores were concordant with ODX RS and 83% of BCI RR was concordant with ODX RR. In a univariate logistic regression model, BCI predictive of ET benefit was associated with discordance (OR 28.00, CI, 10.58-74.02, P < .001). Higher ODX RR was associated with discordance (OR 1.92, CI, 1.42-2.59, P < .001). CONCLUSION: We found a significant association between ODX and BCI predictive and prognostic scores. BCI predictive of extended ET benefit was associated with discordance with ODX RS. Higher predicted RR on ODX was associated with discordance with BCI predicted RR.

Emerging Disease of the Desert: Rise of West Nile Virus Chorioretinitis in Arizona.

Purpose: To present 7 cases of West Nile virus (WNV)-related chorioretinitis in Arizona. Methods: Retina clinic charts with the terms "chorioretinitis" and "West Nile" were selected from April 1, 2012, to February 1, 2023. Results: Seven patients with initial visits between August 2019 and February 2023 were included. The majority of WNV chorioretinitis cases were seen in the last 4 years of the selected dates. Only 1 patient presented before this time but was excluded for inadequate baseline testing. All 7 patients had hospitalization for neuroinvasive disease before clinical presentation. All patients achieved a final visual acuity of 20/25 to 20/70. Conclusions: In the last 4 years of the study period, an uptrend in WNV chorioretinitis was found in our retina clinics in Arizona, reflecting the overall rise in WNV outbreaks across the state. As WNV continues to rise, the eye specialist should have high suspicion for WNV ocular disease, even in states where WNV had been an uncommon entity.

Outcomes in Premenopausal Patients with HR+/HER2- Breast Cancer and Lymph Node Micrometastasis Based on the 21-Gene Recurrence Score.

BACKGROUND: Postmenopausal patients with hormone receptor positive, HER2-negative (HR+/HER2-) early breast cancer (EBC) and 21-gene OncotypeDX (ODX) recurrence scores (RS) <26 do not benefit from chemoendocrine therapy ("CET") compared to endocrine monotherapy ("E"), regardless of nodal status. In premenopausal patients, nodal status is significant in interpretation of RS. However, guidelines are not explicit in recommendations for patients with micrometastasis ("pN1mi" staging). METHODS: A cohort of patients aged <50 years with HR+/HER2- EBC who underwent ODX testing was identified within the National Cancer Database 2004-2019 dataset. We confirmed the prognostic value of ODX in pN1mi disease with multivariate Cox regression for overall survival (OS). We explored how patterns of practice differed by nodal status in cases of low RS (<26) with chi-squared testing. Finally, we performed Kaplan-Meier models comparing OS for those with RS <26 receiving E versus CET, controlling for nodal status. RESULTS: Of 72 068 patients aged <50 years with HR+/HER2- EBC, 6.1% (n = 4402) had micrometastasis. Multivariate Cox regression confirmed prognostic value of ODX in this pN1mi cohort (P < .001). In the context of RS <26, CET was used most commonly in patients with 1-3 involved lymph nodes ("pN1a-c" disease), less frequently in pN1mi disease, and least in node-negative ("pN0") disease. A benefit in OS was observed in cases with RS <26 and pN1a-c receiving CET vs. E (P = .017), but not in pN1mi (P = .49) or pN0 (P = .57) disease. CONCLUSION: Our large registry analysis found CET was associated with improved OS in pN1a-c, but not in pN1mi or pN0 disease.

Anti-Factor Xa Level Monitoring for Enoxaparin Prophylaxis and Treatment in High-Risk Patient Groups.

Description Monitoring anti-factor Xa levels is a controversial topic in the inpatient setting due to resource utilization and unclear conditional guideline recommendations regarding this practice. Enoxaparin dosing in certain high-risk patient populations such as those with low body weight, obesity, renal insufficiency, and pregnancy has not been determined. The objective of this review was to assess the safety and efficacy of enoxaparin monitoring via anti-factor Xa levels in high-risk patient populations. The PubMed database was searched for articles related to low-molecular-weight heparin monitoring. Randomized controlled trials and meta-analyses that evaluated the safety and efficacy of enoxaparin prophylaxis and treatment in patients with extremes of weight, renal insufficiency, and pregnancy were selected. Fourteen studies representing four high-risk population patient groups were included. Patients with extremes of weight or who were pregnant were found to have subtherapeutic anti-factor Xa levels due to the weight-based dosing of enoxaparin. Those with renal insufficiency were found to be accumulating enoxaparin, indicating the need for a lower dose. Studies have shown that monitoring may be required in specific high-risk patient groups. Dose adjustments based on anti-factor Xa levels can prevent adverse events associated with enoxaparin. Further research involving larger patient populations would be necessary to determine the clinical efficacy of enoxaparin monitoring with anti-factor Xa levels.

Transient Severe Functional Mitral Valve Regurgitation: An Extremely Rare Cause of Recurrent Pulmonary Edema.

A 79-year-old woman presented with recurrent pulmonary edema. Extensive testing spanning 5 admissions showed only mild mitral regurgitation (MR). A transthoracic echocardiogram with the patient in the supine position and passive leg raise showed severe MR. This suggested transient severe MR. She underwent mitral valve replacement and had an uneventful postoperative course without recurrence of symptoms. (Level of Difficulty: Intermediate.).

Exposure of progressive immune dysfunction by SARS-CoV-2 mRNA vaccination in patients with chronic lymphocytic leukemia: A prospective cohort study.

BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) have reduced seroconversion rates and lower binding antibody (Ab) and neutralizing antibody (NAb) titers than healthy individuals following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccination. Here, we dissected vaccine-mediated humoral and cellular responses to understand the mechanisms underlying CLL-induced immune dysfunction. METHODS AND FINDINGS: We performed a prospective observational study in SARS-CoV-2 infection-naïve CLL patients (n = 95) and healthy controls (n = 30) who were vaccinated between December 2020 and June 2021. Sixty-one CLL patients and 27 healthy controls received 2 doses of the Pfizer-BioNTech BNT162b2 vaccine, while 34 CLL patients and 3 healthy controls received 2 doses of the Moderna mRNA-1273 vaccine. The median time to analysis was 38 days (IQR, 27 to 83) for CLL patients and 36 days (IQR, 28 to 57) for healthy controls. Testing plasma samples for SARS-CoV-2 anti-spike and receptor-binding domain Abs by enzyme-linked immunosorbent assay (ELISA), we found that all healthy controls seroconverted to both antigens, while CLL patients had lower response rates (68% and 54%) as well as lower median titers (23-fold and 30-fold; both p < 0.001). Similarly, NAb responses against the then prevalent D614G and Delta SARS-CoV-2 variants were detected in 97% and 93% of controls, respectively, but in only 42% and 38% of CLL patients, who also exhibited >23-fold and >17-fold lower median NAb titers (both p < 0.001). Interestingly, 26% of CLL patients failed to develop NAbs but had high-titer binding Abs that preferentially reacted with the S2 subunit of the SARS-CoV-2 spike. Since these patients were also seropositive for endemic human coronaviruses (HCoVs), these responses likely reflect cross-reactive HCoV Abs rather than vaccine-induced de novo responses. CLL disease status, advanced Rai stage (III-IV), elevated serum beta-2 microglobulin levels (ß2m >2.4 mg/L), prior therapy, anti-CD20 immunotherapy (<12 months), and intravenous immunoglobulin (IVIg) prophylaxis were all predictive of an inability to mount SARS-CoV-2 NAbs (all p ≤ 0.03). T cell response rates determined for a subset of participants were 2.8-fold lower for CLL patients compared to healthy controls (0.05, 95% CI 0.01 to 0.27, p < 0.001), with reduced intracellular IFNγ staining (p = 0.03) and effector polyfunctionality (p < 0.001) observed in CD4+ but not in CD8+ T cells. Surprisingly, in treatment-naïve CLL patients, BNT162b2 vaccination was identified as an independent negative risk factor for NAb generation (5.8, 95% CI 1.6 to 27, p = 0.006). CLL patients who received mRNA-1273 had 12-fold higher (p < 0.001) NAb titers and 1.7-fold higher (6.5, 95% CI 1.3 to 32, p = 0.02) response rates than BNT162b2 vaccinees despite similar disease characteristics. The absence of detectable NAbs in CLL patients was associated with reduced naïve CD4+ T cells (p = 0.03) and increased CD8+ effector memory T cells (p = 0.006). Limitations of the study were that not all participants were subjected to the same immune analyses and that pre-vaccination samples were not available. CONCLUSIONS: CLL pathogenesis is characterized by a progressive loss of adaptive immune functions, including in most treatment-naïve patients, with preexisting memory being preserved longer than the capacity to mount responses to new antigens. In addition, higher NAb titers and response rates identify mRNA-1273 as a superior vaccine for CLL patients.

Discrepancies in estradiol levels in a premenopausal woman receiving abemaciclib despite ovarian function suppression and bilateral salpingo-oophorectomy.

Abemaciclib is approved for use in the adjuvant setting in combination with endocrine therapy for patients with high-risk, hormone receptor-positive, HER2-negative early-stage breast cancer based on the monarchE trial. Options for endocrine therapy for premenopausal women include an aromatase inhibitor with ovarian function suppression or tamoxifen with or without ovarian suppression. We describe a unique case of a premenopausal woman with early-stage breast cancer receiving adjuvant abemaciclib and an aromatase inhibitor with elevated estradiol levels as measured by the Abbott Alinity chemiluminescent immunoassay despite chemical and surgical ovarian function suppression. Given low estradiol levels using liquid chromatography-mass spectrometry testing following a bilateral salpingo-oopherectomy, our case report suggests an interference of abemaciclib with the Abbott Alinity immunoassay. This possible interference has significant impacts on clinical care as false elevations in estradiol levels measured by immunoassays can lead to unnecessary treatment changes, including surgery.

An emerging generation of endocrine therapies in breast cancer: a clinical perspective.

Anti-estrogen therapy is a key component of the treatment of both early and advanced-stage hormone receptor (HR)-positive breast cancer. This review discusses the recent emergence of several anti-estrogen therapies, some of which were designed to overcome common mechanisms of endocrine resistance. The new generation of drugs includes selective estrogen receptor modulators (SERMs), orally administered selective estrogen receptor degraders (SERDs), as well as more unique agents such as complete estrogen receptor antagonists (CERANs), proteolysis targeting chimeric (PROTACs), and selective estrogen receptor covalent antagonists (SERCAs). These drugs are at various stages of development and are being evaluated in both early and metastatic settings. We discuss the efficacy, toxicity profile, and completed and ongoing clinical trials for each drug and highlight key differences in their activity and study population that have ultimately influenced their advancement.

Correlation of the Ki67 Working Group prognostic risk categories with the Oncotype DX Recurrence Score in early breast cancer.

BACKGROUND: The relationship between Ki67 assessed by immunohistochemistry (IHC) and the Oncotype DX Recurrence Score (RS) is unclear. The objective of this study was to determine the correlation between the 21-gene RS and IHC-measured Ki67 with the prognostic classification groups recommended by the International Ki67 Working Group (IKWG). METHODS: The authors performed a retrospective chart review of women who had hormone receptor (HR)-positive, human epidermal growth factor receptor 2-negative early breast cancer with zero to three positive lymph nodes and both Ki67 and the 21-gene RS performed at their institution from 2013 to 2021. Patients were categorized into low (≤5%), intermediate (6%-29%), and high Ki67 groups (≥30%) according to IKWG recommendations. Overall agreement and risk-stratified agreement between Ki67 and RS were assessed with the proportion of agreement and the κ statistic. RESULTS: The study included 525 patients with HR-positive breast cancer. Among the 49% of patients with intermediate Ki67 values of 6%-29%, the distribution of low (0-10), intermediate (11-25), and high RS (26-100) was 19%, 66%, and 15%, respectively. There was slight agreement (κ = 0.01-0.20) between Ki67 and RS (κ = 0.027) in the overall population, although this was not significant (p = .1985). There was fair agreement (κ = 0.21-0.40) between high Ki67 and RS values (κ = 0.280; p < .0001). A higher progesterone receptor percentage was associated with lower RS values (p > .0001) but not lower Ki67 values. A positive nodal status and a larger tumor size were associated with higher Ki67 values (p = .0059 and p < .0001) but not with RS. CONCLUSIONS: In this group of patients selected to have a 21-gene RS, there was no significant correlation between Ki67 and RS in the overall population, and there was fair agreement between high Ki67 and high RS values. LAY SUMMARY: In patients with early-stage, hormone receptor-positive breast cancer, decisions on adjuvant chemotherapy are based on certain biological features of the cancer and genomic assays such as the Oncotype DX Recurrence Score (RS). The goal of this study was to determine the correlation between Ki67, a marker of proliferation, and the Oncotype DX RS, a 21-gene assay demonstrated to be predictive of an adjuvant chemotherapy benefit in patients with early-stage breast cancer. In 525 patients, the authors did not find a significant correlation between Ki67 and RS.

Presentation of concurrent thrombotic thrombocytopenic purpura and Graves' disease.

Thrombotic thrombocytopenic purpura (TTP) is a type of thrombotic microangiopathy caused by deficient activity of ADAMTS13 that most commonly occurs secondary to an acquired autoantibody. There are limited data on the association between TTP and autoimmune thyroid disease. We present a case of acquired TTP in the setting of thyrotoxicosis from Graves' disease. Our patient improved with standard treatment of both TTP and thyrotoxicosis. A retrospective review of patients with TTP at our institution demonstrated that 32% had another autoimmune disorder, highlighting the concept of polyautoimmunity. These findings suggest an association between TTP and uncontrolled autoimmune disease. In patients with newly diagnosed TTP, physicians should evaluate for other autoimmune diseases and check thyroid function tests.

Outcomes of heart transplantation in cardiac amyloidosis: an updated systematic review.

Cardiac amyloidosis is one of the most common infiltrative cardiomyopathies that is characterized by the extracellular deposition of misfolded fibrillar protein. Several studies have previously found that patients with amyloid in the past have performed poorly after heart transplantation. Recent advancements in treatments have been made that have significantly improved outcomes in these patients. The study aimed to evaluate the outcomes of heart transplantation in cardiac amyloidosis. We systematically searched EMBASE, PubMed/MEDLINE, and Cochrane Library databases on 30 December 2021 following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We identified 22 studies that examined 42,951 patients with cardiac amyloidosis of which only 1,329 patients underwent isolated heart transplantation. Seven studies reported individual patient data. The results of 123 patients have been pooled for analysis. There were 70 male patients, 45 female patients, and eight patients who did not report their gender. Among the types of amyloids, 63 (51%) patients were found to have light chain amyloidosis (AL) and 33 (27%) patients had transthyretin amyloidosis (ATTR). Only 41 patients (33.3%) reported a monoclonal component. There were 30 patients with AL that underwent autologous hematopoietic stem cell transplant (ASCT). The mean survival of 24 out of 30 patients was 4.33 years. In addition, the reported data include 13 patients requiring intra-aortic balloon pump (IABP), six with cardiac resynchronization therapy (CRT), and four with implantable cardioverter defibrillator (ICD). With the current advancements in treatments in combination with a multidisciplinary approach and careful patient selection, patients undergoing heart transplantation for amyloidosis may have encouraging results in the current era. Further studies will be needed to evaluate the outcomes of heart transplantation in amyloidosis patients now that several advances have been made in the field.

Impact of body mass index on the efficacy of aromatase inhibitors in patients with metastatic breast cancer.

PURPOSE: Higher levels of estrogen in obese patients may lead to incomplete inhibition by aromatase inhibitors (AIs). The aim of this study was to determine the impact of body mass index (BMI) on efficacy of AIs in patients with metastatic hormone receptor (HR)-positive breast cancer (BC). METHODS: We performed a retrospective chart review of all female patients with metastatic HR-positive BC on an AI in first- or second-line settings and seen at our academic institution between 2001 and 2020. The primary endpoint was progression-free survival (PFS), defined as the time from start of AI to disease progression or death from any cause. RESULTS: We identified 219 patients who had received an AI in the first- or second-line settings for metastatic HR-positive BC and with documented information on BMI. Of the 219 patients, 56% (123) had a low BMI (defined as < 27 kg/m2) and 44% (96) had a high BMI (≥ 27 kg/m2). The median PFS was 21.9 months (95% CI 14.5 to 28.4) in the low BMI group versus 20.2 months (95% CI 14.3 to 27.5) in the high BMI group (p = 0.73). CONCLUSION: While BMI influences efficacy of AIs in the adjuvant setting, our results suggest that in the metastatic setting, BMI may not impact the efficacy of AIs. This discrepancy could be due to other differences in disease characteristics that make complete aromatase inhibition more important in the adjuvant setting when disease burden is the lowest.

SARS-CoV-2 mRNA vaccination exposes progressive adaptive immune dysfunction in patients with chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) patients have lower seroconversion rates and antibody titers following SARS-CoV-2 vaccination, but the reasons for this diminished response are poorly understood. Here, we studied humoral and cellular responses in 95 CLL patients and 30 healthy controls after two BNT162b2 or mRNA-2173 mRNA immunizations. We found that 42% of CLL vaccinees developed SARS-CoV-2-specific binding and neutralizing antibodies (NAbs), while 32% had no response. Interestingly, 26% were seropositive, but had no detectable NAbs, suggesting the maintenance of pre-existing endemic human coronavirus-specific antibodies that cross-react with the S2 domain of the SARS-CoV-2 spike. These individuals had more advanced disease. In treatment-naïve CLL patients, mRNA-2173 induced 12-fold higher NAb titers and 1.7-fold higher response rates than BNT162b2. These data reveal a graded loss of immune function, with pre-existing memory being preserved longer than the capacity to respond to new antigens, and identify mRNA-2173 as a superior vaccine for CLL patients.

An Interactive Mock Paging Curriculum to Prepare New Internal Medicine Interns for Inpatient Wards.

Introduction: The July effect refers to an increase in adverse outcomes during periods of physician trainee turnover in teaching hospitals. We created an interactive resident-led curriculum to train new internal medicine interns for routine encounters on inpatient wards by role-playing through mock paging scenarios and focusing on practical information relevant to intern year. Methods: A formal assessment of the academic year 2018 intern boot camp curriculum revealed that interns preferred sessions that involved active learning strategies and covered common issues. In the first week of academic year 2019, interns participated in two 1-hour small-group sessions involving mock paging scenarios. Interns were divided into small groups with one facilitator who was a senior medicine resident. Within these groups, facilitators acted as the nurse and provided pages. Interns took turns answering these mock pages based on a sign-out of patients. The facilitator emphasized desired learner actions and teaching points using a provided guide. Results: Twenty interns participated in the curriculum. Interns rated the curriculum highly and felt that the sessions improved their knowledge, comfort, and skills in managing routine inpatient encounters. On a 2-week follow-up knowledge test to determine if they retained the information from the curriculum, interns scored an average of 85% (response rate: 60%, N = 12), indicating that they could apply the knowledge/skills learned to new scenarios. Discussion: This curriculum prepares medicine interns to manage common inpatient issues at the beginning of their residency. After completing the curriculum, interns reported increased confidence in handling these issues.

An Ethically Justified Approach That Integrates Advance Directives Discussions With Care of the Patient With Cancer.

Although the frequency of advance directives discussions may be increasing, there is a need to improve the quality of these discussions. In a range of advanced medical illnesses, including cancer, poor outcomes with advanced cardiopulmonary life support (ACLS) have been well documented. However, when speaking to patients at the end-of-life, physicians frequently withhold evidence-based information and guidance about prognosis or outcomes of ACLS. Tools and models developed to facilitate communication at the end-of-life do not explicitly include recommendations on advance directives and specifically do not discuss the available evidence on ACLS outcomes in the seriously ill. Here, we review the current literature on outcomes of ACLS and current tools and communications for end-of-life discussions. A majority of patients have a preference for truth-telling and guidance. We advocate an approach that integrates individual goals and preferences with a shared understanding of prognosis and appropriate management options, as judged and recommended by the disease experts, in order to reach an evidence-based decision on advance directives. This pragmatic and ethically justified approach emphasizes active empathic communication to prioritize the care of the patient over the mechanical details of ACLS, thereby aligning end-of-life discussions with current practices in other domains of medicine.

Immunotherapy-induced severe neutropenia with neurotoxicity: A case of a 75-year-old woman with ulcerative colitis diagnosed with melanoma.

INTRODUCTION: Immune checkpoint inhibitors have transformed the field of oncology moving immuno-oncology to the forefront of cancer treatment. However, immune checkpoint inhibitors can result in serious immune-related adverse events. Hematologic toxicities are rare with incidence of neutropenia from nivolumab less than 1%. CASE REPORT: We present a case of refractory neutropenia in a 75-year-old woman with ulcerative colitis on adjuvant nivolumab for stage III melanoma. MANAGEMENT AND OUTCOME: The patient's neutropenia did not improve with high-dose intravenous steroids, filgrastim, mycophenolate mofetil, or intravenous immunoglobulin. She also developed significant neurological symptoms from nivolumab. She was transitioned to comfort measures given her persistent symptoms and poor functional status. DISCUSSION: Though hematologic malignancies of immune checkpoint inhibitors are rare, they should be considered after other diagnoses are excluded. We discuss the serious immune-related adverse effects of immune checkpoint inhibitors in a patient with an underlying autoimmune disease and general treatment approaches.

Primum Non Nocere: A Rare Case of Amplatzer Erosion and Cardiac Pseudoaneurysm with Multimodality Imaging.

Complications of septal-occluder devices include erosion, perforation, and embolization, which are most commonly caused by oversized devices or thin rim margins. Cardiac pseudoaneurysm is a rare phenomenon that forms as a result of device erosion into the myocardium. Although this is often an incidental finding, they are at risk for rupture. (Level of Difficulty: Intermediate.).