Surgical Management of the Axilla in HR+/HER2- Breast Cancer in the Z1071 Era: A Propensity Score-Matched Analysis of the National Cancer Database.

BACKGROUND: Axillary management varies between sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) for patients with clinical N1 (cN1), hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)/neu-negative (HER2-), infiltrative ductal carcinoma (IDC) who achieve a complete clinical response (cCR) to neoadjuvant systemic therapy (NAST). This study sought to evaluate clinical practice patterns and survival outcomes of SLNB versus ALND in this patient subset. METHODS: Patients with cN1, HR+/HER2-, unilateral IDC demonstrating a cCR to NAST were identified from the 2012-2017 National Cancer Database (NCDB) and stratified based on final axillary surgery management (SLNB vs ALND). After propensity score-matching, overall survival (OS) was compared using a Kaplan-Meier analysis, and significant OS predictors were identified using Cox regression. RESULTS: Of the 1676 patients selected for this study, 593 (35.4%) underwent SLNB and 1083 (64.6%) underwent ALND. Use of SLNB increased by 28 % between 2012 and 2017. Among a total of 584 matched patients, 461 matched ypN0 patients, and 108 matched ypN+ patients, mean OS did not differ between SLNB and ALND (all patients [92.1 ± 0.8 vs 90.2 ± 1.0 months; p = 0.157], ypN0 patients [92.4 ± 0.8 vs 89.9 ± 0.9 months; p = 0.105], ypN+ patients [83.5 ± 2.3 vs 91.7 ± 2.7 months; p ± 0.963). Cox regression identified age, Charlson score, clinical T stage, and pathologic nodal status as significant predictors of OS. CONCLUSION: The final surgical management strategy used for cN1, HR+/HER2- IDC patients who achieved a cCR to NAST did not have a significant impact on survival outcomes in this analysis. Potential opportunities for de-escalation of axillary management among this patient subset exist, and validation studies are needed.

Surgeon and Radiologist Evaluation of Electromagnetic Chip Localization for Benign and Malignant Breast Lesions.

BACKGROUND: SmartClipTM is a food and drug administration-approved, electromagnetic chip (EMC) localization system that provides three-dimensional navigation for the excision of soft tissue lesions. The purpose of this study was to analyze the accuracy and feasibility of EMC radiologic and surgical localization for benign and malignant breast lesions. PATIENTS AND METHODS: An institutional review board-approved, single institution, prospective study from October 2020 to September 2022 of 38 women undergoing breast conserving surgery with EMC localization of a single lesion > 5 mm on mammogram (MMG) or ultrasound (US) imaging. Surveys from performing breast radiologists and breast surgeons were collected after image-guided localization and surgical excision. RESULTS: Seventy-six survey responses from nine radiologists and four surgeons were received. The deployment needle and EMC were highly visible in 86.8% and 76.3% of procedures, respectively. There was no difficulty in deployment for 92.1% of procedures. The EMC was in the correct location on postdeployment MMG in 97.4% of cases. Three instances of EMC migration occurred, one 1 cm from target lesion. The targeted mass and EMC were within the surgical specimen in 97.4% of cases. On specimen radiograph, 39.5% of the EMCs were 0-1 mm from the center of the target lesion, 18.4% were within 2-4 mm, and 23.7% were within 5-10 mm. Mean operating room time for all cases was 65 min. One case required US to localize the target due to console malfunction. CONCLUSION: There was successful EMC deployment by radiologists with accurate visualization and successful surgical excision in most cases. The EnVisioTM SmartClipTM system is a reproducible and accurate localization method for benign and malignant breast lesions.

Retrospective Study of Treatment Patterns and Natural History of Patients with T1a/b N0 Triple-Negative Breast Cancers: A Single-Institution Experience.

INTRODUCTION: T1a/b, node-negative (node-), triple-negative breast cancers (TNBCs) are underrepresented in randomized drug-approving clinical trials. Given their low incidence, the clinicopathological features, natural history, and treatment patterns of these tumors remain insufficiently understood. METHODS: We conducted a single-institution retrospective cohort study of patients with T1a/b, N0, M0 TNBCs. Deidentified patient- and tumor-related data were collected and summarized. Kruskal-Wallis, χ2, or Fisher exact tests were used to evaluate associations of interest. Kaplan-Meier methods, log-rank tests, and Cox's proportional hazards models were applied for survival analyses. RESULTS: Of 108 cases of node- TNBCs measuring ≤2 cm, 34 node- T1a/b tumors were included in our analysis. All cases had an intermediate to high histological grade, and most had a Ki-67 score of ≥20%. All patients received adjuvant chemotherapy, and many underwent mastectomy (47%). Docetaxel combined with cyclophosphamide was the most common adjuvant chemotherapy regimen (75%). We did not observe significant associations between improved outcomes and treatment with anthracycline-containing regimens. Among patients with node- pT1a/b tumors, the estimated 3-year recurrence-free survival (RFS) and distant RFS rates were both 96.3% (95% CI: 76.5-99.5), and the overall survival rate was estimated to be 100% (95% CI: 100-100). There were no cases of local recurrences observed. CONCLUSIONS: In our cohort, all patients with T1a/b node- TNBCs were treated with adjuvant chemotherapy and had favorable outcomes even when treated with anthracycline-sparing regimens.

Breast Surgical Oncology Fellowship applicant selection and ranking: A survey of Society of Surgical Oncology programs.

BACKGROUND AND OBJECTIVES: In 2003, the Society of Surgical Oncology (SSO) initiated a breast surgical oncology fellowship, which has now grown to 60 SSO accredited programs as of 2021. Limited knowledge exists on the traits of successful applicants and the factors influencing the rank list. METHODS: A web-based, anonymous survey was sent to all SSO Breast Surgical Oncology Fellowship program directors. The survey consisted of 26 questions. Descriptive statistics were used to analyze survey responses and evaluate impact on applicant interview and rank list. RESULTS: Thirty-four programs (57% response rate) completed the survey. Programs received an average of 70 applications and granted 24 interviews. Most programs reported a minimum ABSITE cut-off score (n = 28, 82%) and a defined publication requirement (n = 22, 65%), including a first-author requirement (n = 18, 53%) to extend an invitation to interview. For postinterview rank, applicant interpersonal skills were highly valued. The interview was the most important aspect for the rank list. CONCLUSIONS: Many programs have ABSITE and publication thresholds before offering an interview. Upon receiving interview invitation, the applicant's interview performance, interpersonal skills, and letters of recommendation were the most important aspect in rank list decision making.

Surgical Management of Axilla of Triple-Negative Breast Cancer in the Z1071 Era: A Propensity Score-Matched Analysis of the National Cancer Database.

BACKGROUND: The role of sentinel lymph node biopsy (SLNB) in triple-negative breast cancer (TNBC) patients who present with clinical N1 (cN1) disease and undergo complete clinical response (cCR) to neoadjuvant systemic therapy (NAST) remains unclear. We aimed to study the outcomes of SLNB versus axillary lymph node dissection (ALND) in this setting. PATIENTS AND METHODS: Patients with cN1 TNBC who showed cCR to NAST were selected from the National Cancer Database (NCDB), and propensity score matched 1:1 between SLNB and ALND in all-comers, ypN0, and ypN1 subgroups. Overall survival (OS) was compared using the Kaplan-Meier method. Cox regression was used to identify predictors of OS. RESULTS: Of the 2953 patients selected. 1062 (36.0%) underwent SLNB and 1891 (64.0%) underwent ALND. There was a chronological increase in national SLNB utilization (from 20% in 2012 to 46% in 2017). One thousand three patients were propensity matched between SLNB and ALND, and no OS difference was noted (81.73 ± 1.04 vs. 80.07 ± 0.70 months; p = 0.127). In the ypN0 subgroup, 884 pairs were matched and no significant OS difference was found (85.29 ± 0.84 vs. 82.60 ± 0.68 months; p = 0.638). In ypN+ patients, 129 pairs were matched and demonstrated a trend toward decreased OS with SLNB (64.37 ± 3.12 vs. 72.45 ± 72.45; p = 0.085). Cox regression identified age, inner tumors, advanced T stage, partial/no in-breast response, and nodal status as unfavorable predictors of OS. Definitive axillary surgical procedure was not a predictor in the final model. CONCLUSION: SLNB and ALND appear to yield comparable OS in cN1 TNBC patients who demonstrate cCR to NAST. Caution should be exercised in ypN1 patients as worse OS could be associated with SLNB.

Surgical Management of the Axilla of HER2+ Breast Cancer in the Z1071 Era: A Propensity-Score-Matched Analysis of the NCDB.

INTRODUCTION: We aim to analyze survival outcomes for sentinel lymph node biopsy (SLNB) versus axillary lymph node dissection (ALND) in human epidermal growth factor receptor (HER2)+ infiltrative ductal carcinoma (IDC) that demonstrate complete clinical response (cCR) to neoadjuvant systemic therapy (NAST) after initial presentation with clinical N1 (cN1) disease. METHODS: NCDB 2004-2017 was utilized for the analysis. Female patients with unilateral HER2+ IDC, stage cT1-T4 cN1, who demonstrated cCR to NAST with reported definitive axillary surgical management were included. Patients were propensity score matched, and overall survival (OS) was compared. Cox regression analysis was used to identify survival predictors. RESULTS: 6453 patients were selected, of whom 2461 (38.1%) had SLNB and 3992 (69.1%) had ALND as definitive axillary surgical management. The trend of SLNB utilization increased from 20% in 2012 to 50% in 2017. A total of 2454 patients were matched from each group with adequate adjustment for all variables. There was no difference in OS between SLNB versus ALND (84.03 ± 0.36 versus 84.62 ± 0.42 months; p = 0.522). Cox regression identified age, cT stage, primary tumor response to NAST, ypN+, and endocrine therapy as significant OS predictors. In subgroup analysis of patients with ypN+ who had SLNB as a definitive procedure, primary tumor response to NAST and continuation of adjuvant chemotherapy were associated with improved OS. CONCLUSION: In cN1 HER2+ IDC patients who demonstrate cCR to NAST, SLNB is a reasonable definitive procedure for axillary management with comparable OS outcomes to ALND. However, higher-level data are required to determine the appropriate management in the case of ypN+.

Comparison of three anti-coccidioides antibody enzyme immunoassay kits for the diagnosis of coccidioidomycosis.

Coccidioidomycosis is a common cause of community-acquired pneumonia in endemic areas of the southwestern United States. Clinical presentations range from self-limited disease to severe, disseminated disease. As such, early and accurate diagnosis is essential to ensure appropriate treatment and monitoring. Currently available diagnostic testing has variable accuracy, particularly in certain patient populations, and new tests may offer improved accuracy for the diagnosis of coccidioidomycosis. Serum samples from patients with coccidioidomycosis and controls were tested for immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies using the MVista Coccidioides antibody detection EIA and two commonly used commercial enzyme immunoassay (EIA) kits: the IMMY Omega EIA and the Meridian Premier EIA. The sensitivity of the IgG antibody detection was 87.4% using the MVista test compared to 46.6% for IMMY and 70.9% for Meridian. The sensitivity for IgM antibody detection was 61.2% for the MVista test, 22.3% for IMMY and 29.1% for Meridian. For IgG antibody detection, specificity was 90% for the MVista EIA, 94.6% for IMMY, 96.4% for Meridian. For IgM antibody detection, specificity was 95.3% for the MVista test 98.2% for IMMY and 99.1% for Meridian. The MVista Coccidioides antibody EIA offers improved sensitivity, including among high-risk patient populations, for the detection of IgG and IgM antibodies in comparison to other currently available EIAs.

Coccidioidomycosis in selected immunosuppressed hosts.

After contracting coccidioidomycosis, persons with impaired cellular immunity are more likely than healthy persons to have severe infection, disseminated infection, and higher mortality rates. In this brief review, we summarize the clinical manifestations, diagnosis, treatment, and prevention of coccidioidomycosis in persons infected with human immunodeficiency virus (HIV), recipients of solid organ or hematopoietic stem cell transplants, and recipients of biologic response modifiers. Among individuals infected with HIV, a diagnosis of acquired immunodeficiency syndrome (AIDS) and a CD4 T-lymphocyte count <250 cells/µl were associated with more severe coccidioidomycosis, whereas less severe disease occurred among those with undetectable HIV-RNA and higher CD4 T-lymphocyte counts, indicating that controlled HIV viremia and improved cellular immune status are important in limiting disease. For transplant recipients whose immunosuppression typically peaks in the first 3 to 6 months and tapers thereafter, the greatest risk of acute coccidioidomycosis occurs 6 to 12 months after transplantation. Relapses of recent coccidioidomycosis may occur during ongoing immunosuppression when patients are not taking suppressive antifungal medication. Recipients of biologic agents, especially those that impair tumor necrosis factor α (TNF-α), may be at increased risk for poorly controlled coccidioidomycosis; however, the best way to prevent and treat such infections has yet to be defined.

Management of asymptomatic coccidioidomycosis in patients with rheumatic diseases.

Coccidioidomycosis is an endemic fungal infection common in the southwestern United States. Some rheumatology clinics periodically screen patients with coccidioidal serology, resulting in the identification of patients who are serologically positive but without clinical symptoms. The management of such patients is unclear. A retrospective study was conducted between 2007 and 2015 at two arthritis centers in Tucson, Arizona. The asymptomatic patients were identified who were receiving disease-modifying antirheumatic agents and had a positive coccidioidal serology. Serological testing including IgM and IgG was performed by enzyme immunoassay (EIA), immunodiffusion (IDTP and IDCF), or complement fixation. Out of 71 patients who were identified with positive coccidioidal serologies, 19 were asymptomatic. 18/19 patients continued antirheumatic therapy, 13 without interruption. 13/19 patients received no antifungal treatment, including 10 who remained on antirheumatic treatment. The other six were started on fluconazole, ranging from 8 to 73 months (median 30.5 months). After a median follow-up of 43 months, no patient developed clinically active coccidioidomycosis. Overall, 14 had only a positive EIA serological test. These results suggest that continued antirheumatic therapy is safe in asymptomatic patients with positive coccidioidal serological tests and that routine implementation of antifungal treatment may not always be warranted. The findings also raise concern regarding the utility of routine serological testing of asymptomatic patients residing in the coccidioidal endemic area, mainly using the EIA test.

The Impact of Molecular Testing for Pathogens of Community-Acquired Pneumonia on Antibiotic Utilization.

Community-acquired pneumonia (CAP) is a common and costly problem in U.S. healthcare. A major challenge in development of targeted treatment strategies has been limitations in diagnostic testing to confirm specific pathogens, including viruses. The recent and widespread use of multiplex polymerase chain reaction (mPCR) to identify pathogens has created an opportunity to improve diagnostic testing and subsequent antibiotic stewardship. We performed a retrospective cohort study examining 233 inpatients with pneumonia of which 70 patients underwent testing with mPCR. A specific pathogen was identified by mPCR in 24 percent of these patients and there was a statistically significant decrease in antibiotic use between patients who tested negative (average 8.3 days of antibiotics) versus patients who tested positive (average 4.9 days of antibiotics). This highlights the potential utility of mPCR implementation as an antibiotic stewardship strategy.

Enhanced Antibody Detection and Diagnosis of Coccidioidomycosis with the MiraVista IgG and IgM Detection Enzyme Immunoassay.

Coccidioidomycosis is a common cause of community-acquired pneumonia in areas of the southwestern United States in which the disease is endemic. Clinical presentations range from self-limited disease to severe disseminated disease. Therefore, early and accurate diagnosis is essential to ensure appropriate treatment and monitoring. Currently available diagnostic tests have variable accuracy, particularly in certain patient populations, and new tests may offer improved accuracy for the diagnosis of coccidioidomycosis. Serum samples from 103 cases of coccidioidomycosis and 373 controls were tested for IgG and IgM antibodies using the MVista anti-Coccidioides antibody enzyme immunoassay. Serum specimens from 170 controls from areas in which the disease is endemic and 44 cases were tested by immunodiffusion at MiraVista Diagnostics. The sensitivity of the MVista antibody assay was 88.3%, and the specificity was 90%. The sensitivity was maintained in the presence of immunocompromising conditions or immunosuppressive therapies. The sensitivity of immunodiffusion was 60.2%, and the specificity was 98.8%. The sensitivity of complement fixation (62 cases) was 66.1%, but the specificity could not be determined. The MVista anti-Coccidioides antibody enzyme immunoassay offers improved sensitivity, compared with immunodiffusion and complement fixation, is not impaired in immunocompromised patients, and permits highly reproducible semiquantification.

Early Postoperative Complications after Oncoplastic Reduction.

BACKGROUND: Breast-conserving surgery with adjuvant radiation therapy (BCT) has been established as safe oncologically. Oncoplastic breast surgery uses both oncologic and plastic surgery techniques for breast conservation to improve cosmetic outcomes. We evaluated the risk factors associated with complications after oncoplastic breast reduction. METHODS: A single-institution, institutional review board-approved, retrospective review of electronic medical records of female patients with breast cancer who underwent oncoplastic breast reduction from 2008 to 2014. A review of electronic medical records collected relevant medical history, clinical and pathological information, and data on postoperative complications within 6 months stratified into major or minor complications. Categorical variables analyzed with the χ2 exact method; continuous variables were analyzed with the Wilcoxon rank sum test exact method. RESULTS: We identified 59 patients; 4 required re-excision for positive margins, and 1 moved on to completion mastectomy. The overall complication rate was 33.9% (n = 20): 12 major (20.3%) and 8 minor (13.6%). Of the continuous variables (age, body mass index, and tissue removed), increased age was associated with minor complications (P = 0.02). Among the categorical variables (stratified body mass index, prior breast surgery, hypertension, diabetes mellitus, hyperlipidemia, vascular disease, pulmonary disease, and stratified weight of tissue removed), none were associated with overall or major complications. Pulmonary disease was associated with minor complications (P = 0.03). Bilateral versus unilateral oncoplastic breast reduction showed no statistically significant increase in complications. CONCLUSIONS: The overall complication rate after oncoplastic breast reduction was markedly higher than that in nationally published data for breast-conserving surgery. The complication rate resembled more closely the complication rate after bilateral mastectomy with immediate reconstruction. No risk factors were associated with major or overall complications. Age and pulmonary disease were associated with minor complications. Patients should be selected and counseled appropriately when considering oncoplastic breast reduction.

Duration of Antibiotics Prescribed at Hospital Discharge.

INTRODUCTION: A patient's transition from hospitalization to discharge may represent an additional opportunity for antibiotic stewardship. METHODS: We reviewed antimicrobial drugs prescribed at discharge to patients at our medical center over a nine-month period, and calculated the total duration of inpatient and outpatient antibiotic therapy. RESULTS: The median duration of inpatient antibiotics was three days (interquartile range [IQR] four days), of outpatient antibiotics was seven days (IQR six days), and of total antibiotics 10 days (IQR six days). CONCLUSIONS: Our results align with the only previously published study of oral antibiotics prescribed at hospital discharge, both in the duration of inpatient and outpatient therapy and in the fact that about 60 percent of the treatment duration occurred after discharge. However, the median total antibiotic duration of 10 days is longer than that recommended by national and institutional guidelines for some of the most common infections in hospitalized patients.

Executive Summary: 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Treatment of Coccidioidomycosis.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Infectious Diseases Society of America considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.Coccidioidomycosis, also known as San Joaquin Valley fever, is a systemic infection endemic to parts of the southwestern United States and elsewhere in the Western Hemisphere. Residence in and recent travel to these areas are critical elements for the accurate recognition of patients who develop this infection. In this practice guideline, we have organized our recommendations to address actionable questions concerning the entire spectrum of clinical syndromes. These can range from initial pulmonary infection, which eventually resolves whether or not antifungal therapy is administered, to a variety of pulmonary and extrapulmonary complications. Additional recommendations address management of coccidioidomycosis occurring for special at-risk populations. Finally, preemptive management strategies are outlined in certain at-risk populations and after unintentional laboratory exposure.

2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Treatment of Coccidioidomycosis.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Infectious Diseases Society of America considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.Coccidioidomycosis, also known as San Joaquin Valley fever, is a systemic infection endemic to parts of the southwestern United States and elsewhere in the Western Hemisphere. Residence in and recent travel to these areas are critical elements for the accurate recognition of patients who develop this infection. In this practice guideline, we have organized our recommendations to address actionable questions concerning the entire spectrum of clinical syndromes. These can range from initial pulmonary infection, which eventually resolves whether or not antifungal therapy is administered, to a variety of pulmonary and extrapulmonary complications. Additional recommendations address management of coccidioidomycosis occurring for special at-risk populations. Finally, preemptive management strategies are outlined in certain at-risk populations and after unintentional laboratory exposure.

Recurrent Systemic Anaplastic Lymphoma Kinase-Negative Anaplastic Large Cell Lymphoma Presenting as a Breast Implant-Associated Lesion.

A woman aged 48 years presented with fevers, chills, weight loss, and night sweats. She had significant lymphadenopathy of the left neck as well as the left axilla. Her history was significant for bilateral breast augmentation with textured silicone implants more than 25 years ago. Excisional biopsy of a cervical lymph node revealed large, atypical cells positive for CD4 and CD30 and negative for Epstein-Barr virus-encoded ribonucleic acid, CD2, CD3, CD5, CD7, CD8, CD15, CD20, pan-keratin, S100, anaplastic lymphoma kinase (ALK), and paired box 5. These findings were consistent with Ann Arbor stage IIIB ALK-anaplastic large cell lymphoma (ALCL). The patient was started on 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone. She initially had no signs or symptoms of breast involvement; however, after developing seroma during the clinical course, the patient underwent capsulectomy and removal of the intact, textured silicone implants. Pathological evaluation demonstrated ALK-ALCL in the left breast capsule with cells displaying a significant degree of pleomorphism with binucleated forms and numerous mitoses. Fluorescence in situ hybridization confirmed the tumor was negative for t(2;5). She presented 8 weeks later showing evidence of recurrent systemic disease.

Menopausal status does not predict Oncotype DX recurrence score.

BACKGROUND: Adjuvant treatment for early stage, estrogen receptor (ER) positive invasive breast cancer has been based on prognosticators such as menopausal status. The recurrence score (RS) from the 21-gene assay Oncotype DX (ODX) is predictive of a 10-y distant recurrence in this population but is rarely applied to premenopausal patients. The relationship between menopausal status and RS was evaluated. MATERIALS AND METHODS: An institutional review board-approved retrospective review was conducted of invasive breast cancer patients with known RS. ODX eligibility was based on National Comprehensive Cancer Network guidelines or physician discretion. Perimenopausal women were classified as premenopausal for statistical analyses. Comparisons of menopausal status and RS were made using general linear regression model and the exact Wilcoxon rank-sum test. RESULTS: Menopausal status was available for 575 patients (142 premenopausal, 433 postmenopausal). Median age was 46 y for premenopausal and 62 y for postmenopausal. Median invasive tumor size was 1.5 cm for both cohorts. Mastectomy rate was higher in the premenopausal group (54.8%) than postmenopausal (42%; P = 0.0001). Premenopausal women had a higher local-regional recurrence rate (2.8% versus 0%; P = 0.0384) but distant recurrence and overall survival were not statistically different (P = 0.6808). Median ER H-score was lower in premenopausal (H-score = 270) than postmenopausal women (H-score = 280; P < 0.0001). Median RS was 16 for both premenopausal (range, 0-54) and postmenopausal (range, 0-63) women. Menopausal status as a categorical variable was not predictive of RS (P-value = 0.6780). CONCLUSIONS: Menopausal status has limited predictive power for distant recurrence. Therefore, menopausal status alone should not preclude performance of ODX in ER-positive, early stage breast cancer.

Recent advances in our understanding of the environmental, epidemiological, immunological, and clinical dimensions of coccidioidomycosis.

Coccidioidomycosis is the endemic mycosis caused by the fungal pathogens Coccidioides immitis and C. posadasii. This review is a summary of the recent advances that have been made in the understanding of this pathogen, including its mycology, genetics, and niche in the environment. Updates on the epidemiology of the organism emphasize that it is a continuing, significant problem in areas of endemicity. For a variety of reasons, the number of reported coccidioidal infections has increased dramatically over the past decade. While continual improvements in the fields of organ transplantation and management of autoimmune disorders and patients with HIV have led to dilemmas with concurrent infection with coccidioidomycosis, they have also led to advances in the understanding of the human immune response to infection. There have been some advances in therapeutics with the increased use of newer azoles. Lastly, there is an overview of the ongoing search for a preventative vaccine.

Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis.

BACKGROUND: Impaired signaling in the IFN-γ/IL-12 pathway causes susceptibility to severe disseminated infections with mycobacteria and dimorphic yeasts. Dominant gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis. OBJECTIVE: We sought to identify the molecular defect in patients with disseminated dimorphic yeast infections. METHODS: PBMCs, EBV-transformed B cells, and transfected U3A cell lines were studied for IFN-γ/IL-12 pathway function. STAT1 was sequenced in probands and available relatives. Interferon-induced STAT1 phosphorylation, transcriptional responses, protein-protein interactions, target gene activation, and function were investigated. RESULTS: We identified 5 patients with disseminated Coccidioides immitis or Histoplasma capsulatum with heterozygous missense mutations in the STAT1 coiled-coil or DNA-binding domains. These are dominant gain-of-function mutations causing enhanced STAT1 phosphorylation, delayed dephosphorylation, enhanced DNA binding and transactivation, and enhanced interaction with protein inhibitor of activated STAT1. The mutations caused enhanced IFN-γ-induced gene expression, but we found impaired responses to IFN-γ restimulation. CONCLUSION: Gain-of-function mutations in STAT1 predispose to invasive, severe, disseminated dimorphic yeast infections, likely through aberrant regulation of IFN-γ-mediated inflammation.