Immunization adherence among children with sickle cell disease and sickle cell trait: Results of a population-based study.

INTRODUCTION: Despite the importance of timely vaccine completion for protection from infectious disease, there is limited knowledge of the immunization adherence rates of children with sickle cell disease (SCD). METHODS: This is a retrospective cohort study comparing the immunization rates of children with SCD to those with sickle cell trait between 2008 and 2019 in Georgia. Completion rates for each vaccine and the proportion of children with up-to-date status at 24 and 35 months were calculated and compared between the cohorts. Chi-square tests with odds ratios (OR) for differences and 95% confidence intervals (CIs) were reported on the overall up-to-date rates and rates for individual vaccines at 24 and 35 months for the two cohorts. RESULTS: Children with SCD had higher up-to-date rates than children with sickle cell trait at 24 and 35 months. At 35 months, the overall up-to-date rates (OR = 1.17; 95% CI, 1.04-1.31; p = .004) and the four-dose pneumococcal conjugate vaccine series (OR = 1.36; 95% CI, 1.18-1.57; p < .001) were significantly different between the groups. Both cohorts had the highest completion rates for the hepatitis B series and the lowest rates for the varicella vaccine. Doses of diphtheria, tetanus, and acellular pertussis vaccine; varicella; and pneumococcal conjugate vaccines were most commonly missed by children in both cohorts. CONCLUSIONS: Children with SCD have better immunization coverage than children with sickle cell trait, but there is an opportunity for improvement. Policymakers and healthcare professionals should focus on increasing access to care coordination services among children with SCD to ensure on-time and preventive healthcare services.

Mediator complex subunit 1 architects a tumorigenic Treg cell program independent of inflammation.

While immunotherapy has revolutionized cancer treatment, its safety has been hampered by immunotherapy-related adverse events. Unexpectedly, we show that Mediator complex subunit 1 (MED1) is required for T regulatory (Treg) cell function specifically in the tumor microenvironment. Treg cell-specific MED1 deletion does not predispose mice to autoimmunity or excessive inflammation. In contrast, MED1 is required for Treg cell promotion of tumor growth because MED1 is required for the terminal differentiation of effector Treg cells in the tumor. Suppression of these terminally differentiated Treg cells is sufficient for eliciting antitumor immunity. Both human and murine Treg cells experience divergent paths of differentiation in tumors and matched tissues with non-malignant inflammation. Collectively, we identify a pathway promoting the differentiation of a Treg cell effector subset specific to tumors and demonstrate that suppression of a subset of Treg cells is sufficient for promoting antitumor immunity in the absence of autoimmune consequences.

Uptake of Lung Cancer Screening CT After a Provider Order for Screening in the PROSPR-Lung Consortium.

BACKGROUND: Uptake of lung cancer screening (LCS) has been slow with less than 20% of eligible people who currently or formerly smoked reported to have undergone a screening CT. OBJECTIVE: To determine individual-, health system-, and neighborhood-level factors associated with LCS uptake after a provider order for screening. DESIGN AND SUBJECTS: We conducted an observational cohort study of screening-eligible patients within the Population-based Research to Optimize the Screening Process (PROSPR)-Lung Consortium who received a radiology referral/order for a baseline low-dose screening CT (LDCT) from a healthcare provider between January 1, 2015, and June 30, 2019. MAIN MEASURES: The primary outcome is screening uptake, defined as LCS-LDCT completion within 90 days of the screening order date. KEY RESULTS: During the study period, 18,294 patients received their first order for LCS-LDCT. Orders more than doubled from the beginning to the end of the study period. Overall, 60% of patients completed screening after receiving their first LCS-LDCT order. Across health systems, uptake varied from 41 to 87%. In both univariate and multivariable analyses, older age, male sex, former smoking status, COPD, and receiving care in a centralized LCS program were positively associated with completing LCS-LDCT. Unknown insurance status, other or unknown race, and lower neighborhood socioeconomic status, as measured by the Yost Index, were negatively associated with screening uptake. CONCLUSIONS: Overall, 40% of patients referred for LCS did not complete a LDCT within 90 days, highlighting a substantial gap in the lung screening care pathway, particularly in decentralized screening programs.

Ubiquitin-specific peptidase 22 controls integrin-dependent cancer cell stemness and metastasis.

Integrins plays critical roles in connecting the extracellular matrix and actin skeleton for cell adhesion, migration, signal transduction, and gene transcription, which upregulation is involved in cancer stemness and metastasis. However, the molecular mechanisms underlying how integrins are upregulated in cancer stem cells (CSCs) remain as a biomedical mystery. Herein, we show that the death from cancer signature gene USP22 is essential to maintain the stemness of breast cancer cells through promoting the transcription of a group of integrin family members in particular integrin ß1 (ITGB1). Both genetic and pharmacological USP22 inhibition largely impaired breast cancer stem cell self-renewal and prevented their metastasis. Integrin ß1 reconstitution partially rescued USP22-null breast cancer stemness and their metastasis. At the molecular level, USP22 functions as a bona fide deubiquitinase to protect the proteasomal degradation of the forkhead box M1 (FoxM1), a transcription factor for tumoral ITGB1 gene transcription. Importantly unbiased analysis of the TCGA database revealed a strong positive correlation between the death from cancer signature gene ubiquitin-specific peptidase 22 (USP22) and ITGB1, both of which are critical for cancer stemness, in more than 90% of human cancer types, implying that USP22 functions as a key factor to maintain stemness for a broad spectrum of human cancer types possibly through regulating ITGB1. To support this notion, immunohistochemistry staining detected a positive correlation among USP22, FoxM1 and integrin ß1 in human breast cancers. Collectively, our study identifies the USP22-FoxM1-integrin ß1 signaling axis critical for cancer stemness and offers a potential target for antitumor therapy.

CDK4/6-MEK Inhibition in MPNSTs Causes Plasma Cell Infiltration, Sensitization to PD-L1 Blockade, and Tumor Regression.

PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) are lethal, Ras-driven sarcomas that lack effective therapies. We investigated effects of targeting cyclin-dependent kinases 4 and 6 (CDK4/6), MEK, and/or programmed death-ligand 1 (PD-L1) in preclinical MPNST models. EXPERIMENTAL DESIGN: Patient-matched MPNSTs and precursor lesions were examined by FISH, RNA sequencing, IHC, and Connectivity-Map analyses. Antitumor activity of CDK4/6 and MEK inhibitors was measured in MPNST cell lines, patient-derived xenografts (PDX), and de novo mouse MPNSTs, with the latter used to determine anti-PD-L1 response. RESULTS: Patient tumor analyses identified CDK4/6 and MEK as actionable targets for MPNST therapy. Low-dose combinations of CDK4/6 and MEK inhibitors synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death, and decreased clonogenic survival of MPNST cells. In immune-deficient mice, dual CDK4/6-MEK inhibition slowed tumor growth in 4 of 5 MPNST PDXs. In immunocompetent mice, combination therapy of de novo MPNSTs caused tumor regression, delayed resistant tumor outgrowth, and improved survival relative to monotherapies. Drug-sensitive tumors that regressed contained plasma cells and increased cytotoxic T cells, whereas drug-resistant tumors adopted an immunosuppressive microenvironment with elevated MHC II-low macrophages and increased tumor cell PD-L1 expression. Excitingly, CDK4/6-MEK inhibition sensitized MPNSTs to anti-PD-L1 immune checkpoint blockade (ICB) with some mice showing complete tumor regression. CONCLUSIONS: CDK4/6-MEK inhibition induces a novel plasma cell-associated immune response and extended antitumor activity in MPNSTs, which dramatically enhances anti-PD-L1 therapy. These preclinical findings provide strong rationale for clinical translation of CDK4/6-MEK-ICB targeted therapies in MPNST as they may yield sustained antitumor responses and improved patient outcomes.

Real time patient-reported outcome measures in patients with cancer: Early experience within an integrated health system.

BACKGROUND: While patient-reported outcome measures (PROMs) have benefit in cancer clinical trials, real-world applications are lacking. This study describes the method of implementation of a cancer enterprise-wide PROMs platform. METHODS: After establishing a multispecialty stakeholder group within a large integrated health system, domain-specific instruments were selected from the National Institutes of Health's Patient-Reported Outcomes Measurement Information System (PROMIS) instruments (pain interference, fatigue, physical function, and depression) and were administered at varying frequencies throughout each patient's cancer journey. All cancer patients with an oncologic visit were eligible to complete the PROMs prior to the visit using a patient portal, or at the time of the visit using a tablet. PROMs were integrated into clinical workflow. Clinical partnerships were essential for successful implementation. Descriptive preliminary data were compared using multivariable logistic regression to determine the factors associated with method of PROMs completion. RESULTS: From September 16, 2020 to July 23, 2021, 23 of 38 clinical units (60.5%) implemented PROMs over 2392 encounters and 1666 patients. Approximately one third of patients (n = 629, 37.8%) used the patient portal. Black patients (aOR 0.70; 95% CI: 0.51-0.97) and patients residing in zip codes with higher percentage of unemployment (aOR: 0.07, 95% CI: 0.01-0.41) were among the least likely to complete PROMs using the patient portal. CONCLUSIONS: Successful system-wide implementation of PROMs among cancer patients requires engagement from multispecialty stakeholders and investment from clinical partners. Attention to the method of PROMs collection is required in order to reduce the potential for disparities, such as Black populations and those residing in areas with high levels of unemployment.

Esophagectomies for Malignancy Among General and Thoracic Surgeons: A Propensity Score Matched National Surgical Quality Improvement Program Analysis Stratified by Surgical Approach.

Previous studies of esophagectomy outcomes by surgical specialty do not address malignancy or surgical approach. We sought to evaluate these cases using a national database. The National Surgical Quality Improvement Program (NSQIP)-targeted esophagectomy data set was queried for esophagectomies for malignancy and grouped by surgeon specialty: thoracic surgery (TS) or general surgery (GS). 1:1 propensity score matching was performed. Associations of surgical specialty with outcomes of interest (30-day mortality, anastomotic leak, Clavien-Dindo grade ≥ 3, and positive margin rate) were assessed overall and in surgical approach subsets. 1463 patients met inclusion criteria (512 GS and 951 TS). Propensity score matching yielded matched groups of 512, with similar demographics, preoperative stage, and neoadjuvant therapy rates. All outcomes of interest were similar between TS and GS groups, both overall and when stratified by surgical approach. Esophagectomy for malignancy has a similar perioperative safety profile and positive margin rate among general and thoracic surgeons, regardless of surgical approach.

The Detroit Keloid Scale: A Validated Tool for Rating Keloids.

Background: Comparing keloid treatment modalities and assessing response to treatments may be predicted by a better classification system. Objectives: To develop and validate the Detroit Keloid Scale (DKS), a standardized method of keloid assessment. Methods: Forty-seven physicians were polled to develop the DKS. The scale was validated in 52 patients against the Vancouver Scar Scale (VSS), Patient and Observer Scar Assessment Scale (POSAS), and Dermatology Life Quality Index (DLQI). Results: The inter-rater reliability was "substantial" for observer DKS and only "moderate" for VSS and observer POSAS (intraclass correlation coefficient were 0.80, 0.60, and 0.47, respectively). Pearson's correlation indicated "moderate" association between observer DKS with observer POSAS (ρ = 0.56, p < 0.001) and "substantial" relationship between observer DKS and VSS (ρ = 0.63, p < 0.001). Pearson's correlation indicated "moderate" association between patient portion of DKS and patient portion of POSAS and patient portion of the DKS and DLQI (0.61 and 0.60, respectively, p < 0.05). DKS total score consistently showed significant "substantial" relationship with POSAS total score (ρ = 0.65, p < 0.001). Conclusions: The DKS offers a validated keloid-specific outcome measure for comparing keloid treatments.

Trends in blood transfusion, hydroxyurea use, and iron overload among children with sickle cell disease enrolled in Medicaid, 2004-2019.

BACKGROUND: There have been significant changes in clinical guidelines for sickle cell disease (SCD) over the past two decades, including updated indications for hydroxyurea, transfusions, and iron overload management. In practice however, there are few studies that examine SCD care utilization over time. METHODS: We conducted a serial cross-sectional cohort study of pediatric SCD patients from 2004 to 2019 using Georgia Medicaid claims data. For each year, we reported receipt of any transfusion, chronic transfusion, or three or more filled hydroxyurea prescriptions. For children receiving chronic transfusion (six or more annual transfusions), we evaluated iron overload diagnosis, monitoring, and chelation use. Among children with sickle cell anemia (SCA), we examined rates of transfusions and hydroxyurea use. The Cochran-Armitage test was used to assess trend. RESULTS: There were 5316 unique children 2-18 years old with SCD enrolled in Georgia Medicaid from 2004 to 2019. Children receiving any transfusion increased from 2004 to 2010, then stabilized. In SCA patients, chronic transfusions initially increased from 2004 to 2010, then stabilized from 2010 to 2019. For chronically transfused children, monitoring of iron burden and filled chelator prescriptions both increased significantly. Hydroxyurea use in SCA patients increased from 12% to 37%, with increases noted within each age group, most notably from 21% to 60% in the 13-18-year-old cohort. CONCLUSION: We demonstrated changes in SCD care utilization over time, including increased hydroxyurea use, changes in transfusion rates, and increased attention to iron overload management. While trends in clinical management do follow updates in treatment guidelines, there is still delayed and suboptimal uptake of guideline recommendations in pediatric SCD patients.

Persistent EGFR/K-RAS/SIAH pathway activation drives chemo-resistance and early tumor relapse in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. It disproportionately affects BRCA mutation carriers and young women, especially African American (AA) women. Chemoresistant TNBC is a heterogeneous and molecularly unstable disease that challenges our ability to apply personalized therapies. With the approval of immune checkpoint blockade (ICB) for TNBC, the addition of pembrolizumab to systemic chemotherapy has become standard of care (SOC) in neoadjuvant systemic therapy (NST) for high-risk early-stage TNBC. Pembrolizumab plus chemotherapy significantly increased the pathologic complete response (pCR) and improved event-free survival in TNBC. However, clinical uncertainties remain because similarly treated TNBC partial responders with comparable tumor responses to neoadjuvant therapy often experience disparate clinical outcomes. Current methods fall short in accurately predicting which high-risk patients will develop chemo-resistance and tumor relapse. Therefore, novel treatment strategies and innovative new research initiatives are needed. We propose that the EGFR-K-RAS-SIAH pathway activation is a major tumor driver in chemoresistant TNBC. Persistent high expression of SIAH in residual tumors following NACT/NST reflects that the EGFR/K-RAS pathway remains activated (ON), indicating an ineffective response to treatment. These chemoresistant tumor clones persist in expressing SIAH (SIAHHigh/ON) and are linked to early tumor relapse and poorer prognosis. Conversely, the loss of SIAH expression (SIAHLow/OFF) in residual tumors post-NACT/NST reflects EGFR/K-RAS pathway inactivation (OFF), indicating effective therapy and chemo-sensitive tumor cells. SIAHLow/OFF signal is linked to tumor remission and better prognosis post-NACT/NST. Therefore, SIAH is well-positioned to become a novel tumor-specific, therapy-responsive, and prognostic biomarker. Potentially, this new biomarker (SIAHHigh/ON) could be used to quantify therapy response, predict chemo-resistance, and identify those patients at the highest risk for tumor relapse and poor survival in TNBC.

Cetuximab and anemia prevention in head and neck cancer patients undergoing radiotherapy.

BACKGROUND: Epidermal growth factor receptor (EGFR) activation is associated with increased production of interleukin 6 (IL6), which is intensified by radiotherapy (RT) induced inflammatory response. Elevated IL6 levels intensifies RT-induced anemia by upregulating hepcidin causing functional iron deficiency. Cetuximab, an EGFR inhibitor, has been associated with lower rates of anemia for locally advanced head and neck squamous cell carcinoma (HNSCC). We hypothesized that concomitant cetuximab could prevent RT-induced anemia. METHODS: We queried our institutional head and neck cancers database for non-metastatic HNSCC cases that received RT with concomitant cetuximab or RT-only between 2006 and 2018. Cetuximab was administered for some high-risk cases medically unfit for platinum agents per multidisciplinary team evaluation. We only included patients who had at least one complete blood count in the 4 months preceding and after RT. We compared the prevalence of anemia (defined as hemoglobin (Hb) below 12 g/dL in females and 13 g/dL in males) and mean Hb levels at baseline and after RT. Improvement of anemia/Hb (resolution of baseline anemia and/or an increase of baseline Hb ≥1 g/dL after RT), and overall survival (OS) in relation to anemia/Hb dynamics were also compared. RESULTS: A total of 171 patients were identified equally distributed between cetuximab-plus-RT and RT-only groups. The cetuximab-plus-RT group had more locally-advanced stage, oropharyngeal and high grade tumors (p < 0.001 for all). Baseline anemia/Hb were similar, however anemia after RT conclusion was higher in the cetuximab-plus-RT vs RT-only (63.5% vs. 44.2%; p = 0.017), with a mean Hb of 11.98 g/dL vs. 12.9 g/dL; p = 0.003, for both respectively. This contributed to significantly worse anemia/Hb improvement for cetuximab-plus-RT (18.8% vs. 37.2%; p = 0.007). This effect was maintained after adjusting for other factors in multivariate analysis. The prevalence of iron, vitamin-B12 and folate deficiencies; and chronic kidney disease, was non-different. Baseline anemia was associated with worse OS (p = 0.0052) for the whole study cohort. Nevertheless, improvement of anemia/Hb was only marginally associated with better OS (p = 0.068). CONCLUSIONS: In contrast to previous studies, cetuximab was not associated with lower rates of anemia after RT for nonmetastatic HNSCC patients compared to RT-alone. Dedicated prospective studies are needed to elucidate the effect of cetuximab on RT-induced anemia.

Epidemiology and outcomes in patients with anemia of CKD not on dialysis from a large US healthcare system database: a retrospective observational study.

BACKGROUND: Optimal management of anemia of chronic kidney disease (CKD) remains controversial. This retrospective study aimed to describe the epidemiology and selected clinical outcomes of anemia in patients with CKD in the US. METHODS: Data were extracted from Henry Ford Health System databases. Adults with stages 3a-5 CKD not on dialysis (estimated glomerular filtration rate < 60 mL/min/1.73m2) between January 1, 2013 and December 31, 2017 were identified. Patients on renal replacement therapy or with active cancer or bleeding were excluded. Patients were followed for ≥12 months until December 31, 2018. Outcomes included incidence rates per 100 person-years (PY) of anemia (hemoglobin < 10 g/dL), renal and major adverse cardiovascular events, and of bleeding and hospitalization outcomes. Adjusted Cox proportional hazards models identified factors associated with outcomes after 1 and 5 years. RESULTS: Among the study cohort (N = 50,701), prevalence of anemia at baseline was 23.0%. Treatments used by these patients included erythropoiesis-stimulating agents (4.1%), iron replacement (24.2%), and red blood cell transfusions (11.0%). Anemia incidence rates per 100 PY in patients without baseline anemia were 7.4 and 9.7 after 1 and 5 years, respectively. Baseline anemia was associated with increased risk of renal and major cardiovascular events, hospitalizations (all-cause and for bleeding), and transfusion requirements. Increasing CKD stage was associated with increased risk of incident anemia, renal and major adverse cardiovascular events, and hospitalizations. CONCLUSIONS: Anemia was a prevalent condition associated with adverse renal, cardiovascular, and bleeding/hospitalization outcomes in US patients with CKD. Anemia treatment was infrequent.

Bowel Preparation for Elective Hartmann Operation: Analysis of the National Surgical Quality Improvement Program Database.

Background: Use of pre-operative bowel preparation in colorectal resection has not been examined solely in patients who have had colorectal resection with primary colostomy (Hartmann procedure). We aimed to evaluate the association of bowel preparations with short-term outcomes after non-emergent Hartmann procedure. Patients and Methods: The National Surgical Quality Improvement Program Participant Use File colectomy database was queried for patients who had elective open or laparoscopic Hartmann operation. Patients were grouped by pre-operative bowel preparation: no bowel preparation, oral antibiotic agents, mechanical preparation, or both mechanical and oral antibiotic agent preparation (combined). Propensity analysis was performed, and outcomes were compared by type of pre-operative bowel preparation. The primary outcome was rate of any surgical site infection (SSI). Secondary outcomes included overall complication, re-operation, re-admission, Clostridioides difficile colitis, and length of stay. Results: Of the 4,331 records analyzed, 2,040 (47.1%) patients received no preparation, 251 (4.4%) received oral antibiotic preparation, 1,035 (23.9%) received mechanical bowel preparation, and 1,005 (23.2%) received combined oral antibiotic and mechanical bowel preparation. After propensity adjustment, rates of any SSI, overall complication, and length of hospital stay varied significantly between pre-operative bowel regimens (p < 0.005). The use of combined bowel preparation was associated with decreased rate of SSI, overall complication, and length of stay. No difference in rate of re-operation or post-operative Clostridioides difficile infection was observed based on bowel preparation. Conclusions: Compared with no pre-operative bowel preparation, any bowel preparation was associated with reduced rate of SSI, but not rate of re-operation or post-operative Clostridioides difficile infection.

Vaginal vault smear cytology in detection of recurrence after hysterectomy for early cervical cancer.

OBJECTIVE: To determine the role of vaginal vault cytology as a surveillance tool for the detection of recurrence in patients with early stage cervical cancer treated with hysterectomy without adjuvant therapy. METHODS: A retrospective cohort study was conducted of all women with cervical cancer treated with a hysterectomy from January 2000 to July 2016 at the Royal Brisbane & Women's Hospital, Australia. Women included were diagnosed with the equivalent of International Federation of Gynecology and Obstetrics (FIGO) 2018 stage 1A1 to 1B3 squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma, received either simple or radical hysterectomy with or without pelvic lymph node dissection, and did not receive adjuvant therapy. Age, stage, histology, surgical procedure, and details of individual surveillance regimens including examination findings and indications and results for all vault cytology tests performed in the first 5 years following surgical management were collected. RESULTS: A total of 155 women met the inclusion criteria. Most cases were FIGO 2018 stage 1B1 (61.9%) and squamous cell carcinoma (64.5%). Included women underwent a median of 80 months of surveillance (range 25-200, IQR 64-108). In the first 5 years of surveillance, there were a total of 1001 vault cytology smears performed, with a median of 6 smears (IQR 5-9) per woman. A total of 19 smears were abnormal (1.9%). Of the cohort of 155 women, 19 (12.3%) had an abnormality detected; 1 (0.65%) had a high-grade intraepithelial abnormality and 2 (1.3%) had recurrences detected on cytology; however, a lesion was also seen and biopsied in all three women. A total of 16 of 1001 smears (1.6%) had low-grade abnormalities detected, all of which resolved with clinical observation only. All were alive and well at last review. There were in total 6 (3.9%) recurrences, 2 (33%) of which had abnormal cytology as above, and all of which had a lesion to biopsy and/or abnormal medical imaging. CONCLUSIONS: The routine use of vaginal vault cytology in surveillance following hysterectomy for early stage cervical cancer did not appear to alter the detection of recurrent malignancy.

Prerenal Transplant Education and Evaluation Positively Impacts Outcomes.

Introduction: An outstanding question in kidney transplantation is how to prepare candidates and their social supports for optimal posttransplant outcomes. Project Aims: This program evaluation assessed whether a pretransplant quality improvement clinic improved clinical outcomes in the year posttransplant compared to recipients receiving standard of care. Design: The Countdown to Transplant Clinic was implemented with kidney transplant candidates expected to receive a transplant within the next few months. The clinic included an enhanced education session on posttransplant lifestyle management, confirmation of support (≥2 adults), and evaluations by transplant social work, psychology, and nephrology. Results: Seventy-five patients participated in the clinic and underwent a transplant. A retrospective chart review of posttransplant laboratory values, rehospitalizations (within 3-months posttransplant), biopsy-confirmed graft failure, and mortality (within 1-year posttransplant) were collected from both groups. Univariate and multivariate propensity score-weighted linear or logistic regression models were used to evaluate the association between clinic participation and outcomes. In models adjusting for relevant covariates, participation in The Countdown to Transplant Clinic (vs standard care) was associated with a lower coefficient of variation of serum tacrolimus (all values collected 3-12 months posttransplant), 30-day posttransplant white blood cell counts (but not 90-day), 90-day posttransplant potassium, and 30 and 31 to 90 days rehospitalizations. Clinic participation did not predict serum glucose levels at 30- or 90-days posttransplant. Due to low rates of rejection and mortality, meaningful comparisons were not possible. Conclusion: Participation in a pretransplant, multicomponent clinic may improve certain outcomes of interest posttransplantation. Pilot testing for feasibility for randomized controlled trials is a necessary next step.

Real-world effectiveness of the pegfilgrastim on-body injector in preventing severe neutropenia.

INTRODUCTION: Granulocyte colony-stimulating factors are used in medical oncology for the prevention of neutropenia. On-body injectors (OBI) have an advantage over the traditional injection (TI) method of not requiring a second visit to the clinic, but these devices are subject to failure. The objective of this study was to assess the efficacy of OBIs in the real-world. METHODS: Women with breast cancer diagnosed between June 2015 and June 2016 treated with cytotoxic chemotherapy and a granulocyte colony-stimulating factor were retrospectively identified from the medical records of Henry Ford Hospital. The primary outcome was the incidence of severe neutropenia (SN), defined as an absolute neutrophil count (ANC) ≤500. Secondary outcomes included incidence of neutropenia (ANC ≤ 1500), neutropenic fever, and mortality. A secondary analysis of the data was performed to identify predictors of SN. RESULTS: A total of 837 cycles of chemotherapy were analyzed. The OBI was used in 395 cycles and the TI in 442. The OBI group had patients that were older, had higher baseline ANC, and were more often white. The incidences of SN, neutropenic fever and neutropenia were not different between groups. Patients with a lower baseline ANC and white ethnicity were at a higher risk for SN. AC (doxorubicin and cyclophosphamide) was the most commonly used chemotherapy regimen (38% of total cycles). CONCLUSIONS: There was no difference in the efficacy of the OBI and TI methods for preventing SN, neutropenic fever and neutropenia.

Intraoperative Nerve Monitoring in Thyroidectomies for Malignancy: Does It Matter?

BACKGROUND: Recurrent laryngeal nerve (RLN) injury and postoperative hypocalcemia are potential complications of thyroidectomy, particularly in malignancy. Intraoperative nerve monitoring (IONM) remains controversial. We sought to evaluate the impact of IONM on these complications using a national data set. METHODS: The American College of Surgeons National Surgical Quality Improvement Program thyroidectomy-targeted data set was queried for patients who underwent thyroidectomies from 2016 to 2017. Patients were grouped according to IONM use. Logistic regression models were constructed to evaluate associations of variables with 30-day hypocalcemic events (HCEs) and RLN injury. Associations were expressed as odds ratios (ORs) with 95% confidence intervals (95% CIs). A subgroup analysis was performed of patients with malignancy. RESULTS: A total of 9527 patients were identified; 5969 (62.7%) underwent thyroidectomy with IONM and 3558 (37.3%) without. By multivariable analysis, IONM had protective associations with HCE (OR = .81, 95% CI = .68-.96; P = .013) and RLN injury (OR = .83, 95% CI = .69-.98; P = .033). Malignancy increased risk of HCE (OR = 1.21, 95% CI=1.01-1.45; P = .038) and RLN injury (OR = 1.22, 95% CI = 1.02-1.46; P = .034). A large proportion (5943/9527, 62.4%) of patients had malignancy; 3646 (61.3%) underwent thyroidectomy with IONM and 2297 (38.7%) without. In the subgroup analysis, IONM had stronger protective associations with HCE (OR = .73, 95% CI = .60-.90; P = .003) and RLN injury (OR = .76, 95% CI = .62-.94; P = .012). DISCUSSION: Malignancy was associated with increased risk of HCE and RLN injury. Intraoperative nerve monitoring had a protective association with HCE and RLN injury, both overall, and in the malignant subgroup. Intraoperative nerve monitoring was correlated with improved thyroidectomy outcomes, especially if the indication was malignancy. This warrants further study to clarify cause and effect.

The ubiquitin-specific peptidase 22 is a deubiquitinase of CD73 in breast cancer cells.

Cancer cells evade the immune system by expressing inhibitory immune checkpoint receptors such as ecto-5'-nucleotidase (NT5E), also known as CD73, which consequently suppress tumor neoantigen-specific immune response. Blockade of CD73 in mouse models of breast cancer showed a reduction in tumor growth and metastasis. CD73 expression is elevated in a variety of human tumors including breast cancer. While the regulation of CD73 expression at the transcriptional level has been well understood, the factors involved in regulating CD73 expression at the post-transcriptional level have not been identified. Herein, we discovered that the ubiquitin-specific peptidase 22 (USP22), a deubiquitinase associated with poor prognosis and overexpressed in breast cancers, is a positive regulator for CD73. Targeted USP22 deletion resulted in a statistically significant reduction in CD73 protein expression. In contrast, CD73 mRNA expression levels were not reduced, but even slightly increased by USP22 deletion. Further analysis demonstrated that USP22 is a deubiquitinase that specifically interacts with and inhibits CD73 ubiquitination. Consequently, USP22 protects CD73 from ubiquitin-mediated proteasomal degradation in breast cancer cells. Targeted USP22 deletion, inhibits syngeneic breast cancer growth. Collectively, our study reveals USP22 as a positive regulator to promote CD73 expression in breast cancer and provides a rationale to target USP22 in antitumor immune therapy.