PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial.

Despite recent therapeutic advances, metastatic castration-resistant prostate cancer (mCRPC) remains lethal. Chimeric antigen receptor (CAR) T cell therapies have demonstrated durable remissions in hematological malignancies. We report results from a phase 1, first-in-human study of prostate stem cell antigen (PSCA)-directed CAR T cells in men with mCRPC. The starting dose level (DL) was 100 million (M) CAR T cells without lymphodepletion (LD), followed by incorporation of LD. The primary end points were safety and dose-limiting toxicities (DLTs). No DLTs were observed at DL1, with a DLT of grade 3 cystitis encountered at DL2, resulting in addition of a new cohort using a reduced LD regimen + 100 M CAR T cells (DL3). No DLTs were observed in DL3. Cytokine release syndrome of grade 1 or 2 occurred in 5 of 14 treated patients. Prostate-specific antigen declines (>30%) occurred in 4 of 14 patients, as well as radiographic improvements. Dynamic changes indicating activation of peripheral blood endogenous and CAR T cell subsets, TCR repertoire diversity and changes in the tumor immune microenvironment were observed in a subset of patients. Limited persistence of CAR T cells was observed beyond 28 days post-infusion. These results support future clinical studies to optimize dosing and combination strategies to improve durable therapeutic outcomes. ClinicalTrials.gov identifier NCT03873805 .

Counting the Cost of Daptomycin Versus Vancomycin in Hospitalized Patients: A Cost Minimization Analysis.

Daptomycin use for gram-positive infections has increased. This cost minimization analysis aimed to determine cost and/or time savings of daptomycin over vancomycin. The estimated hospital cost savings was US$166.41 per patient, and pharmacist time saved of almost 20 minutes per patient. Daptomycin has the potential to save both time and money.

Debate as an Active Learning Pedagogy Among Pharmacy Students in a Public Health Course.

OBJECTIVE: To evaluate the impact of a debate activity on pharmacy students' knowledge of public health and health policy topics. METHODS: Forty-six second-year pharmacy students in a required public health and health policy course debated universal healthcare coverage for Americans using the Lincoln-Douglas oral debate format. Demographic data, including age and gender, were collected. Knowledge (before/after) of universal healthcare principles was assessed via a rubric-embedded quiz related to the activity objectives. The students' perceptions of the educational value of the debate were assessed before and after the debate using a 12-item Likert scale (1 = strongly disagree through 5 = strongly agree) and open-ended questions. Descriptive statistics and thematic analysis were conducted using SPSS v25 and Atlas.ti version 9, respectively. Wilcoxon t tests were conducted to compare preknowledge and postknowledge scores. An α level of 0.05 was utilized. RESULTS: Forty-two students completed the perceptions survey, yielding a 96 % response rate. The mean age was 24 ± 4 years and primarily female (63 %). Most students had no previous experience with debates (80.4 %) and there was a statistically significant improvement in knowledge after the debate from 66.5 % ± 13.4 % to 80.7 % ± 12 % , for a total increase of 14.2 %. Open responses indicated that students believed their overall knowledge about other healthcare systems increased and they developed literature review and communications skills. CONCLUSION: The debate activity enhanced the students' knowledge and assessment of controversial public health issues that will be useful during their pharmacy education and careers. The students perceived that the debates enriched their learning.

Methicillin-Resistant Staphylococcus aureus Bacteremia Treated With Vancomycin Calculated by Area-Under-the-Curve in Patients With Elevated Vancomycin Minimum Inhibitory Concentrations.

Purpose: Vancomycin is recommended as first-line treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, dosed by area-under-the-curve (AUC) with an assumed minimum inhibitory concentration (MIC) of 1 mcg/mL via broth microdilution. The purpose of this study was to compare effectiveness of AUC-based and trough-based dosing in MRSA bacteremia with an MIC > 1 mcg/mL via Etest. Methods: This was a retrospective, observational cohort that compared vancomycin dosed by AUC or trough between January 1, 2017 and September 1, 2022. The primary outcome was a composite of treatment failure defined as peristent bacteremia ≥ 7 days, inpatient mortality within 90 days, or microbiologic relapse or readmission within 30 days. Secondary outcomes compared nephrotoxicity, hospital and ICU length of stay, MIC differences, and difference in exposure measured by AUC. Results: Twenty-four patients in each group met inclusion criteria. For the primary outcome, there was no statistical difference in treatment failure between trough and AUC groups, respectively [10 (41.7%) vs 10 (41.7%), P = 1.000]. There was no statistical difference in secondary outcomes, with incidence of nephrotoxicity [3 (12.5%) trough vs 2 (8.33%) AUC, P = 1.000] and median AUC exposure over treatment course [502.9 mcg.h/mL (454.1-599.9) vs 474 mcg.h/mL (435.3-533), P = .312] similar between groups. Conclusion: There was no statistically significant difference in treatment failure for vancomycin by AUC or trough with an Etest MIC > 1 mcg/mL. Overall exposure to vancomycin and incidence of nephrotoxicty were numerically higher in the trough group, suggesting that dosing by AUC may limit exposure without impact on treatment failure.

Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial.

Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 106 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362 .

Interactive multidisciplinary pilot workshop to improve medical student perception of and interest in breast surgical oncology.

BACKGROUND: Exposure to breast surgical oncology (BSO) and the multidisciplinary management of patients with breast cancer is limited in medical school. The purpose of this study was to assess changes in student perceptions of BSO as a career following an interactive multidisciplinary workshop. METHODS: Pre-clinical medical students participated in a multidisciplinary, hands-on workshop, composed of breast radiology (BR), breast surgical oncology (BSO) and breast plastic reconstructive surgery (B-PRS). BR presented students screening and diagnostic breast imaging followed by hands-on ultrasound-guided biopsy on phantom simulators. BSO demonstrated lumpectomy, mastectomy, sentinel lymph node biopsy, and axillary lymph node dissections while B-PRS demonstrated oncoplastic techniques and autologous flap reconstruction with cadavers. Pre-and post-workshop surveys assessed student opinions on surgery and BSO. Results were compared using Wilcoxon Signed Rank, Wilcoxon Rank Sum, and Fisher's Exact. RESULTS: The workshop was attended by twenty-four students. There was a statistically significant increase in interest in BSO from 52% to 86% after the workshop (p = 0.003). The event improved understanding of the work and lifestyle in BSO for 79% (19/24). All students (100%) expressed interest to further explore BSO. The most common attractors to a career in BSO were impacts on patients' lives (N = 23), intellectual stimulation (N = 22), and earnings (N = 20). The most reported deterrents were lack of personal time (N = 18) and stress (N = 15). CONCLUSION: An interactive, anatomically based exposure to multidisciplinary breast cancer surgery improves medical student perception and interest in BSO. Medical schools should consider incorporating similar events to foster interest in BSO and other surgical subspecialties.

High-dose amphotericin: yay or nay? A case series and literature review.

Invasive fungal infections pose significant morbidity and mortality risks, particularly those caused by moulds. Available antifungal classes are limited by toxicities and are increasingly susceptible to resistance, particularly amongst challenging fungal pathogens. The purpose of this case series and literature review was to characterize the use of a high-dose lipid formulation of amphotericin B. A case series is presented including patients who received high-dose lipid formulation amphotericin B (≥7.5 mg/kg/day) between June 2012 and August 2021. Additionally, a systematic literature review was conducted by searching the PubMed database for English-language studies involving individuals who received high-dose amphotericin B therapy (≥7.5 mg/kg) using lipid formulations. Nine patients were included in the case series, receiving an average of 8.9 ± 1.3 mg/kg liposomal amphotericin B over a mean of 11.0 ± 10.8 days predominantly for mould infections including Mucorales, aspergillosis and Fusarium. The patients were primarily cared for in intensive care units, with varying treatment histories and outcomes. A total of 11 studies (n=260 patients) met inclusion criteria for the literature review. Responses to high-dose liposomal amphotericin B ranged from 8% to 100%, often showing favourable outcomes. High doses of liposomal amphotericin B were well tolerated both in the case series and in published literature, with serum creatinine changes being the most commonly reported adverse event. However, multi-patient studies continue to report less than favourable (range 8-62%) response rates. High-dose liposomal amphotericin B, either alone or in combination with other antifungal agents, might be a viable strategy for managing invasive fungal infections when few treatment choices exist. This article is part of the Challenges and strategies in the management of invasive fungal infections Special Issue: https://www.drugsincontext.com/special_issues/challenges-and-strategies-in-the-management-of-invasive-fungal-infections.

Advanced degrees, gender, and professional rank in surgery, disparities in academic medicine.

INTRODUCTION: Women comprise nearly half of all residents in training, yet there is a significant disparity of women in academic leadership. Surgical subspecialties are dominated by men in both percentages of physicians and leadership positions. We sought to examine the association of advanced non-medical degrees with academic rank and gender in academic surgery departments. METHODS: Faculty from 126 ACGME-accredited academic medical centers were analyzed to identify faculty gender as described in online biographical information, advanced non-medical degrees, academic rank, and additional leadership positions held. Descriptive statistics and logistic regression models were used for statistical analyses. RESULTS: 4536 surgeons were identified, 69.3% men, 27.3% female, and 3.3% unlisted. Female surgeons were more likely to hold advanced non-doctoral degrees than men (18.2% vs. 13.8%, p â€‹< â€‹0.002). Among those with advanced degrees, PhDs were held by 3.3% of women and 5.7% of men (p â€‹< â€‹0.001). Female surgeons were less likely to hold the rank of Professor than male surgeons (15.8% vs 30.3%, p â€‹< â€‹0.001), and more likely to hold the rank of Assistant Professor than male surgeons (51.9% vs 36.1%, p â€‹< â€‹0.001). This likelihood remained true when analyzing only surgeons with one or more advanced non-medical degrees. Men were more likely to be Chair of Surgery (3.0%), Division Chief (9.6%), and Research Chair (0.5%); compared to women (1.3%; 4.8%; 0.2%; p â€‹= â€‹0.001, <0.001, 0.21 respectively). CONCLUSIONS: There continues to be a significant male predominance in general surgery. Gender discrepancy is also seen in professional rank and academic title despite women holding more advanced degrees. Advanced degrees are currently considered academic qualifications, but this does not reflect surgical academic leadership roles or rank.

Clinical and Biomarker Findings of Neoadjuvant Pembrolizumab and Carboplatin Plus Docetaxel in Triple-Negative Breast Cancer: NeoPACT Phase 2 Clinical Trial.

Importance: Addition of pembrolizumab to anthracycline-based chemotherapy improves pathologic complete response (pCR) and event-free survival (EFS) in triple-negative breast cancer (TNBC). The efficacy of anthracycline-free chemoimmunotherapy in TNBC has not been assessed. Objective: To assess the efficacy of the anthracycline-free neoadjuvant regimen of carboplatin and docetaxel plus pembrolizumab in TNBC. Design, Setting, and Participants: This was an open-label phase 2 clinical trial including a single group of patients with stage I to III TNBC enrolled at 2 sites who received neoadjuvant carboplatin and docetaxel plus pembrolizumab every 21 days for 6 cycles. Participants were enrolled from 2018 to 2022. Intervention or Exposure: Carboplatin (with an area under the free carboplatin plasma concentration vs time curve of 6) and docetaxel (75 mg/m2) plus pembrolizumab (200 mg) every 21 days for 6 cycles. Myeloid growth factor support was administered with all cycles. Main Outcomes and Measures: Primary end point was pathologic complete response (pCR) defined as no evidence of invasive tumor in breast and axilla. The secondary end points were residual cancer burden, EFS, toxicity, and immune biomarkers. RNA isolated from pretreatment tumor tissue was subjected to next-generation sequencing. Specimens were classified as positive or negative for the 44-gene DNA damage immune response (DDIR) signature and for the 27-gene tumor immune microenvironment (TIM; DetermaIO) signature using predefined cutoffs. Stromal tumor-infiltrating lymphocytes (sTILs) were evaluated using standard criteria. Programmed cell death-ligand 1 (PD-L1) testing was performed using a standard immunohistochemical assay. Results: Among the eligible study population of 115 female patients (median [range] age, 50 [27-70] years) who enrolled from September 2018 to January 2022, 39% had node-positive disease. pCR and residual cancer burden 0 + 1 rates were 58% (95% CI, 48%-67%) and 69% (95% CI, 60%-78%), respectively. Grade 3 or higher immune-mediated adverse events were observed in 3.5% of patients. sTILs, PD-L1, DDIR, and TIM were each predictive of pCR in multivariable analyses. The areas under curve for pCR were 0.719, 0.740, 0.699, and 0.715 for sTILs, PD-L1, DDIR, and TIM, respectively. Estimated 3-year EFS was 86% in all patients; 98% in pCR group and 68% in no-pCR group. Conclusions and Relevance: The findings of the phase 2 clinical trial indicate that neoadjuvant carboplatin and docetaxel plus pembrolizumab shows encouraging pCR and 3-year EFS. The regimen was well tolerated, and immune enrichment as identified by various biomarkers was independently predictive of pCR. These results provide data on an alternative anthracycline-free chemoimmunotherapy regimen for patients who are not eligible for anthracycline-based regimens and support further evaluation of this regimen as a chemotherapy de-escalation strategy in randomized studies for TNBC. Trial Registration: ClinicalTrials.gov Identifier: NCT03639948.

Evaluation of learning curve with Indocyanine Green (IcG) versus blue dye for sentinel lymph node biopsy in breast cancer.

BACKGROUND: Indocyanine green (IcG) is an alternative to isosulfan blue (IB) for sentinel lymph node (SLN) mapping in breast cancer (BC). IcG carries improved cost and safety, but oncologic data upon implementation in practice is limited. We evaluated the learning curve defined as oncologic yield and operative (OR) time for IcG in SLN mapping in BC. METHODS: Retrospective review of patients >18 years with cTis-2 cN0 BC undergoing surgery first with SLN biopsy using IB or IcG. Analysis compared IB versus IcG across three time cohorts. RESULTS: Of 278 patients, 77 received IB and 201 received IcG. OR time was longer for IcG (p â€‹= â€‹0.022). There was no difference in oncologic yield between groups (p â€‹= â€‹0.35, p â€‹= â€‹0.61). CONCLUSIONS: Surgeons may be able to safely transition from IB to IcG for patients with early-stage breast cancer undergoing surgery first. Individuals should track their own data to confirm safety of the technique.

Expansion of endogenous T cells in CSF of pediatric CNS tumor patients undergoing locoregional delivery of IL13R〿2-targeting CAR T cells: an interim analysis.

Outcomes for pediatric brain tumor patients remain poor, and there is optimism that chimeric antigen receptor (CAR) T cell therapy can improve prognosis. Here, we present interim results from the first six pediatric patients treated on an ongoing phase I clinical trial (NCT04510051) of IL13BBζ-CAR T cells delivered weekly into the lateral cerebral ventricles, identifying clonal expansion of endogenous CAR-negative CD8+ T cells in the cerebrospinal fluid (CSF) over time. Additionally, of the five patients evaluable for disease response, three experienced transient radiographic and/or clinical benefit not meeting protocol criteria for response. The first three patients received CAR T cells alone; later patients received lymphodepletion before the first infusion. There were no dose limiting toxicities (DLTs). Aside from expected cytopenias in patients receiving lymphodepletion, serious adverse events possibly attributed to CAR T cell infusion were limited to one episode of headache and one of liver enzyme elevation. One patient withdrew from treatment during the DLT period due to a Grade 3 catheter-related infection and was not evaluable for disease response, although this was not attributed to CAR T cell infusion. Importantly, scRNA- and scTCR-sequence analyses provided insights into CAR T cell interaction with the endogenous immune system. In particular, clonally expanded endogenous CAR- T cells were recovered from the CSF, but not the peripheral blood, of patients who received intraventricular IL13BBζ-CAR T cell therapy. Additionally, although immune infiltrates in CSF and post-therapy tumor did not generally correlate, a fraction of expanded T cell receptors (TCRs) was seen to overlap between CSF and tumor. This has important implications for what samples are collected on these trials and how they are analyzed. These initial findings provide support for continued investigation into locoregionally-delivered IL13BBζ-CAR T cells for children with brain tumors.

Evaluation of the Closure of Patent Ductus Arteriosus With Ibuprofen Compared to Indomethacin.

OBJECTIVE: Limited data exist comparing indomethacin and ibuprofen for the treatment of patent ductus arteriosus (PDA). The objective was to compare the safety and efficacy of indomethacin and ibuprofen for treatment of PDA closure. METHODS: This single-center, pre-test/post-test quasi-experiment included preterm infants admitted to the neonatal intensive care unit who received indomethacin (July 1, 2013-September 30, 2015) or ibuprofen (December 1, 2015-July 31, 2019) for PDA. Patients were excluded if they were thrombocytopenic, had existing kidney injury, unresolved intraventricular hemorrhage (IVH) or necrotizing enterocolitis (NEC) at treatment initiation. Data were obtained from the electronic health record. Study outcomes were complete PDA closure, degree of PDA closure, resolution of symptoms, and new-onset acute kidney injury (AKI), IVH, or NEC. RESULTS: A total of 114 patients were included: 44 (39%) received indomethacin and 70 (61%) received -ibuprofen. Twenty-one (21%) patients experienced successful PDA closure within 1 week: 13 (32%) indomethacin patients and 8 (13%) ibuprofen patients (p = 0.023). PDA size reduction occurred in 43 (46%) patients with 29 (25%) experiencing complete symptom resolution. Significantly more indomethacin patients compared with ibuprofen patients experienced new-onset AKI (48% vs 17%; p < 0.001) and received concomitant nephrotoxins (68% vs 39%; p = 0.002). There were no significant differences in new-onset IVH or NEC. CONCLUSIONS: Indomethacin administration successfully closed the PDA in more neonates than ibuprofen but resulted in higher rates of AKI. However, this was confounded by more frequent administration of concomitant nephrotoxins. Larger trials are needed to help elucidate the optimal drug for closure of the PDA in neonates.

Contemporary pharmacologic treatments of MRSA for hospitalized adults: rationale for vancomycin versus non-vancomycin therapies as first line agents.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) remains an important pathogen in the hospital setting and causes significant morbidity and mortality each year. Since the initial discovery over 60 years ago, vancomycin has remained a first-line treatment for many different types of MRSA infections. However, significant concerns related to target attainment and nephrotoxicity have spurred efforts to develop more effective agents in the last two decades. AREAS COVERED: Newer anti-MRSA antibiotics that have been approved since 2000 include linezolid, daptomycin, and ceftaroline. As clinical evidence has accumulated, these newer agents have become more frequently used, and some are now recommended as co-first-line options (along with vancomycin) in clinical practice guidelines. For this review, a scoping review of the literature was conducted to support our findings and recommendations. EXPERT OPINION: Vancomycin remains an important standard of care for MRSA infections but is limited with respect to nephrotoxicity and rapid target attainment. Newer agents such as linezolid, daptomycin, and ceftaroline have specific indications for treating different types of MRSA infections; however, newer agents also have unique attributes which require consideration during therapy.

The Essential Role of Senior Care Pharmacists in Antimicrobial Stewardship: An Updated Position Statement on Behalf of the American Society of Consultant Pharmacists and the Society of Infectious Diseases Pharmacists.

Senior care pharmacists are well-positioned to lead and drive antimicrobial stewardship (AMS) initiatives, not only through audit and data collection, but also through communication, collaboration, and cooperation with prescribers and nurses to influence prescribing behaviors. Senior care pharmacists are in a unique position to take a leadership role within the interprofessional team to achieve AMS goals. They should engage with the interprofessional team to promote the judicious and appropriate use of antimicrobials at their practice sites. This position statement is an update of the 2017 version by the American Society of Consultant Pharmacists (ASCP) Antimicrobial Stewardship and Infection and Prevention Control Committee and the Society of Infectious Diseases Pharmacists (SIDP).

Breast Cancer-Related Lymphedema (BCRL) and Bioimpedance Spectroscopy: Long-Term Follow-Up, Surveillance Recommendations, and Multidisciplinary Risk Factors.

BACKGROUND: Early detection and intervention for breast cancer-related lymphedema (BCRL) significantly decreases progression to persistent BCRL (pBCRL). We aimed to provide long-term follow-up on our early detection with bioimpedance spectroscopy (BIS) and early home intervention demonstrating reduced pBCRL to guide surveillance recommendations. PATIENTS AND METHODS: In total, 148 female patients with breast cancer who had axillary lymph node dissection (ALND) from November 2014 to December 2017 were analyzed. Baseline BIS measurements and postoperative follow-up occurred every 3 months for 1 year, biannual for 1 year, and then annually. An elevated BIS triggered evaluation and initiation of at-home interventions with reassessment for resolution versus persistent BCRL (pBCRL). High-risk factors and timing were analyzed. RESULTS: Mean follow-up was 55 months, and 65 (44%) patients had an abnormal BIS. Of these, 54 (82%) resolved with home intervention. The overall pBCRL rate was 8%. Average time to first abnormal BIS was 11.7 months. None of the stage 0 patients (0/34) and only 5/25 (20%) of stage 1 patients had pBCRL. All of stage 2 and stage 3 patients (7/7) had pBCRL. pBCRL correlated with number of positive nodes, percentage of positive nodes, stage of lymphedema at diagnosis, and recurring abnormal BIS measurements (p < 0.05). CONCLUSIONS: We have shown that patients undergoing ALND with early BCRL identified by BIS who performed home interventions had an 8% pBCRL rate. Patients at high risk for pBCRL should have routine surveillance starting at 9 months postoperatively to identify an opportunity for early intervention.