Hackensack University Medical Center
  • Hackensack, New Jersey, United States
Recent publications
The prevalence of COVID-19 infection-related myocarditis, its in-hospital cardiovascular outcomes, and its impact on hospital cost and stay at national level are not well studied in the literature. The Nationwide Inpatient Sample Database from 2020 was queried to identify patients with COVID-19 and myocarditis versus those without myocarditis. Cardio-vascular outcomes and resource utilization were studied among cohorts with COVID-19, with and without myocarditis, using descriptive statistics, multivariate regression matching , and propensity score matching using STATA version 17. Of 1,678,995 patients, 3,565 (0.21%) had COVID-19 with myocarditis, and 1,675,355 (99.78%) had COVID-19 without myocarditis. On multivariate regression analysis, we found higher odds of in-hospital mortality (adjusted odds ratio [aOR] 1.59, 95% confidence interval [CI] 1.27 to 1.9) in patients with myocarditis than in those without myocarditis, in addition to higher odds of major adverse cardiovascular and cerebrovascular events (aOR 3.54, 95% CI 2.8 to 4.4), acute kidney injury (aOR 1.29, 95% CI 1.27 to 1.9), heart failure (aOR 2.77, 95% CI 2.3 to 3.4), cardiogenic shock (aOR 10.2, 95% CI 7.9 to 13), myocardial infarction (aOR 5.74, 95% CI 4.5 to 7.3), and use of mechanical circulatory support (aOR 2.81, 95% CI 1.6 to 4.9). The propensity-matched cohort also favored similar outcomes. In conclusion, patients with COVID-19 and myocarditis had worse clinical outcomes, having a higher rate of in-hospital mortality, major adverse cardiovascular and cerebrovascular events with longer length of hospital stay, and higher hospitalization costs. Large prospective trials are necessary to validate these findings with diagnostic measures, including biopsy and cardiac magnetic resonance imaging for the extent of myocardial involvement.
Background This phase 1b/2 PCYC-1123-CA study evaluated efficacy and safety of the combination of ibrutinib, lenalidomide, and rituximab (iR² regimen) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) ineligible for stem cell transplantation. Methods In phase 2, patients with relapsed/refractory non-germinal centre B-cell–like DLBCL received oral ibrutinib 560 mg once daily and oral lenalidomide 20 mg or 25 mg once daily on Days 1–21 of each 28-day cycle until disease progression or unacceptable toxicity and intravenous rituximab 375 mg/m² on Day 1 of Cycles 1–6. The primary endpoint was overall response rate (ORR) in the response-evaluable population (received any study treatment and had ≥1 post-baseline disease assessment). The study was done at 24 academic and community hospitals in Belgium, Germany, United Kingdom, and USA. This study was registered with ClinicalTrials.gov, NCT02077166. Findings Between March 13, 2014 and October 2, 2018, 89 patients were enrolled with a median time on study of 35.0 months. Best ORR in the response-evaluable population (n = 85) was 49% (95% confidence interval [CI], 38–61) across dose cohorts and 53% (95% CI, 39–67) and 44% (95% CI, 26–62) in the 20 mg and 25 mg lenalidomide cohorts, respectively, with complete responses in 24/85 (28%), 17/53 (32%), and 7/32 (22%) patients, respectively. Grade 3/4 adverse events (AEs) occurred in 81/89 patients (91%), most frequently neutropenia (36/89; 40%), maculopapular rash (16/89; 18%), anaemia (12/89; 13%), and diarrhoea (9/89; 10%). Serious adverse events occurred in 57/89 patients (64%). Fatal AEs occurred in 12/89 patients (13%); causes of death were worsening of DLBCL (n = 7), pneumonia (n = 3), sepsis (n = 1), and cardiac arrest (n = 1). Interpretation The most frequent AEs (diarrhoea, neutropenia, fatigue, cough, anaemia, peripheral oedema, and maculopapular rash) were consistent with known safety profiles of the individual drugs. The iR² regimen demonstrated antitumour activity with durable responses in patients with relapsed/refractory DLBCL. Funding Pharmacyclics LLC, an AbbVie Company.
708 Background: PDAC has a 5-year survival rate of <5% in patients with metastatic disease. Despite established frontline therapy with gemcitabine + nab-paclitaxel (GnP), outcomes remain poor and additional therapies are urgently needed. SEA-CD40 is a receptor-agonistic, nonfucosylated IgG1 antibody directed to CD40. SEA-CD40 binding to FcγRIIIa results in enhanced effector function and CD40 agonism, allowing amplification of immune stimulation and antitumor activity. In preliminary results of a phase 1 study, SEA-CD40 + GnP + pembrolizumab (pembro) showed a tolerable safety profile and evidence of immune activation in patients (pts) with PDAC. Here, we present updated clinical results for this cohort. Methods: Pts were ≥18 years old with untreated metastatic PDAC and ECOG Performance Status of 0 or 1. Gemcitabine (1000 mg/m ² ) and nab-paclitaxel (125 mg/m ² ) were given on days 1, 8, and 15 and SEA-CD40 (10 or 30 µg/kg) was given on day 3 of each 28-day cycle. Pembro (400 mg) was given every 6 weeks starting on day 8 for up to 2 years. Results: As of August 16, 2022, 61 pts were treated with 10 µg/kg (N=40) or 30 µg/kg (N=21) SEA-CD40. Median duration of exposure was 25.1 weeks. Confirmed objective responses were observed in 19 pts (48% [95% CI 31.5, 63.9]) at 10 µg/kg and 8 pts (38% [95% CI 18.1, 61.6]) at 30 µg/kg. Median duration of response (months) was 5.7 (95% CI 3.9, 7.4) and 5.7 (95% CI 2.3, 9.2) for the 10 and 30 µg/kg dose groups, respectively. Additional efficacy results are summarized. The most common treatment-emergent adverse events (TEAEs) across dose groups were fatigue (84%), nausea (74%), and neutropenia (67%). The most common grade ≥3 TEAEs across the groups were neutropenia (61%), anemia (33%), and thrombocytopenia (20%). TEAEs leading to treatment discontinuation were reported in 10% of pts, including immune-mediated lung disease (n=3) and septic shock (n=1) in the 10 µg/kg dose group, and colitis (n=1) and portal vein thrombosis (n=1) in the 30 µg/kg dose group. Conclusions: The combination of SEA-CD40 + GnP + pembro has an acceptable safety profile and shows evidence of antitumor activity in pts with PDAC. This regimen may warrant further evaluation. Clinical trial information: NCT02376699 . [Table: see text]
113 Background: Bevacizumab (BVZ), a recombinant humanized monoclonal IgG antibody, is commonly used as first- and second-line adjuvant therapy in metastatic colorectal cancer. Recent guidelines have shown that a combination of three cytotoxic drug regimens FOLFOX (fluorouracil, leucovorin and oxaliplatin) along with BVZ is regarded as one of the first-line options. As we see an upward trend in using BVZ; it is crucial to analyze the side effects and potential toxicities. A frequent adverse effect with BVZ is hypertension. The prevailing hypothesis for the mechanism of BVZ induced hypertension is an increase in vascular tone due to the inhibition of VEGF-mediated vasodilation. A persistent elevation of arterial blood pressure is generally asymptomatic, but unmanaged hypertension can lead to cardiovascular complications, encephalopathy, and subarachnoid hemorrhage. Therefore, this meta-analysis aims to evaluate and assess the risk of BVZ induced hypertension. Methods: Our search included articles from PubMed, EMBASE, Web of Science, and Cochrane Library from 1980 to March 2022. Randomized controlled trials and clinical trials with BVZ as an add-on therapy mentioning cardiovascular side effects were included. Full analysis control group included various guideline directed chemotherapies and the subgroup analysis control group focused on FOLFOX therapy. A random-effects model was used with Review Manager, and a P value < 0.05 was considered significant. Results: We included a total of 17,807 patients in our study with an average age of 65 years. Analysis pooled from 19 RCTs showed that the odds of hypertension (Grade 3 or more) in patients treated with BVZ were about four times higher than the control group (OR 3.82, 95% CI 3.35-4.36, p-value < 0.00001, I2 = 78%). In a subgroup analysis, BVZ was compared with FOLFOX group, with odds of hypertension (Grade 3 or more) in BVZ group being about five times higher than in FOLFOX group (OR 5.24, 95% CI 4.06-6.77, p-value < 0.00001, I2 = 58%). Conclusions: Our meta-analysis demonstrates a significant cardiovascular risk of Bevacizumab when added to the standard regime for advanced colorectal cancer treatment. When BVZ was used as an add-on therapy to FOLFOX regimens for colorectal cancer, it was associated with about five times higher odds of developing hypertension (Grade 3 or more) in the treatment group with BVZ. Previous RCTs have demonstrated that BVZ add-on therapy to the standard regime is safe and without significant risk of toxicity. Our findings are important as they give vital information in assessing the risk-benefit ratio of adding BVZ, especially in a population with vascular comorbidities. Now that we have established the statistical significance of hypertensive risk with BVZ, it will be interesting to see how these events can be prevented in patients treated for metastatic colorectal cancer. Dedicated RCTs are needed to confirm these findings.
TPS478 Background: CYNK-101 is a human placental hematopoietic stem/progenitor cell derived NK cell product, that is genetically modified to express a variant of CD16, FcγRIII, via lentiviral vector transduction. The CD16 variant has amino acid modifications to enable high affinity and proteolytic cleavage-resistance for ADCC enhancement. Results from preclinical studies demonstrated enhanced ADCC activity of CYNK-101 in combination with trastuzumab against HER2+ gastric cancer cell lines in vitro, ex vivo and in vivo. Methods: A Phase I/IIa study is a first-line treatment of patients with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Patients are required to have confirmation of HER2 positivity defined as either IHC 3+ or IHC 2+ with a positive FISH or FISH + alone. Following the completion of screening assessments, patients are enrolled to the initial induction period of the trial and receive pembrolizumab, trastuzumab and a fluoropyrimidine/platinum based-chemotherapy for up to six 21-day cycles. In Phase I, patients may skip the initial induction period if they had previously been treated with pembrolizumab or, trastuzumab and a fluoropyrimidine/platinum based-chemotherapy and have not achieved an adequate response. Patients complete a disease assessment and then proceed to a lymphodepletion regimen of cyclophosphamide 900 mg/m ² and fludarabine 30 mg/m ² with MESNA for 3 days. Following 2 days of rest, the NK-cell re-induction period of the study begins with pembrolizumab 200 mg and trastuzumab 6 mg/kg on Day 1 of that cycle and 6M IU of rhIL-2 with CYNK-101 on days 1, 8, 15. CYNK-101 will be administered based on the calculated number of transduced cells per body weight as measured in kilograms (kg). Two dose levels of CYNK-101 (36 x 10 ⁶ transduced cells/kg, and 72 x 10 ⁶ transduced cells/kg) will be evaluated for the NK-Cell reinduction period during the Phase 1 portion of the study in a standard “3+3” dose escalation fashion. Once the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) is determined in Phase I, the designated dosing Cohort level of the NK-Cell re-induction period will be used for the Phase IIa Expansion portion of the study. Both study periods will contain maintenance dosing of pembrolizumab 200 mg, trastuzumab 6 mg/kg and 6M IU rhIL-2 with 3.6 x 10 ⁶ transduced cells/kg of CYNK-101 on Day 1 of a 21-day cycle. Endpoints: Primary endpoints for Phase I, include the incidence of adverse events defined as dose-limiting toxicities (DLTs). Phase IIa will evaluate efficacy as measured by overall response rate and a complete response rate as determined by RECIST 1.1. Approximately 52 patients are planned for this Phase I/IIa study. Clinical trial information: NCT05207722 .
The vaginal microbiome exists in a dynamic state and its disruption, by diminution of Lactobacillus concentrations, can induce a state of microbial imbalance with significant health consequences, such as increased risk of sexually transmitted infection (STI) acquisition, preterm labor, and low birth weight babies. This delicate balance of microbes can be affected by many processes such as mechanical practices (i.e. douching) and hormonal changes: physiologic (i.e. menstrual cycle, menopause, puberty), pathologic (i.e. PCOS), and exogenous (i.e. contraceptives). Contraceptives fall into mechanical and hormonal categories, both of which prevent unintended pregnancy. The mechanical contraceptives of spermicides, diaphragms, and cervical caps alter the vaginal ecosystem, with spermicides being linked to an increased risk of vaginal dysbiosis. The impacts of Copper T intrauterine devices (Cu-IUDs) and hormonal contraceptives on the vaginal microbiome are contradictory. A better understanding and consensus of how contraceptive methods affect the vaginal microbiome is needed.
Precision nanomedicine can be employed as an alternative to chemo- or radiotherapy to overcome challenges associated with the often narrow therapeutic window of traditional treatment approaches, while safely inducing effective, targeted antitumor responses. Herein, we report the formulation of a therapeutic nanocomposite comprising a hyaluronic acid (HA)-coated gold nanoframework (AuNF) delivery system and encapsulated IT848, a small molecule with potent antilymphoma and -myeloma properties that targets the transcriptional activity of nuclear factor kappa B (NF-κB). The porous AuNFs fabricated via a liposome-templated approach were loaded with IT848 and surface-functionalized with HA to formulate the nanotherapeutics that were able to efficiently deliver the payload with high specificity to myeloma and lymphoma cell lines in vitro. In vivo studies characterized biodistribution, pharmacokinetics, and safety of HA-AuNFs, and we demonstrated superior efficacy of HA-AuNF-formulated IT848 vs free IT848 in lymphoma mouse models. Both in vitro and in vivo results affirm that the AuNF system can be adopted for targeted cancer therapy, improving the drug safety profile, and enhancing its efficacy with minimal dosing. HA-AuNF-formulated IT848 therefore has strong potential for clinical translation.
A large proportion of children have been affected by COVID-19; we evaluated the association between comorbidities and hospitalization/ICU (intensive care unit) admission among 4097 children under age 21 years with symptomatic COVID-19 (not just polymerase chain reaction [PCR]-positive or multisystem inflammatory syndrome in children associated with COVID-19 [MIS-C]) from 2 large health systems from March 2020 to September 2021. Significant comorbidities and demographic factors identified by univariable analysis were included in a multivariable logistic regression compared with children ages 6 to 11 without comorbidities. In all, 475 children (11.6%) were hospitalized, of whom 25.5% required ICU admission. Children under 1 year had high hospitalization risk, but low risk of ICU admission. Presence of at least 1 comorbidity was associated with hospitalization and ICU admission (odds ratio [OR] > 4). Asthma, obesity, chronic kidney disease, sickle cell disease, bone marrow transplantation, and neurologic disorders were associated with hospitalization (adjusted odds ratio [AOR] > 2). Malignancy, intellectual disability, and prematurity were associated with ICU admission (AOR > 4). Comorbidities are significantly associated with hospitalization/ICU admission among children with COVID-19.
CAR T cell therapies are FDA approved for patients with triple refractory multiple myeloma (MM). Real-world access to CAR T remains challenging due to supply chain limitations impacting manufacturing. The goal of this study was to evaluate the extent of this issue and how major centers are handling the challenges of CART manufacturing slot allocation. MM CAR T physician leaders at each CART treatment center across the US were surveyed. We received response from 17/20 centers. A median of one slot is allocated per month per center and the median number of patients per center on the waitlist since ide-cel approval was 20 (range 5-100). As a result, patients remained on the waitlist for a median of 6 months prior to leukapheresis (range 2-8). For patient selection, all centers reported using a committee of experienced CART physicians to ensure consistency. To ensure transparency, 15 centers make selection criteria, selection timeline and priority score readily available for CAR-T providers. Centers also reported using ethical values for selection: a) equal treatment: time spent on waiting list (n=12); b) priority to the worst-off: limited therapeutic options (n=14), MM burden (n=11), high comorbidity index (n=5); c) maximize benefit: most likely to complete apheresis (n=13) or infusion (n=13) or achieve response (n=8) and d) social value: younger pts (n=3). Maximizing benefit was considered the most important criterion by 10 centers. Our study is the first attempt to evaluate existing issues with MM CAR T access and the variability and challenges in patient selection. Integrating ethical resource allocation strategies, similar to the ones described here, into formal institutional policies would help streamline CAR-T access and protect the needs of both current and future patients and physicians.
Objective: Neurosurgical residency applicants' prior research experience can amplify their ability to stand out to prospective neurosurgery programs. We attempted to accurately quantify the number of research publications coauthored by applicants by analyzing the publications of those who matched into neurosurgery in the 2021 Match. Methods: Scopus, a peer-reviewed literature database, was queried for publications by those who matched into neurosurgery in the 2021 Match prior to the finalization of rank lists. Conference papers, abstracts, and book chapters were excluded to determine an accurate average of actual publications. Descriptive statistics for resident publication data were utilized, with a Mann-Whitney U test used to compare research productivity between male and female residents. Results: There were 234 positions filled by the 2021 Match and 233 neurosurgical residents were identifiable in this study. 187 residents matching from US MD and DO programs were identified with 946 total publications, an average of 5.1 publications per resident. Analysis of descriptive statistics revealed type of research conducted, authorship information, most published journals, and citation data. Significant differences were found in the number of publications between male and female applicants with averages of 5.6 and 3.8 publications, respectively. Conclusions: Students matriculating to neurosurgery residency programs display a wide range of research productivity; however, typical US MD and DO applicants have coauthored a mean of 5.1 and a median of 4.0 publications. This information may assist program directors in weighing applicants' research background and give medical students interested in the field reasonable research expectations.
Chapter 16 in: Stewart, S., Blood, P. (eds) A Guide to Mechanical Circulatory Support. Springer, Cham. https://doi.org/10.1007/978-3-031-05713-7_16
Background The availability of nonapproved psychoactive substances with addiction potential from internet sources poses a significant threat to public health. Polysubstance abuse or inadvertent contamination of preparations may result in clinically challenging intoxication and withdrawal syndromes. Case Report We report a case of a 32-year-old male with an approximate 2-year history of taking internet-obtained etizolam and tianeptine who presented to the hospital following an overdose. He experienced subsequent withdrawal symptoms consistent with benzodiazepine and opioid withdrawal. Initial attempts at managing symptoms with chlordiazepoxide 25 mg every 6 hours did not relieve his symptoms. On day 3 of admission, addiction medicine was consulted and his regimen was changed to diazepam 80 mg daily with additional as-needed diazepam based on etizolam equivalence. He also received a 5-day methadone taper with plans to transition to buprenorphine in the outpatient setting. Upon discharge he was referred to an addiction medicine specialist who was willing to continue a slow diazepam taper and initiate medications for opioid use disorder to manage both substance use disorders. Discussion This case report demonstrates the effectiveness of diazepam in managing benzodiazepine withdrawal from etizolam while concurrently using methadone to manage opioid withdrawal symptoms from tianeptine in a hospitalized patient following overdose. We highlight the importance of a warm handoff in considering the outpatient discharge plan.
Background Subarachnoid hemorrhage (SAH) is a diagnosis that emergency physicians must have a high index of suspicion for. Many common chief complaints such as headache, nausea, altered mental status, and even syncope may alert clinicians to the possibility of a SAH. Case presentation The authors present an unusual case of SAH in a patient presenting with acute dyskinesia and altered mental status, which has seldom been documented as the presenting feature of SAH, as well as the diagnostic pitfalls encountered in assessing this patient. Conclusion Emergency physicians should maintain a high index of suspicion for dangerous pathology in cases without a clear etiology; they should also utilize metacognition to assess their own biases and thought patterns so as to avoid missing critical diagnoses.
Temporomandibular joint (TMJ) ankylosis is characterized by bony fusion that limits TMJ mobility. We present the case of an elderly woman who was brought to the operating room for dental rehabilitation under general anesthesia. The patient had an undiagnosed TMJ ankylosis, which was discovered only after induction of anesthesia due to her nonverbal status and advanced dementia. The surgical team canceled the case due to limited access to the surgical field. We discuss the factors that suggest TMJ ankylosis and propose the perioperative management when TMJ ankylosis is suspected but unconfirmed.
Background: Juvenile localized scleroderma (LS) and systemic sclerosis (SSc) are rare pediatric conditions often associated with severe morbidities. Delays in diagnosis are common, increasing the risk for permanent damage and worse outcomes. This study explored caregiver perspectives on barriers they encountered while navigating diagnosis and care for their child’s scleroderma. Methods: In this cross-sectional study, caregivers of juvenile LS or SSc patients were recruited from a virtual family scleroderma educational conference and a juvenile scleroderma online interest group. The survey queried respondents about their child’s condition and factors affecting diagnosis and treatment. Results: The response rate was 61% (73/120), with 38 parents of LS patients and 31 parents of SSc patients. Most patients were female (80%) and over half were non-Hispanic white (55%). Most families had at least one person with a college education or higher (87%), traveled < 2 hours to see their doctor (83%), and had private insurance (75%). Almost half had an annual household income > $100,000 (46%). Families identified the following factors as barriers to care: lack of knowledge about scleroderma in the medical community, finding reliable information about pediatric scleroderma, long wait times for a rheumatology/specialist appointment, balance of school/work and child’s healthcare needs, medication side effects, and identifying effective medications. The barrier most identified as a major problem was the lack of knowledge about juvenile scleroderma in the medical community. Diagnosis and systemic treatment initiation occurred at greater than one year from initial presentation for approximately 28% and 36% of patients, respectively. Conclusion: Caregivers of children with LS or SSc reported numerous common barriers to the diagnosis, treatment, and ongoing care of juvenile scleroderma. The major problem highlighted was the lack of knowledge of scleroderma within the general medical community. Given that most of the caregiver respondents to the survey had relatively high socioeconomic status, additional studies are needed to reach a broader audience, including caregivers with limited English proficiency, geographical limitations, and financial constraints, to determine if the identified problems are generalizable. Identifying key care barriers will help direct efforts to address needs, reduce disparities in care, and improve patient outcomes.
Colonic macrophages are critical for maintenance of CD4⁺ T cell homeostasis in intestinal lamina propria. However, the mechanisms by which this process is regulated at the transcriptional level remain unknown. Here, we found that the transcriptional corepressors TLE3 and TLE4, but not TLE1 or TLE2, in colonic macrophages controlled homeostasis of CD4⁺ T cell pool in colonic lamina propria. Mice lacking TLE3 or TLE4 in myeloid cells exhibited markedly increased numbers of Treg and TH17 cells under homeostatic conditions, rendering mice more resistant to experimental colitis. Mechanistically, TLE3 and TLE4 negatively regulated Mmp9 transcription in colonic macrophages. Tle3 or Tle4 deficiency in colonic macrophages resulted in upregulated MMP9 production and thus enhanced latent TGF-β activation, which subsequently led to Treg and TH17 cell expansion. These results advanced our knowledge regarding the intricate crosstalk between the intestinal innate and adaptive immune compartments.
Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Children's Brain Tumor Network (CBTN) is a multi-institutional international clinical research consortium created to advance therapeutic development through the collection and rapid distribution of biospecimens and data via open-science research platforms for real-time access and use by the global research community. The CBTN's 32 member institutions utilize a shared regulatory governance architecture at the Children's Hospital of Philadelphia to accelerate and maximize the use of biospecimens and data. As of August 2022, CBTN has enrolled over 4700 subjects, over 1500 parents, and collected over 65,000 biospecimen aliquots for research. Additionally, over 80 preclinical models have been developed from collected tumors. Multi-omic data for over 1000 tumors and germline material are currently available with data generation for > 5000 samples underway. To our knowledge, CBTN provides the largest open-access pediatric brain tumor multi-omic dataset annotated with longitudinal clinical and outcome data, imaging, associated biospecimens, child-parent genomic pedigrees, and in vivo and in vitro preclinical models. Empowered by NIH-supported platforms such as the Kids First Data Resource and the Childhood Cancer Data Initiative, the CBTN continues to expand the resources needed for scientists to accelerate translational impact for improved outcomes and quality of life for children with brain and spinal cord tumors.
Background: Acne scarring is disfiguring and psychologically taxing on patients. Many energy-based modalities have emerged and been studied for the treatment of acne scarring; however, there is a paucity of these studies in skin phototypes IV-VI. Objective: To review the medical literature and discuss the most significant studies regarding safety and efficacy of energy-based devices (ablative lasers, non-ablative lasers, and radiofrequency microneedling) in the treatment of ethnic skin (skin phototypes IV-VI). Methods: A literature search was conducted using the PubMed database and bibliographies of relevant articles. Results: Ablative and non-ablative lasers have proven to be effective for treatment of acne scars in ethnic skin. The risk of developing adverse effects such as post-inflammatory hyperpigmentation is contingent upon several factors including skin phototype, laser device, fluence, and moreso density settings. Non-ablative fractional lasers have been considered first line for the treatment of acne scars in skin of color due to their better safety profile; however, they are less efficacious and require more treatments compared to ablative lasers. Studies regarding efficacy and safety of radiofrequency microneedling for treatment of acne scarring in skin of color are limited, but are promising. Conclusion: Ablative lasers, non-ablative lasers, and radiofrequency microneedling are all useful treatments for acne scarring in ethnic skin when appropriate settings are used. Further head-to-head studies are needed to evaluate their efficacy and safety in darker skin phototypes V-VI.
Purpose: Epcoritamab is a subcutaneously administered CD3xCD20 T-cell-engaging, bispecific antibody that activates T cells, directing them to kill malignant CD20+ B cells. Single-agent epcoritamab previously demonstrated potent antitumor activity in dose escalation across B-cell non-Hodgkin lymphoma subtypes. Patients and methods: In the dose-expansion cohort of a phase I/II study (ClinicalTrials.gov identifier: NCT03625037), adults with relapsed or refractory CD20+ large B-cell lymphoma and at least two prior therapy lines (including anti-CD20 therapies) received subcutaneous epcoritamab in 28-day cycles (once weekly step-up doses in weeks 1-3 of cycle 1, then full doses once weekly through cycle 3, once every 2 weeks in cycles 4-9, and once every 4 weeks in cycle 10 and thereafter) until disease progression or unacceptable toxicity. The primary end point was overall response rate by the independent review committee. Results: As of January 31, 2022, 157 patients were treated (median age, 64 years [range, 20-83]; median of three [range, 2-11] prior therapy lines; primary refractory disease: 61.1%; prior chimeric antigen receptor (CAR) T-cell exposure: 38.9%). At a median follow-up of 10.7 months, the overall response rate was 63.1% (95% CI, 55.0 to 70.6) and the complete response rate was 38.9% (95% CI, 31.2 to 46.9). The median duration of response was 12.0 months (among complete responders: not reached). Overall and complete response rates were similar across key prespecified subgroups. The most common treatment-emergent adverse events were cytokine release syndrome (49.7%; grade 1 or 2: 47.1%; grade 3: 2.5%), pyrexia (23.6%), and fatigue (22.9%). Immune effector cell-associated neurotoxicity syndrome occurred in 6.4% of patients with one fatal event. Conclusion: Subcutaneous epcoritamab resulted in deep and durable responses and manageable safety in highly refractory patients with large B-cell lymphoma, including those with prior CAR T-cell exposure.
Aging is associated with defects within blood stem cells, termed hematopoietic stem cells (HSC), including a loss of their self-renewal potential and a skewed differentiation towards myeloid lineages at the expense of lymphoid cells. Collectively, these HSC defects manifest as anemias, poor response to vaccines and an increased incidence of myeloid neoplasms in older adults. Unlike other somatic stem cells, aged HSCs have been shown to be refractory towards established anti-aging interventions including caloric restriction, exercise, parabiosis and plasma transfer. Thrombospondin-1 (TSP1) was initially discovered as an anti-angiogenic molecule, and recent studies have identified that TSP1 promotes age-related pathologies including chronic inflammation, reactive oxygen species (ROS) generation, and mitochondrial dysfunction. Notably, each of these TSP-1 regulated processes have been shown to critically influence HSC biology, particularly in the context of aging. However, whether TSP-1 directly regulates HSC activity remains unexplored. Here, we sought to determine whether TSP-1 is essential for HSC development, and whether blocking TSP1 signaling could ameliorate age-related HSC defects. Utilizing murine models, we demonstrate that TSP-1 is dispensable for normal HSC development and hematopoiesis. We show that deletion of TSP-1 is sufficient to preserve HSC fitness during aging, as evidenced by preservation of youthful self-renewal potential and balanced lineage reconstitution during serial HSC transplantation assays. Mechanistically, we identify that TSP-1 adversely impacts mitochondrial metabolism within HSCs, and show that loss of TSP-1 prevents the age-related decline in HSC mitochondrial membrane potential. Our findings identify TSP-1 as a pro-geronic factor that can be targeted to preserve HSC healthspan.
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420 members
Christine M Rini
  • John Theurer Cancer Centet
Florian P Thomas
  • Neuroscience Institute, Department of Neurology
David J O'Connor
  • Division of Vascular Surgery
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