The Evolving Role of Bruton's Tyrosine Kinase Inhibitors in B Cell Lymphomas.

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase crucial for B cell development and function, acts downstream of the B cell receptor (BCR) in the BCR pathway. Other kinases involved downstream of the BCR besides BTK such as Syk, Lyn, PI3K, and Mitogen-activated protein (MAP) kinases also play roles in relaying signals from the BCR to provide pro-survival, activation, and proliferation cues. BTK signaling is implicated in various B-cell lymphomas such as mantle cell lymphoma, Waldenström Macroglobulinemia, follicular lymphoma, and diffuse large B cell lymphoma, leading to the development of transformative treatments like ibrutinib, the first-in-class covalent BTK inhibitor, and pirtobrutinib, the first-in-class noncovalent BTK inhibitor. However, kinase-deficient mutations C481F, C481Y, C481R, and L528W in the BTK gene confer resistance to both covalent and non-covalent BTK inhibitors, facilitating B cell survival and lymphomagenesis despite kinase inactivation. Further studies have revealed BTK's non-catalytic scaffolding function, mediating the assembly and activation of proteins including Toll-like receptor 9 (TLR9), vascular cell adhesion protein 1 (VCAM-1), hematopoietic cell kinase (HCK), and integrin-linked kinase (ILK). This non-enzymatic role promotes cell survival and proliferation independently of kinase activity. Understanding BTK's dual roles unveils opportunities for therapeutics targeting its scaffolding function, promising advancements in disrupting lymphomagenesis and refining B cell lymphoma treatments.

Blastic Plasmacytoid Dendritic Cell Neoplasm: A Comprehensive Review of the Disease, Central Nervous System Presentations, and Treatment Strategies.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy with poor outcomes. The World Health Organization (WHO) redefined BDCN as a distinct disease entity in 2016. BPDCN arises from plasmacytoid dendritic cells, manifesting primarily in the skin, bone marrow, and lymph nodes, occasionally involving the central nervous system (CNS). This presents challenges in diagnosis and treatment, with CNS involvement often overlooked in standard diagnostic workups due to BPDCN's rarity and patients often being neurologically asymptomatic at diagnosis. CNS involvement typically emerges during relapse, yet clinical trials often exclude such cases, limiting our understanding of its development and treatment. Treatment options for CNS involvement include intrathecal (IT) chemotherapies like methotrexate and cytarabine, often in combination with systemic agents. Tagraxofusp and traditional regimens for acute myeloid leukemia show limited success at preventing CNS relapse, prompting exploration of combined therapies like hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HyperCVAD) with venetoclax and adding IT chemotherapy to other backbones. Ongoing clinical trials investigating emerging therapies offer hope despite limited focus on CNS implications. Trials incorporating CNS-involved patients aim to pioneer novel treatment approaches, potentially reshaping BPDCN management. Understanding CNS involvement's complexities in BPDCN remains crucial for tailored treatments and better patient outcomes.

The impact of influenza vaccination on surgical outcomes in COVID-19 positive patients: An analysis of 43,580 patients.

BACKGROUND: Multiple recent studies suggest a possible protective effect of the influenza vaccine against severe acute respiratory coronavirus 2 (SARS-CoV-2). This effect has yet to be evaluated in surgical patients. This study utilizes a continuously updated federated electronic medical record (EMR) network (TriNetX, Cambridge, MA) to analyze the influence of the influenza vaccine against post-operative complications in SARS-CoV-2-positive patients. METHODS: The de-identified records of 73,341,020 patients globally were retrospectively screened. Two balanced cohorts totaling 43,580 surgical patients were assessed from January 2020-January 2021. Cohort One received the influenza vaccine six months-two weeks prior to SARS-CoV-2-positive diagnosis, while Cohort Two did not. Post-operative complications within 30, 60, 90, and 120 days of undergoing surgery were analyzed using common procedural terminology(CPT) codes. Outcomes were propensity score matched for characteristics including age, race, gender, diabetes, obesity, and smoking. RESULTS: SARS-CoV-2-positive patients receiving the influenza vaccine experienced significantly decreased risks of sepsis, deep vein thrombosis, dehiscence, acute myocardial infarction, surgical site infections, and death across multiple time points(p<0.05, Bonferroni Correction p = 0.0011). Number needed to vaccinate (NNV) was calculated for all significant and nominally significant findings. CONCLUSION: Our analysis examines the potential protective effect of influenza vaccination in SARS-CoV-2-positive surgical patients. Limitations include this study's retrospective nature and reliance on accuracy of medical coding. Future prospective studies are warranted to confirm our findings.

Risk stratification of surgical-site outcomes by BMI and flap type in autologous breast reconstruction.

INTRODUCTION: Afflicting 2 million lives annually worldwide, breast cancer remains devastating. This study utilized a continuously updated network of electronic medical records (TriNetX Inc, Cambridge, MA) for analysis of 90-day postoperative outcomes of autologous breast reconstruction by increasing body mass index (BMI). METHODS: The deidentified electronic medical records (EMRs) of 29,453,000 females, age 18-99 years, were retrospectively screened from 45 healthcare organizations. A combined cohort of 7136 patients undergoing autologous breast reconstruction via transverse rectus abdominus muscle (TRAM), deep inferior epigastric perforator (DIEP), or latissimus flap was categorized by BMI into 5 subgroups: normal (n = 3568), overweight (n = 1239), class I (n = 1166), class II (n = 807), and class III (n = 356) obesity. The normal BMI cohort was then compared with each elevated BMI cohort. BMI strata were analyzed for risk of surgical-site occurrences within 90 days of surgery using CPT codes. Stringent propensity score matching was performed. RESULTS: For the combined group (N = 7136), significant linear increases in risk were observed with increasing BMI for infection (risk ratio [RR] 1.39-2.91,p < 0.05) and dehiscence (RR 2.65-5.17, p < 0.05). Similar linear increases were observed for the abdominally based group (N = 5454) for infection (RR 1.45-2.47, p < 0.05) and dehiscence (RR 2.54-4.77, p < 0.05). For DIEP (N = 4874), near-linear increases were observed for infection (RR 1.60-2.79, p < 0.05) and dehiscence (RR 1.57-5.59, p < 0.05). For TRAM (N = 714), significant increases were observed for seroma, infection, dehiscence, deep vein thrombosis (DVT), sepsis, and PE while increased risks of seroma, DVT, PE, and hernia were observed for latissimus (N = 1380). CONCLUSIONS: Regardless of flap type, our analysis suggests that a BMI> 39.9 is the inflection point beyond which it may be beneficial not to perform autologous breast reconstruction. Limitations include this study's retrospective nature; thus, future prospective studies would be beneficial.