Unveiling the Prognostic Significance of BCL6+/CD10+ Mantle Cell Lymphoma: Meta-Analysis of Individual Patients and Systematic Review.

Mantle cell lymphoma (MCL) is a type of non-Hodgkin lymphoma (NHL) characterized by a hallmark translocation of t (11; 14). CD10 negativity has been used to differentiate MCL from other NHL types; however, recently, there has been an increase in the number of reported cases of CD10-positive MCL. This warrants further investigation into this rarer immunophenotype and its clinical significance. BCL6, which is a master transcription factor for the regulation of cell proliferation and key oncogene in B cell lymphomagenesis, has been reported to have co-expression with CD10 in MCL. The clinical significance of this aberrant antigen expression remains unknown. We conducted a systematic review by searching four databases and selected five retrospective analyses and five case series. Two survival analyses were conducted to determine if BCL6 positivity conferred a survival difference: 1. BCL6+ vs. BCL6- MCL. 2. BCL6+/CD10+ vs. BCL6-/CD10+ MCL. Correlation analysis was conducted to determine if BCL6 positivity correlated with the Ki67 proliferation index (PI). Overall survival (OS) rates were performed by the Kaplan-Meier method and log-rank test. Our analyses revealed that BCL6+ MCL had significantly shorter overall survival (median OS: 14 months vs. 43 months; p = 0.01), BCL6+/CD10+ MCL had an inferior outcome vs. BCL6+/CD10- MCL (median OS: 20 months vs. 55 months p = 0.1828), BCL6+ MCL had significantly higher percentages of Ki67% (Ki67% difference: 24.29; p = 0.0094), and BCL6 positivity had a positive correlation with CD10+ status with an odds ratio 5.11 (2.49, 10.46; p = 0.0000286). Our analysis showed that BCL6 expression is correlated with CD10 positivity in MCL, and BCL6 expression demonstrated an inferior overall survival. The higher Ki67 PI in BCL6+ MCL compared to BCL6- MCL further supports the idea that the BCL6+ immunophenotype may have prognostic value in MCL. MCL management should consider incorporating prognostic scoring systems adjusted for BCL6 expression. Targeted therapies against BCL6 may offer potential therapeutic options for managing MCL with aberrant immunophenotypes.

Comprehensive Review: Unveiling the Pro-Oncogenic Roles of IL-1ß and PD-1/PD-L1 in NSCLC Development and Targeting Their Pathways for Clinical Management.

In the past decade, targeted therapies for solid tumors, including non-small cell lung cancer (NSCLC), have advanced significantly, offering tailored treatment options for patients. However, individuals without targetable mutations pose a clinical challenge, as they may not respond to standard treatments like immune-checkpoint inhibitors (ICIs) and novel targeted therapies. While the mechanism of action of ICIs seems promising, the lack of a robust response limits their widespread use. Although the expression levels of programmed death ligand 1 (PD-L1) on tumor cells are used to predict ICI response, identifying new biomarkers, particularly those associated with the tumor microenvironment (TME), is crucial to address this unmet need. Recently, inflammatory cytokines such as interleukin-1 beta (IL-1ß) have emerged as a key area of focus and hold significant potential implications for future clinical practice. Combinatorial approaches of IL-1ß inhibitors and ICIs may provide a potential therapeutic modality for NSCLC patients without targetable mutations. Recent advancements in our understanding of the intricate relationship between inflammation and oncogenesis, particularly involving the IL-1ß/PD-1/PD-L1 pathway, have shed light on their application in lung cancer development and clinical outcomes of patients. Targeting these pathways in cancers like NSCLC holds immense potential to revolutionize cancer treatment, particularly for patients lacking targetable genetic mutations. However, despite these promising prospects, there remain certain aspects of this pathway that require further investigation, particularly regarding treatment resistance. Therefore, the objective of this review is to delve into the role of IL-1ß in NSCLC, its participation in inflammatory pathways, and its intricate crosstalk with the PD-1/PD-L1 pathway. Additionally, we aim to explore the potential of IL-1ß as a therapeutic target for NSCLC treatment.

Late renal toxicity in patient with radioiodine-refractory differentiated thyroid cancer treated with lenvatinib: A case report and literature review.

INTRODUCTION: Thyroid carcinoma is the most common endocrine neoplasm. Multimodal therapy including surgery, radioactive iodine (RAI) therapy, and indefinite suppression of thyroid-stimulating hormone has led to an 85% cure rate in differentiated thyroid tumors (DTT). Approximately 5-10% of patients will have recurrence or metastases that have the potential to become resistant to RAI treatment.1 10-year overall survival rates are reported to be 10% in these patients versus 56% in patients with RAI avid disease.2 Lenvatinib, a multi-tyrosine-kinase inhibitor (TKI), was shown to have a 65% overall response rate in addition to a significant improvement in progression-free survival (PFS), approved to treat RAI-resistant DTTs.3, 4. CASE REPORT: We are reporting a very rare case of late renal toxicity in a 68-year-old woman with a history of type 2 diabetes and metastatic RAI-resistant follicular thyroid carcinoma (Hurthle cell variant) who developed thrombotic microangiopathy 21 months after initiation of treatment. MANAGEMENT & OUTCOME: It was determined that LEN should be held, due to worsening renal function secondary to TKI-induced kidney injury. Although the patient's renal function eventually improved and returned to her baseline after discontinuation of LEN, there was marked disease progression after drug cessation. DISCUSSION: Renal toxicity is a rare adverse event (AE) that tends to occur typically within three weeks of initiation of treatment. The utilization of TKIs can lead to glomerulosclerosis, and careful considerations and precautions should be taken by clinicians who intend to initiate TKI therapy in patients with pre-existing diabetes to prevent renal toxicity.

Case Report: An exceptional response to neoadjuvant radiotherapy and chemotherapy in undifferentiated pleomorphic sarcoma following checkpoint inhibitor use.

Undifferentiated pleomorphic sarcoma (UPS), a subtype of soft tissue sarcoma (STS), is an uncommon malignancy associated with a poor prognosis. As with other forms of sarcoma, surgical resection remains the only form of treatment with curative potential. The role of perioperative systemic therapy has not been definitively elucidated. Due to high recurrence rates and metastatic potential, management of UPS can pose a difficult task for clinicians. In cases of unresectable UPS due to anatomic limitations and in patients with comorbidities and poor performance status (PS), management options are limited. We describe a patient with UPS involving the chest wall with poor PS who achieved complete response (CR) following neoadjuvant chemotherapy and radiation in the setting of prior immune-checkpoint inhibitor (ICI) therapy.

An innovative intervention for the prevention of vaso-occlusive episodes in sickle cell disease.

OBJECTIVES: Sickle cell disease (SCD) is characterized by a mutation in the beta-globin gene resulting in abnormal hemoglobin S (HgbS). The significant sequela of SCD include anemia and recurrent vaso-occlusive episodes (VOEs) which may effectuate patients to receive chronic blood transfusions. Current pharmacotherapy options for SCD include hydroxyurea, voxelotor, Lglutamine, and crizanlizumab. Simple and exchange transfusions are often utilized as prophylaxis to prevent emergency department (ED)/urgent care (UC) visits or hospitalizations from VOEs by reducing the level of sickled red blood cells (RBCs). In addition, the treatment of VOEs involves intravenous (IV) hydration and pain management. Studies have demonstrated that sickle cell infusion centers (SCIC) decrease hospital admissions for VOEs, and IV hydration and pain medications are the key components of management employed. Thus, we hypothesized that implementing a structured infusion protocol in the outpatient setting would reduce the incidence of VOEs. METHODS: Here, we discuss two patients with SCD who were trialed on scheduled outpatient IV hydration and opioids with the goal of decreasing the frequency of VOEs in the setting of the current blood product shortage and the patients' refusal to receive exchange transfusions. RESULTS: Overall, the two patients had opposing outcomes- one demonstrated reduced frequency of VOEs, whereas the other had mixed results due to noncompliance to scheduled outpatient sessions. DISCUSSION/CONCLUSION: The use of outpatient SCICs may be an effective intervention for prevention of VOEs in patients with SCD, and further patient-centered research and quality improvement initiatives are needed to further quantify and understand the factors contributing to their efficacy.

Clinicopathologic Features and Treatment of CD10-Positive Mantle Cell Lymphoma: A Case Report and Review of Literature.

Mantle cell lymphoma (MCL) is a rare and aggressive non-Hodgkin's B cell lymphoma characterized by the translocation t(11;14) (q13;32) and overexpression of CCND1. MCL is immunophenotypically identified as CD20+, CD5+, CyclinD1+, CD43+, CD10-, BCL6-, and CD23-. It is often distinguished from B cell lymphomas of germinal center cell origin by the absence of CD10 expression. Here we report the unique clinicopathologic features of a patient with CD10+ MCL with gastrointestinal involvement and review current literature identifying this unique immunophenotype.

Nivolumab plus ipilimumab induced endocrinopathy and acute interstitial nephritis in metastatic sarcomatoid renal-cell carcinoma: A case report and review of literature.

The prognosis of sarcomatoid renal cell carcinoma has changed dramatically with the emergence of immune checkpoint inhibitors. Notably the use of nivolumab and ipilimumab combination therapy has demonstrated promising durable therapeutic response for patients with treatment-naïve sarcomatoid renal-cell carcinoma. We present a case of 45-year-old man with a history of metastatic sarcomatoid renal cell carcinoma treated with nivolumab plus ipilimumab who developed type 1 diabetes mellitus, adrenal insufficiency, thyroiditis/hypothyroidism, and acute interstitial nephritis as a result of immunotherapy.

Targeting TKI-Activated NFKB2-MIF/CXCLs-CXCR2 Signaling Pathways in FLT3 Mutated Acute Myeloid Leukemia Reduced Blast Viability.

Disease relapse is a common cause of treatment failure in FMS-like tyrosine kinase 3 (FLT3) mutated acute myeloid leukemia (AML). In this study, to identify therapeutic targets responsible for the survival and proliferation of leukemic cells (blasts) with FLT3 mutations after gilteritinib (GILT, a 2nd generation tyrosine kinase inhibitor (TKI)) treatment, we performed proteomic screening of cytokine release and in vitro/ex vivo studies to investigate their associated signaling pathways and transcriptional regulation. Here, we report that macrophage migration inhibition factor (MIF) was significantly increased in the supernatant of GILT-treated blasts when compared to untreated controls. Additionally, the GILT-treated blasts that survived were found to exhibit higher expressions of the CXCR2 gene and protein, a common receptor for MIF and pro-inflammatory cytokines. The supplementation of exogenous MIF to GILT-treated blasts revealed a group of CD44High+ cells that might be responsible for the relapse. Furthermore, we identified the highly activated non-classical NFKB2 pathway after GILT-treatment. The siRNA transient knockdown of NFKB2 significantly reduced the gene expressions of MIF, CXCR2, and CXCL5. Finally, treatments of AML patient samples ex vivo demonstrated that the combination of a pharmaceutical inhibitor of the NFKB family and GILT can effectively suppress primary blasts' secretion of tumor-promoting cytokines, such as CXCL1/5/8. In summary, we provide the first evidence that targeting treatment-activated compensatory pathways, such as the NFKB2-MIF/CXCLs-CXCR2 axis could be a novel therapeutic strategy to overcome TKI-resistance and effectively treat AML patients with FLT3 mutations.

Targeting the Tumor Microenvironment in Acute Myeloid Leukemia: The Future of Immunotherapy and Natural Products.

The tumor microenvironment (TME) plays an essential role in the development, proliferation, and survival of leukemic blasts in acute myeloid leukemia (AML). Within the bone marrow and peripheral blood, various phenotypically and functionally altered cells in the TME provide critical signals to suppress the anti-tumor immune response, allowing tumor cells to evade elimination. Thus, unraveling the complex interplay between AML and its microenvironment may have important clinical implications and are essential to directing the development of novel targeted therapies. This review summarizes recent advancements in our understanding of the AML TME and its ramifications on current immunotherapeutic strategies. We further review the role of natural products in modulating the TME to enhance response to immunotherapy.

Agrin regulation of alpha3 sodium-potassium ATPase activity modulates cardiac myocyte contraction.

Drugs that inhibit Na,K-ATPases, such as digoxin and ouabain, alter cardiac myocyte contractility. We recently demonstrated that agrin, a protein first identified at the vertebrate neuromuscular junction, binds to and regulates the activity of alpha3 subunit-containing isoforms of the Na,K-ATPase in the mammalian brain. Both agrin and the alpha3 Na,K-ATPase are expressed in heart, but their potential for interaction and effect on cardiac myocyte function was unknown. Here we show that agrin binds to the alpha3 subunit of the Na,K-ATPase in cardiac myocyte membranes, inducing tyrosine phosphorylation and inhibiting activity of the pump. Agrin also triggers a rapid increase in cytoplasmic Na(+) in cardiac myocytes, suggesting a role in cardiac myocyte function. Consistent with this hypothesis, spontaneous contraction frequencies of cultured cardiac myocytes prepared from mice in which agrin expression is blocked by mutation of the Agrn gene are significantly higher than in the wild type. The Agrn mutant phenotype is rescued by acute treatment with recombinant agrin. Furthermore, exposure of wild type myocytes to an agrin antagonist phenocopies the Agrn mutation. These data demonstrate that the basal frequency of myocyte contraction depends on endogenous agrin-alpha3 Na,K-ATPase interaction and suggest that agrin modulation of the alpha3 Na,K-ATPase is important in regulating heart function.

Viral/Nonviral Chimeric Nanoparticles To Synergistically Suppress Leukemia Proliferation via Simultaneous Gene Transduction and Silencing.

Single modal cancer therapy that targets one pathological pathway often turns out to be inefficient. For example, relapse of chronic myelogenous leukemia (CML) after inhibiting BCR-ABL fusion protein using tyrosine kinase inhibitors (TKI) (e.g., Imatinib) is of significant clinical concern. This study developed a dual modal gene therapy that simultaneously tackles two key BCR-ABL-linked pathways using viral/nonviral chimeric nanoparticles (ChNPs). Consisting of an adeno-associated virus (AAV) core and an acid-degradable polymeric shell, the ChNPs were designed to simultaneously induce pro-apoptotic BIM expression by the AAV core and silence pro-survival MCL-1 by the small interfering RNA (siRNA) encapsulated in the shell. The resulting BIM/MCL-1 ChNPs were able to efficiently suppress the proliferation of BCR-ABL+ K562 and FL5.12/p190 cells in vitro and in vivo via simultaneously expressing BIM and silencing MCL-1. Interestingly, the synergistic antileukemic effects generated by BIM/MCL-1 ChNPs were specific to BCR-ABL+ cells and independent of a proliferative cytokine, IL-3. The AAV core of ChNPs was efficiently shielded from inactivation by anti-AAV serum and avoided the generation of anti-AAV serum, without acute toxicity. This study demonstrates the development of a synergistically efficient, specific, and safe therapy for leukemia using gene carriers that simultaneously manipulate multiple and interlinked pathological pathways.

Epidemiologic differentiation of diagnostic and screening populations for the assessment of cervical dysplasia using optical technologies.

BACKGROUND: We report here the logistic modeling of the epidemiologic differences between a diagnostic population and a screening population recruited for the study of optical technologies for cervical cancer detection. OBJECTIVES: The goal of this analysis was to determine if there were differences in the sociodemographic or clinical factors between subjects recruited to our diagnostic and screening trials. METHODS: Epidemiologic data were obtained from a risk factor interview as a component of a multicenter Phase II clinical trial that used fluorescence and reflectance point spectroscopy to diagnose cervical disease. Participants with recent or past abnormal findings on a Papanicolaou smear were grouped into the diagnostic (high-risk) population, whereas those with a history of normal findings on Papanicolaou smears and no cervical treatments were grouped into the screening (low-risk) population. RESULTS: Our model revealed that nonwhite race, higher than a high school education, and peri- and postmenopausal status were associated with the screening population. A history of genital infections, current oral contraceptive use, human papillomavirus positivity (by Hybrid Capture II and consensus polymerase chain reaction), and worst histological diagnosis at clinic visit were important predictors of being in the diagnostic group. CONCLUSIONS: We were successful in recruiting 2 distinctive populations and anticipate being able to use these results to more correctly classify women at higher risk for cervical lesions in our future studies of optical spectroscopy.

Maximizing the diversity of participants in a phase II clinical trial of optical technologies to detect cervical neoplasia.

INTRODUCTION: We compare the racial and ethnic demographics of our participants with the populations where our clinics are located (Texas and British Columbia) and investigate the reasons cited for participation. METHODS: We compared the distribution of participants by race/ethnicity to numbers from the 2000 United States Census and the 2001 Census of Canada. Each participant recorded her reasons for enrolling in the trial in her own words. This information was then categorized for analysis. For participants who provided more than one reason for participation, their responses were weighted accordingly to sum 100% for each race. All analyses were performed using SPSS v12.0 (SPSS, Chicago). RESULTS: In all, 1850 women participated in the study. Except for Asians in the Vancouver population and Native Americans in both populations, all minorities were recruited in proportions in excess of their respective proportions in the general population. Distinct differences in the reasons for participating between sites were noted. Houston patients were more likely to cite concern for one's own health as a reason for participating. On the other hand, Vancouver patients were more likely to cite helping others. This trend was found in both the screening and diagnostic populations. CONCLUSIONS: We attribute our success in recruiting minorities to community outreach, our multicultural staff, and efforts to provide uniform care at all sites.