Harnessing the abscopal effect for gastrointestinal malignancies in the era of immunotherapy.

Gastrointestinal (GI) cancers are among the leading causes of cancer-related mortality and have traditionally been treated using a combination of surgical resection and chemoradiotherapy (CRT). While the introduction of immunotherapies over the last decade have dramatically changed the treatment landscape for some GI malignancies, including esophageal, gastric, and colorectal cancer, treatment resistance remains a major unaddressed obstacle for many patients. There has thus been emerging interest in determining the optimal treatment strategy for the delivery of immunotherapy in combination with traditional therapies. In this regard, a growing number of preclinical and clinical studies have suggested that combining radiation therapy (RT) with immunotherapy may work synergistically to improve treatment response through amplification of the abscopal effect. In this review, we discuss the rationale for RT in combination with immunotherapy. We further discuss how this knowledge may lead to a paradigm shift in the application of RT and highlight remaining issues pertaining to the delivery of combination therapy.

Factors Influencing Physician Discretion to Administer CNS Prophylaxis in Diffuse Large B Cell Lymphoma: A Single Institution Retrospective Study.

INTRODUCTION/BACKGROUND: Central nervous system (CNS) relapse is an infrequent but serious and challenging complication of diffuse large B-cell lymphoma (DLBCL) that carries a dismal prognosis. While several risk factors have been identified to stratify the risk for CNS relapse including the 2015 CNS internal Prognostic index (CNS-IPI), controversy still remains regarding the indication, timing, and method of CNS prophylaxis. The purpose of this study was to determine whether IT-MTX reduced the risk of CNS relapse, as well as treatment related and financial toxicity of CNS prophylaxis. PATIENTS AND METHODS: In this retrospective study, we identified 194 patients with DLBCL who received care at Loma Linda University Cancer Center between January 2010- August 2022. We evaluated the efficacy, side effect profile, and financial toxicity of IT-MTX for CNS prophylaxis in patients with DLBCL. RESULTS: In patients with intermediate to high CNS relapse risk (CNS-IPI 2-5) IT-MTX did not reduce the 1 year risk of CNS relapse (RR 1.1296, 95% CI 0.1933-6.6012, P = .08924). The median time to CNS relapse was longer in patients who had received IT-MTX (13.5 months) vs. those who did not (7 months). Thirty-eight (52.8%) patients reported adverse side effects of any kind as a result of IT-MTX administration, with 23.6% of patients developing grade 2 to 3 adverse events. The average cost for CNS-prophylaxis was estimated to be approximately $8,059.04 over a patient's treatment course, but as high as $20,140. CONCLUSIONS: These findings suggest that IT-MTX has limited and potential transient effectiveness in preventing CNS relapse. Given the high rate of side effects and significant cost of IT-MTX, we recommend that clinicians carefully consider the risks and benefits of prophylaxis before prescribing IT-MTX for CNS-prophylaxis.

Polymyositis/dermatomyositis readmissions: analysis of the nationwide readmission database.

BACKGROUND: There is a scarcity of national population-based studies on polymyositis (PM)/dermatomyositis (DM) readmissions in the USA. In this study, we aim to describe the rates, reasons for readmissions, and characteristics of readmissions for adults hospitalized for PM/DM in the USA. METHODS: We analyzed the 2018 Nationwide Readmissions Database (NRD). We included index hospitalizations for all adult DM/PM patients with a principal diagnosis of PM/DM using ICD-10 codes. We excluded elective and traumatic readmissions. Using a "rank" command in STATA, the most common specific principal diagnosis of readmissions was outlined. Chi-square tests were used to compare baseline characteristics between readmissions and index hospitalizations. STATA 16 was used for analysis. RESULTS: A total of 1610, 1286, and 842 index hospitalizations with a principal diagnosis of PM/DM, that were discharged alive, were included in the 30-, 90-, and 180-day readmission analysis, respectively. Among these, 193 (12%), 276 (21.5%), and 240 (28.5%) were readmitted within 30, 90, and 180 days, respectively. PM and sepsis were the most common reasons for reasons across the 3 timeframes. 30-day readmissions were responsible for an aggregate of 4.1 million US dollars in total hospital cost and 1518 hospital days in 2018. Compared to index hospitalizations, 30-day readmissions have higher Charlson Comorbidity Index scores, severe-extreme loss of function, obesity, and deep venous thrombosis. CONCLUSION: About a third of PM/DM hospitalized patients are readmitted within 180 days. Readmissions constitute a significant economic burden to the health care system. PM and sepsis are the main reasons for readmissions. Key points • About a third of polymyositis (PM)/dermatomyositis (DM) hospitalized patients are readmitted within 180 days • PM and sepsis are the main reasons for readmissions. • Readmissions of PM/DM Patients constitute a significant economic burden to the health care system. • Compared to index hospitalizations, 30-day readmissions have higher Charlson comorbidity index scores, severe-extreme loss of function, obesity, and deep venous thrombosis.

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.

Analysis of Cutaneous Lupus Hospitalizations: A United States National Population-Based Study.

Background There are limited studies analyzing cutaneous lupus erythematosus (CLE) hospitalizations. In this study, we aimed to analyze baseline demographics of systemic lupus erythematosus (SLE) and CLE patients, identify the most common reasons for hospitalizations, and find out the hospitalization outcomes.  Materials and methods We performed the analysis using the National (Nationwide) Inpatient Sample (NIS) database between 2016 and 2019. For the CLE cohort, data for adults aged 18 years and older with the primary or secondary diagnosis of CLE using International Classification of Disease - 10th revision (ICD-10) codes were extracted. For comparison, the SLE cohort was identified by patients aged 18 years and older with primary or secondary diagnoses of SLE using ICD-10 codes. Chi-squared test was used to compare baseline demographic characteristics. Multivariable logistic and linear regression was used to calculate outcomes of interest. Results In comparison to the SLE cohort, the CLE cohort was not only older in age and lower percentage female, but also had shorter length of stay, less total hospital charge, and the majority had Medicare as primary insurance. The SLE cohort included predominantly African American patients while the CLE cohort was majority Caucasian patients. The cardiovascular risks were more prevalent in the CLE cohort and most commonly admitted for sepsis, cardiovascular disease, and mental health disorders. Conclusion Our study highlights the importance of outpatient follow-up in CLE patients to closely monitor cardiovascular risk factors, early identification of infections, and routine mental health screenings to reduce hospitalizations and resource utilization.

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.

Longitudinal Trends of Hospitalizations for Giant Cell Arteritis: A 21-Year Longitudinal National Population-Based Study.

Background Long-term longitudinal studies on giant cell arteritis (GCA) hospitalizations are limited. Here we aim to fill gaps in knowledge by analyzing longitudinal trends of GCA hospitalizations over the last two decades in the United States (U.S.). Materials and methods We performed a 21-year longitudinal trend analysis of GCA hospitalizations using data obtained from the National Inpatient Sample (NIS) database between 1998 and 2018. Using the NIS database, we searched for hospitalizations for patients aged ≥ 50 years with a principal diagnosis of GCA using ICD billing codes. The principal diagnosis was the main reason for hospitalization. We used all hospitalizations in patients without GCA aged ≥50 years as the control population. Multivariable logistic and linear regression analysis was utilized to calculate the adjusted p-trend for outcomes of interest. Results The incidence of GCA hospitalization remained stable at about one per 100,000 U.S. persons throughout the study period. There was no statistically significant change in the inpatient mortality for the GCA group during the study period (adjusted p-trend=0.111). In comparison, inpatient mortality reduced from 4.4% to 3.1% from 1998 to 2018 (adjusted p-trend <0.0001) in the control group. The proportion of whites reduced, while the proportion of racial minorities increased over time in both the GCA and control groups. Conclusion The non-GCA control population saw significant reductions in mortality over time, but unfortunately, the GCA group did not see such improvements. More research into additional treatment modalities for inpatient GCA management may help improve mortality.

Analysis of Emergency Department Visits by Patients With Giant Cell Arteritis: A National Population-Based Study.

Background There is scarcity of national level data on the reasons for Emergency Department (ED) presentation among patients with Giant cell arteritis (GCA) in the United States. This study aims to outline the most common reasons for ED presentation among these patients, and the baseline characteristics and outcomes of ED visits principally for GCA.  Materials and methods We obtained data from the Nationwide Emergency Department Sample (NEDS) 2018 database. Each ED visit in the NEDS has a principal diagnosis (the main reason for the visit) and can have up to 34 other secondary diagnoses. We searched for ED visits for patients aged ≥50 with any diagnosis of GCA using ICD-10 codes. The most common principal discharge diagnoses were divided into organ systems, and specific principal discharge diagnoses were recorded for ED visits among patients with GCA in descending order of frequency. We then outlined baseline characteristics and outcomes of ED visits with a principal diagnosis of GCA. Results There were 20,886 ED visits for patients with GCA in 2018. Infections, as well as rheumatologic and cardiovascular disease were the most common reasons for ED presentation, and GCA was the most common specific principal discharge diagnosis for ED visits. There were 3888 ED visits with a principal diagnosis of GCA. These patients were predominantly elderly females, admitted, Medicare insured, with minimal comorbidity burden, and presented to metropolitan teaching hospitals in the south. Conclusion GCA patients are most likely to present to the ED due to their underlying GCA. Infections and CV are also common reasons for presentation to the ED.

The potential role of the thymus in immunotherapies for acute myeloid leukemia.

Understanding the factors which shape T-lymphocyte immunity is critical for the development and application of future immunotherapeutic strategies in treating hematological malignancies. The thymus, a specialized central lymphoid organ, plays important roles in generating a diverse T lymphocyte repertoire during the infantile and juvenile stages of humans. However, age-associated thymic involution and diseases or treatment associated injury result in a decline in its continuous role in the maintenance of T cell-mediated anti-tumor/virus immunity. Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that mainly affects older adults, and the disease's progression is known to consist of an impaired immune surveillance including a reduction in naïve T cell output, a restriction in T cell receptor repertoire, and an increase in frequencies of regulatory T cells. As one of the most successful immunotherapies thus far developed for malignancy, T-cell-based adoptive cell therapies could be essential for the development of a durable effective treatment to eliminate residue leukemic cells (blasts) and prevent AML relapse. Thus, a detailed cellular and molecular landscape of how the adult thymus functions within the context of the AML microenvironment will provide new insights into both the immune-related pathogenesis and the regeneration of a functional immune system against leukemia in AML patients. Herein, we review the available evidence supporting the potential correlation between thymic dysfunction and T-lymphocyte impairment with the ontogeny of AML (II-VI). We then discuss how the thymus could impact current and future therapeutic approaches in AML (VII). Finally, we review various strategies to rejuvenate thymic function to improve the precision and efficacy of cancer immunotherapy (VIII).

FBP1-Altered Carbohydrate Metabolism Reduces Leukemic Viability through Activating P53 and Modulating the Mitochondrial Quality Control System In Vitro.

Acute myeloid leukemia (AML)-the most frequent form of adult blood cancer-is characterized by heterogeneous mechanisms and disease progression. Developing an effective therapeutic strategy that targets metabolic homeostasis and energy production in immature leukemic cells (blasts) is essential for overcoming relapse and improving the prognosis of AML patients with different subtypes. With respect to metabolic regulation, fructose-1,6-bisphosphatase 1 (FBP1) is a gluconeogenic enzyme that is vital to carbohydrate metabolism, since gluconeogenesis is the central pathway for the production of important metabolites and energy necessary to maintain normal cellular activities. Beyond its catalytic activity, FBP1 inhibits aerobic glycolysis-known as the "Warburg effect"-in cancer cells. Importantly, while downregulation of FBP1 is associated with carcinogenesis in major human organs, restoration of FBP1 in cancer cells promotes apoptosis and prevents disease progression in solid tumors. Recently, our large-scale sequencing analyses revealed FBP1 as a novel inducible therapeutic target among 17,757 vitamin-D-responsive genes in MV4-11 or MOLM-14 blasts in vitro, both of which were derived from AML patients with FLT3 mutations. To investigate FBP1's anti-leukemic function in this study, we generated a new AML cell line through lentiviral overexpression of an FBP1 transgene in vitro (named FBP1-MV4-11). Results showed that FBP1-MV4-11 blasts are more prone to apoptosis than MV4-11 blasts. Mechanistically, FBP1-MV4-11 blasts have significantly increased gene and protein expression of P53, as confirmed by the P53 promoter assay in vitro. However, enhanced cell death and reduced proliferation of FBP1-MV4-11 blasts could be reversed by supplementation with post-glycolytic metabolites in vitro. Additionally, FBP1-MV4-11 blasts were found to have impaired mitochondrial homeostasis through reduced cytochrome c oxidase subunit 2 (COX2 or MT-CO2) and upregulated PTEN-induced kinase (PINK1) expressions. In summary, this is the first in vitro evidence that FBP1-altered carbohydrate metabolism and FBP1-activated P53 can initiate leukemic death by activating mitochondrial reprogramming in AML blasts, supporting the clinical potential of FBP1-based therapies for AML-like cancers.

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.

Capnocytophaga tricuspid valve endocarditis: a case report and literature review.

Capnocytophaga canimorsus is a Gram-negative zoonotic pathogen capable of causing serious infection following dog or cat bite. Infections often manifest as sepsis, fatal septic shock, gangrene, bacteraemia, meningitis and endocarditis. Here we report a case of C. canimorsus bacteraemia complicated by tricuspid valve infective endocarditis and septic pulmonary emboli.

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.

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.

Vitamin D activates FBP1 to block the Warburg effect and modulate blast metabolism in acute myeloid leukemia.

Acute myeloid leukemia (AML) has the lowest survival rate among the leukemias. Targeting intracellular metabolism and energy production in leukemic cells can be a promising therapeutic strategy for AML. Recently, we presented the successful use of vitamin D (1,25VD3) gene therapy to treat AML mouse models in vivo. In this study, recognizing the importance of 1,25VD3 as one of only 2 molecules (along with glucose) photosynthesized for energy during the beginning stage of life on this planet, we explored the functional role of 1,25VD3 in AML metabolism.Transcriptome database (RNA-seq) of four different AML cell lines revealed 17,757 genes responding to 1,25VD3-treatment. Moreover, we discovered that fructose-bisphosphatase 1 (FBP1) noticeably stands out as the only gene (out of 17,757 genes) with a 250-fold increase in gene expression, which is known to encode the key rate-limiting gluconeogenic enzyme fructose-1,6-bisphosphatase. The significant increased expression of FBP1 gene and proteins induced by 1,25VD3 was confirmed by qPCR, western blot, flow cytometry, immunocytochemistry and functional lactate assay. Additionally, 1,25VD3 was found to regulate different AML metabolic processes including gluconeogenesis, glycolysis, TCA, de novo nucleotide synthesis, etc. In summary, we provided the first evidence that 1,25 VD3-induced FBP1 overexpression might be a novel therapeutic target to block the "Warburg Effect" to reduce energy production in AML blasts.

Role of Ketamine and Opioid Rotation in the Management of Opioid Induced Hyperalgesia in a Patient With Acute Promyelocytic Leukemia.

INTRODUCTION: Opioid analgesics are commonly used to manage moderate to severe cancer related pain. However long-term use of opioids has been known to lead to several unintended side effects, including opioid induced hyperalgesia (OIH) which is defined as the paradoxical increase in pain sensitization to pain stimulus following opioid exposure. Currently there are limited reports on the association between patients with cancer and OIH, and this phenomenon is rarely described in patients with leukemia or lymphoma. Here we report a patient with acute promyelocytic leukemia who developed opioid induced hyperalgesia following rapid escalation of opioids. CASE REPORT: A 36-year-old female being treated for acute promyelocytic leukemia presented with rapidly worsening acute on chronic hip pain requiring increasing opioid requriements. Given the rapid escalation of opioid dose with minimal response and physical exam findings consistent with allodynia/hyperalgesia a diagnosis of opioid induced hyperalgesia was made. MANAGEMENT AND OUTCOME: Following recognition of opioid induced hyperalgesia, the patient was managed with opioid rotation and ketamine, which resulted in prompt alleviation of pain. DISCUSSION: Opioid induced hyperalgesia is likely an underrecognized phenomenon in patients with cancer-related pain. A high index of clinical suspicion are necessary for diagnosis and proper management of this disease entity.