Immunological Agents Research Articles

A Treatment Paradigm Shift: Targeted Radionuclide Therapies for Metastatic Castrate Resistant Prostate Cancer

Simple SummaryMetastatic prostate cancer has traditionally been treated with a combination of hormonal and chemotherapy regimens. With the recent FDA approval of targeted radionuclide therapeutics, there is now a new class of therapy that is routinely available to patients and clinicians. This review explores the most commonly studied therapeutic radiopharmaceuticals and their appropriate use and contraindications. Additionally, we detail how these therapeutic radiopharmaceuticals can fit into the common medical oncology practice and future directions of this field of medicine.The recent approval of 177Lu PSMA-617 (Pluvicto®) by the United States Food and Drug Administration (FDA) is the culmination of decades of work in advancing the field of targeted radionuclide therapy for metastatic prostate cancer. 177Lu PSMA-617, along with the bone specific radiotherapeutic agent, 223RaCl2 (Xofigo®), are now commonly used in routine clinical care as a tertiary line of therapy for men with metastatic castrate resistant prostate cancer and for osseus metastatic disease respectively. While these radiopharmaceuticals are changing how metastatic prostate cancer is classified and treated, there is relatively little guidance to the practitioner and patient as to how best utilize these therapies, especially in conjunction with other more well-established regimens including hormonal, immunologic, and chemotherapeutic agents. This review article will go into detail about the mechanism and effectiveness of these radiopharmaceuticals and less well-known classes of targeted radionuclide radiopharmaceuticals including alpha emitting prostate specific membrane antigen (PSMA)-, gastrin-releasing peptide receptor (GRPR)-, and somatostatin targeted radionuclide therapeutics. Additionally, a thorough discussion of the clinical approach of these agents is included and required futures studies.

Engineering nanostructured pure cancer cell membrane‐derived vesicles as a novel therapeutic cancer vaccine

AbstractExtracted cancer cell membrane carries the antigens of the parent tumor cell. This autologous antigen repertoire presents cancer cell membrane‐derived nanoparticles highly immunogenic to the body's immune system. Cancer cell membrane‐derived nanoparticles antigenically recapitulate the parental cancer cells and can be exploited to induce immune response reactive with tumor‐associated antigens (TAAs). The use of the cancer cell membrane‐derived nanoparticles to deliver immunostimulatory adjuvants facilitates the cross‐presentation of tumor antigens by antigen‐presenting cells and their costimulation, triggering potent antigen‐specific T responses to eliminate established tumors. These nanoparticles can be engineered to carry immunostimulatory signals to facilitate the cross‐presentation of TAAs and the induction of potent antitumor immunity. In this study, cancer cell membrane‐based vesicles (CCMVs) are prepared from B16 melanoma cells and engineered to deliver the immunological agent polyinosinic:polycytidylic acid (poly‐IC). We show that CCMV is preferentially uptaken by bone marrow‐derived dendritic cells (BMDCs) as compared to other cell types (macrophages, fibroblasts). The efficient delivery of poly‐IC to BMDCs results in enhanced antigen cross‐presenting capability of BMDCs and T‐cell activation. Additionally, immunization of mice with poly‐IC‐carrying CCMV elicits a potent antitumor immune response. In conclusion, poly‐IC‐decorated tumor‐derived CCMV may be used as a therapeutic vaccine to potentiate antitumor immunity.

Inflammation: A Target for Treatment in Spinal Cord Injury.

Spinal cord injury (SCI) is a significant cause of disability, and treatment alternatives that generate beneficial outcomes and have no side effects are urgently needed. SCI may be treatable if intervention is initiated promptly. Therefore, several treatment proposals are currently being evaluated. Inflammation is part of a complex physiological response to injury or harmful stimuli induced by mechanical, chemical, or immunological agents. Neuroinflammation is one of the principal secondary changes following SCI and plays a crucial role in modulating the pathological progression of acute and chronic SCI. This review describes the main inflammatory events occurring after SCI and discusses recently proposed potential treatments and therapeutic agents that regulate inflammation after insult in animal models.

EFFECTS OF DRUG BETAMETHASONE ON HEMATOLOGICAL PARAMETERS OF RATTUS NORVEGICUS (BERKENHOUT 1769) IN VIVO CONDITIONS

Glucocorticoids prevent or suppress the full inflammatory response to the infectious, immunological or physical agents by inhibiting early inflammatory events such as edema or cell exudation. The main effect of glucocorticoids on the inflammatory process is the inhibition or recruitment of neutrophils and monocytes. In this study, the effect of the glucocorticoid betamethasone on the hematological parameters of rats of the species Rattus norvegicus Berkenhout 1769 was examined in vivo. Betamethasone has been shown to affect the values of hematological parameters four hours after application and leads to a significant decrease in the prevalence of lymphocytes and monocytes, but also leads to a statistically significant increase in erythrocyte count, hemoglobin concentration and hematocrit values.

Porphyrin‐Based Covalent Organic Framework for Imaging‐Guided Cancer Combinatorial Immuno‐Sonodynamic Therapy

AbstractThe rational design of tumor microenvironment (TME)‐activated nanomedicine is driving a new direction in tumor immunology. Furthermore, the novel therapeutic mode of ultrasound‐triggered sonodynamic therapy (SDT) has been proven to specifically activate the immune response. Herein, a well‐defined covalent organic framework (COF) with sonosensitive properties is synthesized through experimental and theoretical verification, followed by the efficient loading of the toll‐like receptor agonist (Poly(I:C)) and in situ growth of paramagnetic transitional metallic oxide of manganese bioxide (MnO2). The MnO2‐Poly(I:C)@COF shell can reverse the reductive TME by consuming glutathione (GSH) to release Mn2+, simultaneously generating marked magnetic resonance imaging signals for real‐time guidance. Importantly, the MnO2 acts as an enzyme‐like nano‐catalyst to promote TME‐overexpressed hydrogen peroxide (H2O2) and produce oxygen, facilitating SDT‐induced reactive oxygen species production, and inducing immunogenic cell death, thereby boosting immune engine and triggering abundant neoantigen exposure. With the powerful assistance of immunological agents Mn2+ and Poly(I:C), the triggered immune engine is amplified by refueling the engine (stepping on the accelerator) to reduce the immunosuppressive state. Overall, this study improves the synthesis of multifunctional COF and expands its application. The developed nano‐sonosensitizer system provides a paradigm to enhance SDT‐based high‐performance multifunctional sonosensitizers, and this SDT‐mediated strong tumor‐suppressive efficiency and activated immune effect represent a promising combinatorial therapeutic strategy for cancer therapy.

Expanding anti-CD38 immunotherapy for lymphoid malignancies

BackgroundLymphoid neoplasms, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and NK/T cell neoplasms, are a major cause of blood cancer morbidity and mortality. CD38 (cyclic ADP ribose hydrolase) is a transmembrane glycoprotein expressed on the surface of plasma cells and MM cells. The high expression of CD38 across MM and other lymphoid malignancies and its restricted expression in normal tissues make CD38 an attractive target for immunotherapy. CD38-targeting antibodies, like daratumumab, have been approved for the treatment of MM and tested against lymphoma and leukemia in multiple clinical trials.MethodsWe generated chimeric antigen receptor (CAR) T cells targeting CD38 and tested its cytotoxicity against multiple CD38high and CD38low lymphoid cancer cells. We evaluated the synergistic effects of all-trans retinoic acid (ATRA) and CAR T cells or daratumumab against cancer cells and xenograft tumors.ResultsCD38-CAR T cells dramatically inhibited the growth of CD38high MM, mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia (WM), T-cell acute lymphoblastic leukemia (T-ALL), and NK/T-cell lymphoma (NKTCL) in vitro and in mouse xenografts. ATRA elevated CD38 expression in multiple CD38low cancer cells and enhanced the anti-tumor activity of daratumumab and CD38-CAR T cells in xenograft tumors.ConclusionsThese findings may expand anti-CD38 immunotherapy to a broad spectrum of lymphoid malignancies and call for the incorporation of ATRA into daratumumab or other anti-CD38 immunological agents for cancer therapy.

Systemically targeted cancer immunotherapy and gene delivery using transmorphic particles

Immunotherapy is a powerful tool for cancer treatment, but the pleiotropic nature of cytokines and immunological agents strongly limits clinical translation and safety. To address this unmet need, we designed and characterised a systemically targeted cytokine gene delivery system through transmorphic encapsidation of human recombinant adeno‐associated virus DNA using coat proteins from a tumour‐targeted bacteriophage (phage). We show that Transmorphic Phage/AAV (TPA) particles provide superior delivery of transgenes over current phage‐derived vectors through greater diffusion across the extracellular space and improved intracellular trafficking. We used TPA to target the delivery of cytokine‐encoding transgenes for interleukin‐12 (IL12), and novel isoforms of IL15 and tumour necrosis factor alpha (TNFα) for tumour immunotherapy. Our results demonstrate selective and efficient gene delivery and immunotherapy against solid tumours in vivo, without harming healthy organs. Our transmorphic particle system provides a promising modality for safe and effective gene delivery, and cancer immunotherapies through cross‐species complementation of two commonly used viruses.

A novel polysaccharide from Boletus edulis: Extraction, purification, characterization and immunologic activity

A novel polysaccharide (BEP) was extracted from Boletus edulis, and its structural characteristics and immunologic activity were evaluated. Our findings revealed that BEP (139 kDa) contained Man, Glc, and Gal in the molar ratio of 1:0.15:0.17 with typical characteristic absorption peaks of polysaccharides. Moreover, the results of methylation and 1D/2D NMR spectroscopy indicated that the backbone of BEP was →6)-α-Manp-(1→ and →3,6)-α-Manp-(1→, with the side chain →3)-β-Manp-(1→, →3)-α-Galp-(1→ and α-Glcp-(1→). The immunological activity tests demonstrated that the BEP could enhance phagocytosis of peritoneal macrophages and secrete NO and cytokines in a dose-dependent by activated macrophage. It was noteworthy that the secretions of NO, IL-6 and TNF-α at 400 μg/mL concentration were increased by 25.50%, 191.67% and 196.05% compared with the control group, respectively. The results illustrated that BEP was a novel polysaccharide, which may be marked as an immunologic agent in the food, pharmaceutical and cosmetic industries.

A single arm phase 2 study of talimogene laherparepvec in patients with low-risk invasive cutaneous squamous cell cancer. interim analysis.

e21583 Background: A compromised immune-surveillance plays an important role in the pathogenesis of cutaneous squamous cell carcinoma (cSCC). Talimogene laherparepvec (TVEC) is an HSV-1 oncolytic immunological agent FDA approved for the local treatment of unresectable recurrent melanoma. It is proposed that T-VEC directly destroys cancer cells, and induces production of GM-CSF to enhance systemic antitumor immune recognition. This proposed mechanism of action supports the innovative approach to implement TVEC in the management of cSCC. Methods: Immunocompetent patients > 18 years of age and diagnosed with at least one > 0.5 cm to < 5.0 cm, primary and histologically confirmed well-moderate differentiated cSCC, without evidence of perineural or vascular invasion were eligible to participate. Unresectable lesions or patients unable/unwilling to undergo standard of care treatment were eligible to participate. Study lesions include target injected lesions (TILs) and target non-injected lesions (TNILs). A total of up to 5 TILs were selected per subject. If feasible, target non-injected lesions (TNILs) were also selected in eligible participants to evaluate for abscopal effect. Every TIL was injected up to 4 times based lesion diameter according to current TVEC approved protocol administration and followed for 1yr after the 1st injection. The primary endpoint of the study was to evaluate the overall response rate (ORR), defined as the proportion of subjects who achieved complete response (CR) and partial response (PR) in the TILs. Safety and adverse effect profile (AEs), duration of ORR, time to response (TTR), durable response rate, and time to progression, were the secondary endpoints included. A Simon 2 stage design was used. Total sample size was calculated to be 20 subjects. Seven subjects were recruited for stage 1 with a plan to recruit an additional 13 patients if five or more subjects met the primary endpoint in stage 1. Results: The interim analysis was conducted after the 7th participant completed Visit 8 (352-266 days from study initiation). For the primary endpoint, all 7 participants achieved an overall complete response (100%; 95% CI: 59.0-100%). NCI CTCAE (v. 4.0) was used to assess the safety and adverse effect profile. All AEs ranged from grades 1-2, and most commonly experienced transient fatigue (n = 3/7), flu like symptoms (n = 2/7) and headaches (n = 2/7). The mean time to response was 43.4 (SD 31.6) days and for duration of ORR 190.0 days (SD 39.3) at the time of analysis. The 2 TNILs evaluated in the interim analysis also demonstrated 100% CR (95% CI: 15.8-100%). Conclusions: TVEC showed extremely impressive ORR for patients with cSCC with a 100% CR in stage 1 of our pilot study. AE profile of TVEC was mild and was well tolerated. Completion of the study will further assess this high response rate. Clinical trial information: 03714828.

Tazemetostat in patients with tumors with alterations in EZH2 or the SWI/SNF complex: Results from NCI-COG Pediatric MATCH trial Arm C (APEC1621C).

10009 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients, age 1-21 years, with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase 2 treatment arms based on genetic alterations detected in their tumor. Arm C evaluated the EZH2 inhibitor tazemetostat in patients whose tumors harbored EZH2 hotspot mutations or SMARCB1 or SMARCA4 loss by immunohistochemistry. Methods: Tazemetostat 1200 mg/m2/dose PO BID was administered to the first 13 patients; after study amendment due to second malignancy noted in the pediatric phase 1 trial, the dose for patients with non-CNS tumors was reduced to 520 mg/m2/dose PO BID. Patients were treated for 28-day cycles until PD or intolerable toxicity (max 26 cycles); response assessments occurred every 2-3 cycles. Primary and secondary endpoints were ORR and PFS, respectively. Results: Twenty eligible and evaluable patients (median age 5 years; range 1-21) were enrolled between Nov 2017 and Sept 2020. SMARCB1 loss was detected in 16/20 (80%) tumors: atypical teratoid rhabdoid tumor (ATRT, n = 8), malignant rhabdoid tumor (MRT, n = 4), epithelioid sarcoma (ES, n = 2), renal medullary carcinoma (RMC, n = 1) and hepatocellular carcinoma (HCC, n = 1). EZH2 mutations were identified in 3/20 (15%) tumors: Ewing sarcoma (n = 2), ependymoma (n = 1). One patient with Langerhans cell histiocytosis (LCH) had SMARCA4 loss. Centrally reviewed, one objective response (PR) was observed (LCH [SMARCA4], 26 cycles at 1200 mg/m2/dose BID). Five other patients had a best response of stable disease (ES [SMARCB1], 26 cycles, 520 mg/m2/dose BID; ATRT [SMARCB1], 13 cycles,1200 mg/m2/dose BID; RMC [SMARCB1], 12 cycles, 520 mg/m2/dose BID; ES [SMARCB1], 9 cycles,1200 mg/m2/dose BID; ATRT [SMARCB1], 6 cycles, 1200 mg/m2/dose BID). No other patients received > 2 cycles. Six-month PFS was 35% (95% CI 15.7%, 55.2%); OS was 45% (95% CI 23.1%, 64.7%). Treatment-related adverse events were consistent with AEs previously reported with tazemetostat, including anemia, thrombocytopenia, elevated LFTs, abdominal pain, dyspnea, infection, and intracranial hemorrhage. Three patients had bromide elevations. Conclusions: In this cohort of children with relapsed tumors harboring EZH2 mutations or loss of SMARCB1 or SMARCA4, tazemetostat did not produce significant objective responses (ORR: 5%, 90% CI 1%, 20%). However, we observed prolonged stable disease of > 6 months (range: 6-26 cycles) in 33% of patients across different histologic diagnoses, including two patients who received the full two years of study therapysuggesting a potential effect of tazemetostat on disease stabilization. Future studies will incorporate tazemetostat in combination with chemotherapy or immunologic agents for patients with these aggressive and difficult to treat tumors. Clinical trial information: NCT03213665.

Economic Burden and Healthcare Resource Use of Alopecia Areata in an Insured Population in the USA

IntroductionComparative data on the economic burden of alopecia areata relative to the general population are limited. The objective of this retrospective database analysis was to evaluate healthcare resource utilization and direct medical costs among patients with alopecia areata from the US payer perspective compared with matched controls.MethodsValidated billing codes were used to identify patients with alopecia areata from the IQVIA PharMetrics Plus (2016–2018) who had continuous pharmacy and medical enrollment for 365 days both before (baseline period) and after (evaluation period) the index date. Demographic and clinical characteristics were characterized, and baseline comorbidities were assessed with the Quan Charlson Comorbidity Index.ResultsUsing the exact matching feature from Instant Health Data, 14,340 patients with alopecia areata were matched with 42,998 control patients aged ≥ 12 years. Patients with alopecia areata had higher healthcare resource utilization and adjusted total all-cause mean medical costs versus matched controls ($8557 versus $6416; p < 0.0001), because of higher inpatient costs, emergency department visits, ambulatory visits, number of prescriptions and prescription costs, and other costs such as durable medical equipment and home healthcare. The number of inpatient visits did not significantly differ between the two groups. Mean ambulatory costs were $3640 for patients with alopecia areata and $2062 for controls, and mean pharmacy costs were $3287 and $1843, respectively (p < 0.0001 for both). Pharmacy costs related to immunologic agents represented 50.0% of the total difference in pharmacy spending between patients with alopecia areata and controls. Surgery on the integumentary system accounted for 9.5% of the total difference in ambulatory costs.ConclusionAlopecia areata is associated with significant incremental healthcare resource utilization and costs relative to matched controls due to increased spending in areas such as surgical procedures and psychological and pharmacological interventions. Costs are primarily driven by ambulatory and pharmacy spending.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-022-00710-4.

Evaluation of the Immunological Activity of Gryllus bimaculatus Water Extract.

Edible insects are commonly consumed across the world because of their size, availability, and nutritional benefits. They have also been recommended as a potential solution to food shortage because of their high nutritional value. In this study, we demonstrated the immunological effects of Gryllus bimaculatus on RAW 264.7 cells and splenocytes obtained from mouse. This is the first study to evaluate the immunological effects of G. bimaculatus water extract. Innate and adaptive immunity were evaluated and measured in RAW 264.7 cells and/or mouse splenocytes using a cell viability assay; changes in cytokine abundance, nitric oxide production, and cell surface molecule abundance were determined using flow cytometry; and western blotting analysis was performed for various immune signaling pathways. G. bimaculatus water extract showed no cytotoxicity in cells, and the results suggest that treatment with G. bimaculatus water extract can induce macrophage activation through mitogen-activated protein kinase and nuclear factor-κB signaling, induction of proinflammatory cytokines [interleukin (IL)-6, IL-1β, and tumor necrosis factor-α] and activation of the expression of cell surface molecules [cluster of differentiation (CD)80, CD86, major histocompatibility complex (MHC) class I, and MHC class II]. Treatment with G. bimaculatus water extract increased the production of cytokines (IL-2, IL-4, and interferon-γ) in splenocytes. The results indicate that G. bimaculatus water extract can regulate innate and adaptive immunity via modulation macrophages and splenocytes activation and can serve as an immunological agent. We inferred that G. bimaculatus is a safe and efficient natural material that enhances immunological activity.

Neoadjuvant Systemic Therapy Prior to Radical Prostatectomy for Clinically Localized High-Risk Prostate Cancer

Radical prostatectomy (RP) remains a standard treatment option for clinically localized high-risk prostate cancer. While RP provides excellent local control, patients with high-risk disease remain at considerable risk for recurrence after surgery. Disease relapse may be the result of occult distant metastases or regional micrometastatic disease at the time of surgery. Accordingly, the role of systemic (neoadjuvant) therapy prior to RP has been investigated. Proposed neoadjuvant regimens: include monotherapy or combinations of chemotherapy, hormonal deprivation, and immunologic agents. Randomized trials using androgen deprivation have demonstrated improved pathologic outcomes, including pathologic downstaging and decreased risk of positive surgical margins, extracapsular extension, and seminal vesical invasion. However, these, albeit early, trials did not reliably demonstrate improved post-prostatectomy oncologic outcomes. More recent trials have evaluated novel combinations of chemo-hormonal therapy and immunologic based therapies. These studies are currently maturing and offer the promise, pending findings, of potentially informing future practice. In this review, we highlight the pathophysiologic basis and contemporary evidence for neoadjuvant therapy prior to RP for clinically localized high-risk prostate cancer.

Molecular Epidemiology of Hypervirulent K. pneumoniae and Problems of Health-Care Associated Infections.

The review describes virulence factors of hypervirulent K. pneumoniae (hvKp) including genes determining its virulence and discusses their role in the development of health-care associated infections. The contribution of individual virulence factors and their combination to the development of the hypervirulence and the prospects of using these factors as biomarkers and therapeutic targets are described. Virulence factors of hvKp and “classical” K. pneumoniae strains (cKp) with no hypervirulence genes were compared. The mechanisms of biofilm formation by hvKp and high incidence of its antibiotic resistance are of particular importance for in health care institutions. Therefore, the development of methods for hvKp identification allowing early prevention of severe hvKp infection and novel approaches to abrogate its spreading are new challenges for epidemiology, infection diseases, and critical care medicine. New technologies including bacteriological and molecular studies make it possible to develop innovative strategies to diagnose and treat infection caused by hvKp. These include monitoring of both genetic biomarkers of hvKp and resistance plasmid that carry of virulence genes and antibiotic resistance genes, creation of immunological agents for the prevention and therapy of hvKp (vaccines, monoclonal antibodies) as well as personalized hvKp-specific phage therapies and pharmaceuticals enhancing the effect of antibiotics. A variety of approaches can reliably prepare our medicine for a new challenge: spreading of life-threatening health-care associated infections caused by antibiotic-resistant hvKp strains.

Purification, characterization, and immunomodulatory activity of a lectin from the seeds of horse chestnut (Aesculus hippocastanum L.)

This work aimed to purify, characterize, and evaluate the immunomodulatory activity of a lectin from Aesculus hippocastanum seeds (AhSL). The lectin was isolated from saline extract through chromatography on a DEAE-Sephadex column. Protein homogeneity and subunit composition were evaluated with polyacrylamide gel electrophoresis (PAGE) under native and denaturing (SDS-PAGE) conditions, respectively. AhSL was evaluated for trypsin inhibitor activity, carbohydrate-binding specificity, and the effects of cations (Ca2+, Mn2+, and Mg2+), temperature, and pH on its hemagglutinating activity. Lectin stability under heating and pH variation was evaluated through fluorometric analysis. The activity of this lectin (12.5 µg/mL) in modulating cytokine release and nitric oxide production by mouse splenocytes was assessed. Isolated AhSL (purification fold: 68.8) showed a single polypeptide band in PAGE for acidic proteins and two polypeptide bands of approximately 68 and 124 kDa in SDS-PAGE. Its hemagglutinating activity was inhibited by monosaccharides, disaccharides, and glycoproteins, but was not affected by cations, and remained stable after heating (30–100 °C) and under pH 4.0–8.0. Fluorometric analysis revealed that the overall lectin conformation was not altered after heating to 100 °C and remained stable under various pH values. AhSL also showed trypsin inhibitor activity (specific activity: 1,280.31 U/mg) and induced the release of interleukins 10 and 6, tumor necrosis factor α, and nitric oxide by splenocytes. In conclusion, AhSL is a bioactive protein with promising biotechnological potential, which may find applications as immunological targeting or antitumor agents.

Allogeneic Stem Cell Transplantation in Multiple Myeloma.

Simple SummaryDue to its graft-versus-myeloma effect, allogeneic hematopoietic stem cell transplantation (allo-SCT) can enable long-term survival or even cure in carefully selected patients with multiple myeloma (MM), but remains controversial due to its relevant treatment-related toxicity. Current data suggest that allo-SCT should be considered in young MM-patients without relevant comorbidities in case of a high-risk constellation according to cytogenetics or stage, primarily as part of a tandem approach with autologous-SCT followed by allo-SCT and early in the course of the disease. Prospective studies are warranted, due to a suspected synergism especially those including new immunotherapeutic approaches for induction, conditioning and maintenance therapy.The development of new inhibitory and immunological agents and combination therapies significantly improved response rates and survival of patients diagnosed with multiple myeloma (MM) in the last decade, but the disease is still considered to be incurable by current standards and the prognosis is dismal especially in high-risk groups and in relapsed and/or refractory patients. Allogeneic hematopoietic stem cell transplantation (allo-SCT) may enable long-term survival and even cure for individual patients via an immune-mediated graft-versus-myeloma (GvM) effect, but remains controversial due to relevant transplant-related risks, particularly immunosuppression and graft-versus-host disease, and a substantial non-relapse mortality. The decreased risk of disease progression may outweigh this treatment-related toxicity for young, fit patients in high-risk constellations with otherwise often poor long-term prognosis. Here, allo-SCT should be considered within clinical trials in first-line as part of a tandem approach to separate myeloablation achieved by high-dose chemotherapy with autologous SCT, and following allo-SCT with a reduced-intensity conditioning to minimize treatment-related organ toxicities but allow GvM effect. Our review aims to better define the role of allo-SCT in myeloma treatment particularly in the context of new immunomodulatory approaches.

A Case Report on Post COVID -19 Vaccine Associated Guillain–Barré Syndrome

Guillain–Barré syndrome (GBS) is an autoimmune demyelinating illness in which a patient’s immune system attacks and cause deterioration of peripheral nervous system leading to progressive paralysis and polyneuropathy. The exact cause of the GBS is unclear but the main mechanism of behindis the demyelination of nerves especially the motor, sensory, and autonomic nerves which can be triggered by any immunologic or infectious agent. The infectious agent elicits the humoral and cellular mediated immune response due to their molecular mimicry in which the antibodies created against the infection matches with the proteins on the nerve. The characteristic features of Guillain–Barré syndrome are ascending flaccid paralysis, paresthesia, impairment of muscle reflexes, respiratory failureetc. The GBS is diagnosed via nerve conduction studies, lumbar puncture (Cerebrospinal fluid analysis), electromyography, Brighton criteria. Treatments like intravenous immunoglobulin therapy, plasma exchange can ease the symptoms and reduce the duration of the illness. This case report focusing on a 43-year-old female patient admitted seeking ventilatory support for respiratory distress caused by Guillain–Barré Syndrome in a tertiary hospital. Patient had developed limb weakness with ascending paralysis along with facial weakness within a couple of weeks after receiving the COVID -19 vaccination (COVISHIELD)one month back. Patient underwent nerve conduction study and routine monitoring of vital parameters. After conservative management with physiotherapy, ventilation, intravenous immunoglobulins and prophylaxis for pain and DVT patient gradually started improving the muscle power and was discharged to continue the rehabilitation care at home.

Genetic characteristics and response to systemic therapies of acral lentiginous melanoma at a tertiary care center—a retrospective review

BackgroundAcral lentiginous melanoma (ALM) is an aggressive subtype of cutaneous malignant melanomas that accounts for 50-80% of melanomas in ethnic minorities. Studies on the genetic profile of these tumors largely result from cohorts in Europe, Asia, and Latin America, few inclusive of Black patients. ObjectiveWe aim to describe the clinicopathological and genetic characteristics in a diverse cohort of ALM patients. MethodsA retrospective analysis of 93 patients with a pathology confirmed diagnosis of ALM between March 1984 and October 2020 was conducted at a large tertiary care center. Melanoma mutation panel testing for frequently mutated regions of the BRAF, NRAS, KIT and PIK3CA genes were reviewed in patient records when available. ResultsOf the 93 patients identified, 62.4% were Caucasian, 25.8% Black, 4.30% Hispanic, 4.30% Asian, and 3.22% identified as other. Fourteen of 17 patients receiving targeted or immunologic agents experienced disease progression during treatment, including all patients with a BRAF V600E mutation. LimitationsThis was a single-center retrospective analysis. ConclusionResponse to targeted and immunologic therapies in ALM patients was overwhelming poor, particularly in BRAF V600E-mutated tumors in contrast to the positive prognosis associated with BRAF V600E mutations in other advanced cutaneous melanoma subtypes.

Incidence of Secondary Microorganism Infections Following Utilization of Tocilizumab for the Treatment of COVID‑19 - A Matched Retrospective Cohort Study

Introduction: immunological disorder agent’s area unit theorized to focus on the protein storm syndrome in COVID‑19. However, the downstream effects concerning susceptibilities to secondary infection risk stay unknown. This study seeks to work out risk variations for secondary infections among COVID‑19 patients World Health Organization did and failed to receive tocilizumab. Methods: we have a tendency to conducted a matched retrospective cohort study from 2 giants, acute care hospitals in Western Connecticut from March 1 to May 31, 2020. we have a tendency to collected variables exploitation manual case history abstraction. the first exposure variable was any dose of tocilizumab. the first outcome was any healthcare‑associated microorganism or mycosis as outlined by the National Care Safety Network. we have a tendency to performed a Kaplan–Meier analysis to assess the crude distinction within the additive likelihood of healthcare‑associated infection (HAI) across exposure teams. we have a tendency to conjointly performed a multivariable Cox multivariate analysis to work out the hazard quantitative relation for HAI by exposure group whereas dominant for potential confounders. Results: The Kaplan–Meier analysis incontestable no distinction within the additive likelihood of HAI across teams. The adjusted hazard of HAI for patients given tocilizumab was zero.85 times that of patients not given tocilizumab (95% confidence interval = zero.29, 2.52, P = 0.780) once dominant for relevant confounders. Conclusions: Tocilizumab failed to increase the incidence of secondary infection among COVID‑19 patients. Larger, irregular trials ought to valuate infection as a secondary outcome to validate this finding.

Estimating Rebates and Other Discounts Received by Medicare Part D.

Spending in Medicare Part D continues to increase. Yet, studies of Medicare Part D are plagued by a common limitation: none can fully account for confidential rebates and other discounts that drug manufacturers and pharmacies pay to Medicare Part D plans. To review existing methods and to propose an approach for estimating rebates and other discounts received by Medicare Part D. Publicly available data from the Boards of Trustees of the Federal Hospital Insurance and Federal Supplementary Medical Insurance Trust Funds, the Centers for Medicare & Medicaid Services, the Medicare Payment Advisory Commission, the Congressional Budget Office, the Government Accountability Office, and the Office of Inspector General. Existing methods for estimating rebates and other discounts in Medicare Part D have several limitations. This analysis used an approach that aims to improve on those methods. Based on this approach, estimated discounts on brand-name drugs increased in Medicare Part D from 25.4% of gross brand-name spending in 2014 to 37.3% in 2018. There was substantial variation between classes, with estimated 2016 discounts surpassing 50% for some drugs (eg, ophthalmologic and gastrointestinal tract agents) while remaining below 10% for others (eg, antineoplastic and immunologic agents). Between 2014 and 2018, estimated net Medicare Part D spending on prescription drugs increased by 21% from $99 billion to $119 billion. With increasing enrollment, estimated annual net spending per beneficiary remained stable, increasing by just 3% from $2622 to $2694, which was below the 6% rate of inflation during the same period. Models that fail to properly account for increasing rebates and other discounts will overestimate Medicare Part D expenditures. Rigorous and transparent methods for estimating discounts are critical for understanding patterns in spending and developing new cost-containment strategies.