Improved Treatment Regimen Research Articles

Abstract 5080: Antibody drug conjugate trastuzumab deruxtecan suppresses leptomeningeal brain metastasis cells and is potentiated by addition of immune check point inhibitor

Abstract Leptomeningeal disease (LMD) is defined by dissemination of metastatic cancer cells into the subarachnoid space with subsequent involvement of the cerebrospinal fluid and leptomeninges. LMD is an aggressive, late-stage development of cancer, which is increasing in prevalence as improved treatments for systemic malignancies are discovered. It leads to significant neurological morbidity and mortality, and outcomes remain poor despite improving cancer treatment strategies. There is a large population of patients with human epidermal growth factor receptor 2 (HER2) expressing cancers, such as breast and lung cancers, who suffer from leptomeningeal metastasis. There has been evolving research looking at antibody drug conjugates for treatment of these primary pathologies, such as Trastuzumab Deruxtecan (TDxd), which shows improved progression free survival and overall survival in those with HER2 expressing primary cancers, as well as in intraparenchymal brain metastasis. However, as of yet there has been no study of its utility in LMD. Additionally, use of immune check point inhibitors (ICI) for treatment of LMD has been studied, showing some efficacy, but less robust response than that in intraparenchymal brain metastasis. Given the significant population of patients who continue to be affected by leptomeningeal metastasis, there is significant need for an improved treatment regimen. We hypothesize that TDxd will have a killing effect on HER2 expressing LMD cells, which can be further potentiated by the addition of ICIs. To test this hypothesis, we developed breast and lung cancer cell lines (SKBrM-LMD, and H2030BrM-LMD) that express HER2 and preferentially metastasize to leptomeningeal space. These cell lines were also labeled with luciferase. We then treated these cell lines with TDxd and found that TDxd had significant growth inhibitory effect on these cells in vitro when compared to the control. Furthermore, we educated human T Cells against the SkBrM-LMD cells and treated these cells with the aforementioned T cells plus the ICI Anti-PD1. Our results showed that ICI had significant killing effect when compared to the control. We have also created an in vivo LMD model by performing intraventricular injection of HER2 expressing tumor cells into a mouse model, which can be used for testing the efficacy of TDxd and ICI by intrathecal injection. In conclusion, our results indicate that TDxd and ICI have significant killing activity against HER2 expressing LMD cells, and therefore intrathecal administration of these drugs is a promising treatment modality that will be demonstrated using a mouse LMD model. Citation Format: Eleanor C. Smith, Shih-Ying Wu, Ravindra P. Deshpande, Abhishek Tyagi, Kounosuke Watabe. Antibody drug conjugate trastuzumab deruxtecan suppresses leptomeningeal brain metastasis cells and is potentiated by addition of immune check point inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5080.

Abstract 1875: Enhanced lung cancer treatment using AOH1996, a potent PCNA inhibitor

Abstract AOH1996 targets a cancer-associated form of PCNA (caPCNA) by altering the protein-protein interface between caPCNA and its many binding partners. AOH1996 does this by inserting into the PCNA-interacting protein-box (PIP-box) pocket that is, in part, defined by the interdomain connecting loop (IDCL), the site of interaction between PCNA and most of its many binding partners. As a result, AOH1996 inhibits PCNA functions such as DNA replication, DNA repair, and transcription-replication conflict (TRC) resolution leading to cell cycle arrest and apoptosis. These effects are cancer specific and AOH1996 has little effect on non-cancerous cells even at 6-fold the effective dose in cancer cells. AOH1996 was developed in our lab and is currently in Phase I human clinical trials. Six patients have been enrolled in the trial and have not experienced AOH1996-related toxicities as the doses have been escalated to levels found to be efficacious in preclinical animal studies. Resistance to EGFR tyrosine kinase inhibitors (TKIs) poses a significant challenge in the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR activating mutations. Initially, EGFR TKIs like gefitinib, erlotinib, afatinib and osimertinib deliver remarkable responses, inducing tumor regression and improving overall survival. However, the emergence of resistance mechanisms, such as secondary EGFR mutations and bypass signaling pathway activation, hampers the efficacy of these drugs over time. The functional relationship between PCNA and EGFR has implications for the treatment of lung cancer patients with activating EGFR mutations. Membrane-localized EGFR modulates the PCNA-centric process of DNA replication through signaling pathways such as the Ras-Raf-Mek-Erk, PI3K/AKT, and PLCγ1/PKC signaling pathways. Nucleus-localized EGFR enhances PCNA stability by phosphorylating PCNA on tyrosine 211 (Y211), which prevents its degradation. In addition, phosphorylation at Y211 by EGFR results in decreased association of PCNA with MutS, which results in reduced mismatch repair (MMR). In this study, we combine AOH1996 and osimertinib as an innovative approach to treating NSCLC cancers with activating EGFR mutations and find that the drug combination: 1.) enhances the killing of NSCLC cell lines with activating EGFR mutations and acquired resistance to TKIs; 2.) enhances the destabilization of PCNA on chromatin; and 3.) causes changes in the localization and colocalization of PCNA and EGFR. We conclude that the combination of AOH1996 and osimertinib holds much potential as an improved treatment regimen for lung cancer patients with activating EGFR mutations. Citation Format: Robert G. Lingeman, Robert J. Hickey, Linda H. Malkas. Enhanced lung cancer treatment using AOH1996, a potent PCNA inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1875.

Immunophenotypic characterisation of non-Hodgkin lymphomas at a tertiary hospital in Ghana.

Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of clonal lymphoid tumours originating from lymphocytes. They constitute about 90% of an estimated 3%-4% worldwide distribution of malignant lymphomas among various cancers. Despite the continuous rise and associated deaths, research on NHLs, and in particular the area of immunophenotypic spectrum is limited in Ghana and sub-Saharan Africa. A retrospective, descriptive study in which archived tissue blocks of histologically diagnosed NHLs at a tertiary hospital in Accra, Ghana, were used. Antigenic phenotypes were determined by immunohistochemistry. A total of 66 cases of NHLs, with a mean age of 50.2 ± 16.1 years, were selected for the study. Among the targeted markers, cluster of differentiation 20 (CD20) was the most commonly expressed in 89.4% (59) cases. Immunohistochemistry studies revealed a greater proportion of B cell lymphomas of 89.4%. Five subtypes were successfully identified, of which diffuse large B cell lymphoma constitutes the predominant group (40.9%). A significant association was observed between phenotypic cell types and outcomes of NHLs (p = 0.011). Adult NHLs were mostly due to the malignant transformation of B cells with diffuse large B cell lymphoma being the commonest subtype. The present study therefore serves as preliminary data for further research towards the adoption of an improved treatment regimen and management of NHLs.

Targeting MUCL1 protein inhibits cell proliferation and EMT by deregulating β‑catenin and increases irinotecan sensitivity in colorectal cancer.

With >1.85 million cases and 850,000 deaths annually, colorectal cancer (CRC) is the third most common cancer detected globally. CRC is an aggressive malignancy with metastasis and, in spite of advances in improved treatment regimen, distant disease failure rates remain disappointingly high. Mucin-like 1 (MUCL1) is a small glycoprotein highly expressed mainly in breast cancer. The involvement of the MUCL1 protein in CRC progression and the underlying mechanism have been largely unknown. The aim of the present study was to investigate the MUCL1 expression profile and its functional significance in CRC. The Cancer Genome Atlas dataset revealed that MUCL1 expression was higher in colorectal tumor compared with normal tissues. MUCL1 was also revealed to be expressed in human CRC cell lines. The results demonstrated that MUCL1 promoted cell proliferation and colony formation, confirming its oncogenic potential. Silencing MUCL1 with short interfering RNA inhibited the protein expression of Bcl2 family proteins, such as Bcl2 and BclxL. Targeting MUCL1 resulted in significant inhibition in cell invasive and migratory behavior of HT-29 and SW620 cells. In addition, the expression of E-cadherin increased whereas the expression of vimentin decreased in MUCL1-silenced cells, confirming inhibition of epithelial-mesenchymal transition (EMT) process. Thus, it was revealed that MUCL1 plays a notable role in cell invasion and migration by inhibiting EMT in CRC. Mechanistically, MUCL1 drives β-catenin activation by Ser-552 phosphorylation, nuclear accumulation and transcriptional activation. Targeting MUCL1 increases the drug sensitivity of CRC cells towards irinotecan. These findings thus demonstrated that MUCL1 acts as a modifier of other pathways that play an important role in CRC progression and MUCL1 was identified as a potential target for CRC therapeutics.

Mouse models of colorectal cancer: Past, present and future perspectives.

Colorectal cancer (CRC) is the third most common diagnosed malignancy among both sexes in the United States as well as in the European Union. While the incidence and mortality rates in western, high developed countries are declining, reflecting the success of screening programs and improved treatment regimen, a rise of the overall global CRC burden can be observed due to lifestyle changes paralleling an increasing human development index. Despite a growing insight into the biology of CRC and many therapeutic improvements in the recent decades, preclinical in vivo models are still indispensable for the development of new treatment approaches. Since the development of carcinogen-induced rodent models for CRC more than 80 years ago, a plethora of animal models has been established to study colon cancer biology. Despite tenuous invasiveness and metastatic behavior, these models are useful for chemoprevention studies and to evaluate colitis-related carcinogenesis. Genetically engineered mouse models (GEMM) mirror the pathogenesis of sporadic as well as inherited CRC depending on the specific molecular pathways activated or inhibited. Although the vast majority of CRC GEMM lack invasiveness, metastasis and tumor heterogeneity, they still have proven useful for examination of the tumor microenvironment as well as systemic immune responses; thus, supporting development of new therapeutic avenues. Induction of metastatic disease by orthotopic injection of CRC cell lines is possible, but the so generated models lack genetic diversity and the number of suited cell lines is very limited. Patient-derived xenografts, in contrast, maintain the pathological and molecular characteristics of the individual patient’s CRC after subcutaneous implantation into immunodeficient mice and are therefore most reliable for preclinical drug development – even in comparison to GEMM or cell line-based analyses. However, subcutaneous patient-derived xenograft models are less suitable for studying most aspects of the tumor microenvironment and anti-tumoral immune responses. The authors review the distinct mouse models of CRC with an emphasis on their clinical relevance and shed light on the latest developments in the field of preclinical CRC models.

The New Approach to the Diagnostics and Treatment of Endogenous Intoxication in Patients with Burn Injury

Background: The main causes of mortality in patients with burn injury are the development of systemic inflammatory process, multiple organ failure and septic complications. The aim of the research: Improvement of diagnostic and therapeutic approaches to the detection and elimination of endogenous intoxication in patients with burn injury. Materials and methods: The main study group consisted of 19 patients and the comparison group—of 10 patients with burn injury. 92 blood serum (BS) samples of the patients of the main group were tested, using the method of fluorescence spectroscopy (MFS). The advanced therapeutic tactics were proposed for the patients of both groups. The control group consisted of 40 healthy individuals (donors). BS of these patients was also tested using MFS. Results: Patients with burn injury have endogenous intoxication in their blood. The effective concentration of albumin is reduced in patients with burn injury due to the blockage of albumin binding centers by bacterial metabolism products. Fluorescence spectra (FS) of BS in patients with burn trauma and donors were obtained and investigated. Based on MFS results, an improved treatment regimen using infusion of albumin solution was proposed. Conclusions: An improved technique for the management of patients with burn injury is based on the use of MFS for the diagnostic evaluation of endogenous intoxication in them. The idea of pathological changes in albumin molecules in patients with burn injury is pathogenetically substantiated by the successful use of infusion of albumin solution in these patients on the basis of the MFS.

PO 8239 BASELINE ASSESSMENT OF LYMPHATIC FILARIASIS IN 18 COMMUNITIES IN WESTERN GHANA BEFORE THE IMPLEMENTATION OF TWICE-YEARLY TREATMENT

BackgroundLymphatic filariasis (LF) is a neglected tropical disease targeted for elimination as a public health problem by 2020, with the main strategy being treatment of entire endemic communities. Since the inception of the Global Programme for the Elimination of LF in 2000, tremendous progress has been made in many endemic countries. However, current observations point to the need for improved treatment regimen, frequency of treatment or drug delivery strategies in order to achieve the elimination goals in certain endemic areas. In this randomised trial, we evaluate the use of twice-yearly treatment with ivermectin and albendazole in 18 LF-endemic communities in Ghana, where despite 15 years of yearly treatment the disease is still above the elimination thresholds.MethodsFollowing demographic data collection, Wuchereria bancrofti antigen, microfilaria and antibody prevalence were assessed in study participants using the Alere FTS kit, nucleopore filtration and Wb123 ELISA, respectively. The study assessed the perspectives of the communities’on persistent transmission of LF in view of implementing effective treatment uptake strategies.ResultsThe baseline assessments revealed antigen prevalence of 8.2% (95% CI=6.8–9.8), with overall microfilaria prevalence of 1.2%. Infections were higher in males and in individuals who spend significant amount of time outdoors for commercial activities. Barriers related to medication, personal, health system, disease and social structure were observed to affect mass drug administration compliance. Community members perceived that they were not susceptible to infection and this together with drug adverse effects strongly affect the ingestion of the drugs.ConclusionWhile this trial is still in an early phase, the baseline assessments reveal programmatic challenges to the implementation of a twice-yearly treatment strategy for the control of LF which must be addressed to enhance implementation success.

Person-centered Nursing to Improve Treatment Regimen Adherence in Patients with Myocardial Infarction

ABSTRACT Introduction: Person-Centred Care (PCC) relies on effective communication and emphasises on co-operation in care between patients and healthcare professionals. WHO advocates this type of care as a key component of quality health care. Aim: To evaluate if person-centred nursing can improve treatment regimen adherence in patients with Myocardial Infarction (MI). Materials and Methods: During August-November 2016, 101 patients with MI, of age .85 years were randomly assigned to person-centred nursing group and usual care group and followed for two months. In the intervention group, a person-centred nursing process was added to care, emphasising the patient as a partner in care. Care was provided in co-operation with the patient, registered nurse and researcher. Data were collected using self-report adherence to the treatment regimen questionnaire and were analysed using SPSS software version 22 and chi-square test, independent samples t-test and paired t-test were applied wherever required. Results: Study results showed that the mean score of treatment regimen adherence did not have a significant difference before intervention, three weeks and two month after intervention in control group (p=0.692; p=0.581), but three weeks after intervention, the intervention group had a significant difference in the mean score of the treatment regimen adherence (p<0.001). Also, paired t-test results showed that two month after intervention the mean of adherence in person-centred nursing group was higher than control group (p<0.001). Conclusion: Person-centered nursing improved treatment regimen adherence in patients with MI. Further work is needed to examine whether this intervention can be sustained to improve clinical outcomes

Anti-Tumor Effects of Peptide Therapeutic and Peptide Vaccine Antibody Co-targeting HER-1 and HER-2 in Esophageal Cancer (EC) and HER-1 and IGF-1R in Triple-Negative Breast Cancer (TNBC).

Despite the promise of targeted therapies, there remains an urgent need for effective treatment for esophageal cancer (EC) and triple-negative breast cancer (TNBC). Current FDA-approved drugs have significant problems of toxicity, safety, selectivity, efficacy and development of resistance. In this manuscript, we demonstrate that rationally designed peptide vaccines/mimics are a viable therapeutic strategy for blocking aberrant molecular signaling pathways with high affinity, specificity, potency and safety. Specifically, we postulate that novel combination treatments targeting members of the EGFR family and IGF-1R will yield significant anti-tumor effects in in vitro models of EC and TNBC possibly overcoming mechanisms of resistance. We show that the combination of HER-1 and HER-2 or HER-1 and IGF-1R peptide mimics/vaccine antibodies exhibited enhanced antitumor properties with significant inhibition of tumorigenesis in OE19 EC and MDA-MB-231 TNBC cell lines. Our work elucidates the mechanisms of HER-1/IGF-1R and HER-1/HER-2 signaling in these cancer cell lines, and the promising results support the rationale for dual targeting with HER-1 and HER-2 or IGF-1R as an improved treatment regimen for advanced therapy tailored to difference types of cancer.

Aprepitant versus ondansetron in preoperative triple-therapy treatment of nausea and vomiting in neurosurgery patients: study protocol for a randomized controlled trial

BackgroundThe incidence of postoperative nausea and vomiting (PONV) is 50% to 80% after neurosurgery. The common prophylactic treatment for postoperative nausea and vomiting is a triple therapy of droperidol, promethazine and dexamethasone. Newer, more effectives methods of prophylaxis are being investigated. We designed this prospective, double-blind, single-center study to compare the efficacy of ondansetron, a neurokinin-1 antagonist, and aprepitant, as a substitute for droperidol, in the prophylactic treatment of postoperative nausea and vomiting after neurosurgery.MethodsAfter obtaining institutional review board approval; 176 patients, 18 to 85 years of age with American Society of Anesthesiologists (ASA) classifications I to III, who did not receive antiemetics 24 h before surgery and were expected to undergo general anesthesia for neurosurgery lasting longer than 2 h were included in this study. After meeting the inclusion and exclusion criteria and providing written informed consent, patients were randomly assigned in a 1:1 ratio to one of two treatment groups: aprepitant or ondansetron. The objective of this study was to conduct a randomized, double-blind, double-dummy, parallel-group and single-center trial to compare and evaluate the efficacies of aprepitant versus ondansetron. Patients received oral aprepitant 40 mg OR oral dummy pill within 2 h prior to induction. At induction, a combination of intravenous dexamethasone 10 mg, promethazine 25 mg, and ondansetron 4 mg OR dummy injection was administered. Therefore, all patients received one dummy treatment and three active PONV prophylactic medications: dexamethasone 10 mg, promethazine 25 mg, and either aprepitant 40 mg OR ondansetron 4 mg infusion. The primary outcome measures were the episodes and severity of nausea and vomiting; administration of rescue antiemetic; and opioid consumption for 120 h postoperatively. Standard safety assessments included adverse event reports, physical and laboratory data, awakening time and duration of recovery from anesthesia.DiscussionThe results of this comparative study could potentially identify an improved treatment regimen that may decrease the incidence and severity of postoperative nausea and vomiting in patients undergoing neurosurgery. Also, this will serve to enhance patient recovery and overall satisfaction of neurosurgical patients in the immediate postoperative period.Trial registrationRegistered at The Ohio State University Biomedical Sciences Institutional Review Board: Protocol Number: 2007 H0053

Outcomes among tuberculosis patients with isoniazid resistance in Georgia, 2007–2009

The optimal management strategy for patients with isoniazid (INH) monoresistant forms of tuberculosis (TB) has been widely debated. The current daily 9-month regimen of rifampin, pyrazinamide and ethambutol was established based largely on trials in settings with low TB rates and low rates of drug resistance. To explore the outcomes of patients with INH-monoresistant TB in the country of Georgia, a setting with both high TB rates and drug-resistant forms of the disease. Retrospective record review of all patients diagnosed with smear-positive pulmonary TB resistant to either INH or INH+SM (streptomycin) in Georgia between 2007 and 2009. Of 8752 patients with pulmonary TB registered in Georgia, 909 were found to have INH or INH+SM resistance. Treatment outcomes were relatively poor in this group, with only 71% treatment success. Outcomes were significantly worse among patients with older age and a history of previous treatment. INH or INH+SM resistance in pulmonary TB patients in Georgia is common. The low rates of treatment success suggest the need for an improved treatment regimen for patients with resistance to these first-line drugs; this need is particularly pronounced among the subset of patients with a history of previous treatment.

Role of immunoglobulin G3 subclass in dilated cardiomyopathy: Results from protein A immunoadsorption

Immunoadsorption (IA) by anti-immunoglobulin G (anti-IgG) columns that effectively eliminates total IgG, including IgG3 subclass, represents an additional therapeutic approach in dilated cardiomyopathy (DCM). A recent study revealed that IA with protein A columns does not effectively remove IgG3 and does not induce hemodynamic improvement in DCM. Eighteen patients with DCM (left ventricular ejection fraction < or =30%) were included in this case-control study. In all patients, IA with protein A was performed in 4 courses, at 1-month intervals until month 3. Nine patients underwent protein A IA with an improved treatment regimen for IgG3 elimination. Data of these patients were compared retrospectively to existing findings for 9 comparable patients treated by protein A IA with ineffective IgG3 reduction. In both groups, IA induced a comparable reduction of the total IgG level. However, reduction of the IgG3 level was different in the 2 groups (P < .001). Hemodynamics did not significantly change throughout the 3 months in the group with ineffective IgG3 reduction. In contrast, the group with improved IgG3 reduction demonstrated during the first IA course an increase in cardiac index from 2.2 +/- 0.1 to 2.8 +/- 0.2 L min(-1) m(-2) (P < .05). After 3 months before the last IA course, cardiac index was 2.2 +/- 0.1 L min(-1) m(-2) in the group with ineffective IgG3 elimination and 2.8 +/- 0.2 L min(-1) m(-2) in the group with improved IgG3 reduction (P < .01). In the group with ineffective IgG3 reduction, left ventricular ejection fraction increased after 3 months from 21.6 +/- 2% to 24.4 +/- 2% (NS), and from 24.3 +/- 2 to 34.7 +/- 4% in the group with improved IgG3 reduction (P < .05). Autoantibodies belonging to IgG3 may play an important role in cardiac dysfunction of patients with DCM. Protein A IA in conjunction with an improved treatment regimen for IgG3 elimination induces hemodynamic benefit in patients suffering from DCM.

Multimodality monitoring and telemonitoring in neurocritical care: from microdialysis to robotic telepresence

This review will highlight the state-of-the-art in brain monitoring in neurointensive care and define methods of integrating this technology into patient care using telemedicine methods. Several new methods of brain monitoring have been established over the last several years including continuous EEG monitoring, brain tissue oxygenation, jugular venous oxygenation, and cerebral microdialysis. Observational research using these monitors has documented that the brain metabolism, blood flow and function are dynamic after a primary insult. The dynamic nature of the brain can predispose the brain to secondary insults that can occur in the setting of intensive care. Several variables of brain metabolism and function can be monitored and directly impact treatment decisions as well as provide diagnostic and prognostic information. General treatment guidelines for brain injury and brain hemorrhage were developed, in part, prior to implementation of use of these monitors, and there is a trend away from adoption of a one-size-fits-all approach and a trend towards monitor-guided therapy. Dealing with the data provided by multimodality monitoring can be overwhelming. Efficient use of such information requires methods to integrate diverse sets of information, and methods to access the online monitoring information remotely and at any time, day or night. Such remote access integration methods will be reviewed. Multimodality and telemedicine techniques have advanced the state of knowledge about brain function in critically ill patients, and are presently being implemented to direct therapy. Increasing complexity of care will become commonplace, but will be facilitated by computer-enhanced tools that permit the intensivist to integrate this information into an improved treatment regimen.

The effect of a 15(S)-15-methyl prostaglandin F 2α (methyl ester) suppository upon termination of early pregnancy

The administration of prostaglandin vaginally to 15 pregnant patients in the first trimester caused abortion in 73% of the cases. Although other regimens have been reported to be effective and well tolerated, the single 3 mg. suppository of 15(S)-15-methyl prostaglandin F 2α (methyl ester) utilized in the present study was associated with a significant incidence of side effects and a relatively high failure rate. However, if an analogue or improved treatment regimen could be found which is more efficient, as well as more pleasant in its effects, the availability and the cost of early abortion would be improved with a concomitant effect on the incidence of late abortion and its complications.