Major Toxicity Research Articles

Stereotactic Arrhythmia Radioablation (STAR)

Ventricular tachycardia(VT) is a wide complex tachyarrhythmia which could be potentially life-threatening. Standard treatment options include catheter ablation, anti-arrhythmic drugs and ICDs (Implantable cardioverter defibrillator). In patients refractory to the above treatments, limited options are available. Stereotactic arrhythmia radio-ablation (STAR) is a novel non-invasive method of ablating the arrhythmogenic substrate using high dose of highly focused radiotherapy. This technique requires a multi-disciplinary team consisting of Cardiologist, Electrophysiologist, Radiation oncologist and Radiologist to integrate pre-treatment imaging and electro-physiological data to generate a target that can be radiated. Studies show excellent control of VT, 6–12 weeks post-treatment with no major toxicities. This article attempts to provide a practical step by step approach to stereotactic arrhythmia radioablation.

Adjuvant Hepatic Arterial Infusion Pump Chemotherapy after Resection of Colorectal Liver Metastases; Surgical Complications, Toxicity, and Survival in a Prospective Study in the Netherlands

Background: Hepatic arterial infusion pump (HAIP) chemotherapy remains a promising treatment for patients with colorectal liver metastases (CRLM). The aim of this study was to investigate surgical complications, toxicity, and survival outcomes of patients who received adjuvant HAIP chemotherapy for CRLM. Methods: A single arm phase II study was performed in four centers. Patients with resectable CRLM without extrahepatic disease were eligible. An infusion pump was implanted after complete local treatment of CRLM followed by a maximum of 6 cycles of HAIP chemotherapy with floxuridine. Outcomes were 90 days pump-related major complications (Clavien Dindo grade ≥III), intra-arterial chemotherapy-related severe toxicity (CTCAE grade ≥III), and overall survival (OS). Results: Twenty-nine patients were included. Four patients (11.8%) had pump-related major complications, all requiring pump replacement; one for pump dysfunction, two for pump dislocation, and one for pump pocket infection. All patients started with HAIP chemotherapy. The median number of cycles was 5 (IQR 4-6), and the median cumulative dosage was 72% (IQR 55-85%). Ten patients (34%) required intra-arterial steroid treatment for biliary toxicity. Seven patients (24%) developed severe toxicity; five patients required stent-placement (three for biliary sclerosis/hyperbilirubinemia, two for persistent increase in liver enzymes without hyperbilirubinemia), one patient developed hepatic artery thrombosis, one patient required endoscopic extraction of an intrahepatic gallstone. Two-year OS was 93% (95%CI: 85-100%). Conclusion: Adjuvant HAIP chemotherapy for CRLM may result in major complications and severe toxicity; 1 in 7 patients required pump replacement and 1 in 6 patients required stent-placement for biliary sclerosis. Two-year OS was 93%.Tabled 1Patient and surgical characteristicsMedian [IQR] / n (%)Age at resection (years)57 [50-64]Clinical Risk Score (Fong score)2 [1-3]Preoperative systemic CTx9 (30)Major hepatectomy6 (21)Synchronous resection with primary CRC3 (10)Open ablation (with or without resection)11 (45)Surgery time (min)247 [204-300]Blood loss (mL)455 [187-762]Postoperative hospital stay (days)8 (6-9) Open table in a new tab

Conventional Versus Different Hypofractionated Radiotherapy Dosage Schedules in Postmastectomy Advanced Breast Cancer.

Introduction:The standard treatment for advanced breast cancer is surgery consisting of breast-conserving surgery or modified radical mastectomy (MRM) postneoadjuvant chemotherapy followed by adjuvant radiation treatment (RT). Conventionally-fractionated whole breast irradiation has been the standard RT regimen, but recently shorter courses of hypofractionated whole breast or chest wall irradiation have been advocated for patient convenience and reduction in health-care costs and resources. Radiation is delivered through the same technique, but tumors receive a higher dose of radiation per treatment session with hypofractionation.Aim:The aim of the study was to compare different fractionation schedules of radiotherapy in postoperative cancer breast with respect to locoregional control and toxicities.Materials and Methods:One hundred and eighty-eight patients of cancer breast, who received RT between January 2017 and December 2019 were assessed. Since hypofractionation is well documented and established and being practiced in prestigious institutes, we treated the patients as per their choice to receive 10.15 or 25 fractions. 72 patients (Group A) were treated with conventional fractionation to a dose of 50 Gy/25 fractions/5 weeks. Second group of 62 patients (Group B) were given 40.5 Gy/15 fractions/3 weeks and third group of 54 patients (Group C) were treated with 34 Gy/10 fractions/2 weeks. All patients were T3 or more and underwent MRM after neoadjuvant chemotherapy. They were in the age group of 30–65 years. All of them received adjuvant chemotherapy and hormone therapy in case of estrogen/and progesterone receptor positivity and anti-Her2neu target therapy in case of Her2neu positivity. They were assessed for locoregional control and acute and chronic toxicities.Results:Grade 3 and 4 skin toxicity was similar in all three groups. At 6 months postcompletion of RT, two patients in Group A, 3 in Group B, and 5 in Group C lost to follow-up. In rest of the subjects, there was no locoregional failure. At 1 year, 1 patient from Group A, 2 from Group B, and 1 from Group C developed locoregional recurrence. There were no major chronic toxicities. Arm edema and Telangiectasia were similar in three groups. No rib fracture or major cardiotoxicity and pulmonary toxicity was seen.Conclusion:Hypofractionated RT is a part of the typical treatment regimen for breast cancer nowadays. The major advantage is of convenience to the patients as it is completed the full course of RT in fewer sessions. With both conventional and hypofractionated radiation, the patient receives radiation 5 days a week. In the conventional regimen, though the schedule lasts for 5 weeks, whereas hypofractionation therapy is completed in 2 to 3 weeks. Local control wise both conventional and hypofractionated regimen is similar in locoregional control and toxicity. Therefore, hypofractionated RT should be practiced in cancer breast as it is economical, convenient, and toxicity wise and result wise similar to conventional radiotherapy.

Right predominant electrical remodeling in a pure model of pulmonary hypertension promotes reentrant arrhythmias.

Electrophysiological (EP) properties have been studied mainly in the monocrotaline model of pulmonary arterial hypertension (PAH). Findings are confounded by major extrapulmonary toxicities, which preclude the ability to draw definitive conclusions regarding the role of PAH per se in EP remodeling. The purpose of this study was to investigate the EP substrate and arrhythmic vulnerability of a new model of PAH that avoids extracardiopulmonary toxicities. Sprague-Dawley rats underwent left pneumonectomy (Pn) followed by injection of the vascular endothelial growth factor inhibitor Sugen-5416 (Su/Pn). Five weeks later, cardiac magnetic resonance imaging was performed invivo, optical action potential (AP) mapping exvivo, and molecular analyses invitro. Su/Pn rats exhibited right ventricular (RV) hypertrophy and were highly prone to pacing-induced ventricular tachycardia/fibrillation (VT/VF). Underlying this susceptibility was disproportionate RV-sided prolongation of AP duration, which promoted formation of right-sided AP alternans at physiological rates. While propagation was impaired at all rates in Su/Pn rats, the extent of conduction slowing was most severe immediately before the emergence of interventricular lines of block and onset of VT/VF. Measurement of the cardiac wavelength revealed a decrease in Su/Pn relative to control. Nav1.5 and total connexin 43 expression was not altered, while connexin 43 phosphorylation was decreased in PAH. Col1a1 and Col3a1 transcripts were upregulated coinciding with myocardial fibrosis. Once generated, VT/VF was sustained by multiple reentrant circuits with a lower frequency of RV activation due to wavebreak formation. In this pure model of PAH, we document RV-predominant remodeling that promotes multiwavelet reentry underlying VT. The Su/Pn model represents a severe form of PAH that allows the study of EP properties without the confounding influence of extrapulmonary toxicity.

Ameliorative effects of morel mushroom (Morchella esculenta) against Cadmium-induced reproductive toxicity in adult male rats.

Cadmium (Cd) is one of the major toxicants, which affects human health through occupational and environmental exposure. In the current study, we evaluated the protective effects of morel mushrooms against Cd-induced reproductive damages in rats. For this purpose, 30 male rats were divided into 6 groups (n=5/group), the first group served as the control group, second group was treated with an intraperitoneal (i.p) injection of 1 mg/kg/day of Cd. Third and fourth groups were co-treated with 1 mg/kg/day of Cd (i.p) and 10 and 20 mg/kg/day of morel mushroom extract (orally) respectively. The final 2 groups received oral gavage of 10 and 20 mg/kg/day of morel mushroom extract alone. After treatment for 17 days, the animals were euthanized, and testes and epididymis were dissected out. One testis and epididymis of each animal were processed for histology, while the other testis and epididymis were used for daily sperm production (DSP) and comet assay. Our results showed that Cd and morel mushrooms have no effect on animal weight, but Cd significantly decreases the DSP count and damages the heritable DNA which is reversed in co-treatment groups. Similarly, the histopathological results of testes and epididymis show that morel mushrooms control the damage to these tissues. Whereas the morel mushroom extract alone could enhance the production of testosterone. These results conclude that morel mushrooms not only control the damage done by Cd, but it could also be used as a protection mechanism for heritable DNA damage.

An investigator-initiated study of gemcitabine and capecitabine in Indian patients with unresectable or metastatic gallbladder cancer

Background: Gallbladder cancer (GBC) has a high incidence rate in the Indo-Gangetic belt and is usually presented in the unresectable advanced or metastatic stage. In this study, we evaluated the response rate and toxicities of the gemcitabine plus capecitabine (GEM-CAP)-based combination chemotherapy in unresectable or metastatic GBC patients. Subjects and Methods: This was an investigator-initiated, single-arm, prospective study conducted on unresectable or metastatic GBC patients at Jaipur, India, for 1 year. All the patients received a GEM-CAP combination chemotherapy regimen which consisted of gemcitabine 1000 mg/m2 intravenously over 30 min on days 1 and 8 and capecitabine at 800 mg/m2 orally twice a day for 14 days, administered every 21 days. The response was evaluated in terms of overall response rate (ORR), tumor control rate (TCR), and progression-free survival (PFS). Both quantitative and qualitative toxicities were assessed. Results: A total of 35 patients were enrolled, of which 3 patients were excluded due to treatment interruption. The mean age of patients was 55 (32–80) years, with the majority being female (77.14%), having an ECOG score of 1 (71.43%), and with Stage IVB disease (77.14%). The ORR was 25%, TCR was 50%, and median PFS was 4 months. Major toxicities noted were Grade I and II hematological and nonhematological toxicities, which were managed adequately. Conclusion: The combination therapy of gemcitabine and capecitabine is reasonable, feasible, and well-tolerated approach for the treatment of unresectable advanced and metastatic GBC patients, a disease that had limited treatment options.

Metabolic alterations in alga Chlamydomonas reinhardtii exposed to nTiO2 materials.

Nano-sized titanium dioxide (nTiO2) is one of the most commonly used materials, however the knowledge about the molecular basis for metabolic and physiological changes in phytoplankton is yet to be explored. In the present study we use a combination of targeted metabolomics, transcriptomics and physiological response studies to decipher the metabolic perturbation in green alga Chlamydomonas reinhardtii exposed for 72 h to increasing concentrations (2, 20, 100 and 200 mg L−1) of nTiO2 with primary sizes of 5, 15 and 20 nm. Results show that the exposure to all three nTiO2 materials induced perturbation of the metabolism of amino acids, nucleotides, fatty acids, tricarboxylic acids, antioxidants but not in the photosynthesis. The alterations of the most responsive metabolites were concentration and primary size-dependent despite the significant formation of micrometer-size aggregates and their sedimentation. The metabolic perturbations corroborate the observed physiological responses and transcriptomic results and confirmed the importance of oxidative stress as a major toxicity mechanism for nTiO2. Transcriptomics revealed also an important influence of nTiO2 treatments on the transport, adenosine triphosphate binding cassette transporters, and metal transporters, suggesting a perturbation in a global nutrition of the microalgal cell, which was most pronounced for exposure to 5 nm nTiO2. The present study provides for the first-time evidence for the main metabolic perturbations in green alga C. reinhardtii exposed to nTiO2 and helps to improve biological understanding of the molecular basis of these perturbations.

Radiation-based, multi-modality therapy for elderly patients with muscle-invasive bladder cancer: Utility, Rationale, and Efficacy

Muscle-invasive bladder cancer (MIBC) typically affects older adults, with a median age at diagnosis of 73. Due to its aggressive disease course, definitive treatment is required. With curative-intent treatment, patients with muscle-invasive bladder cancer have an overall survival ranging from 48-57% with a cancer-specific survival ranging from 52-71% at 5 years. Radical cystectomy (RC) +/- neoadjuvant chemotherapy (CHT) has been considered a standard of care for MIBC. However, RC carries a high incidence of perioperative complications, including a mortality rate of 1.5-3%. In addition, many elderly patients with bladder cancer suffer from additional comorbidities, prohibiting RC. These patients are often not offered other curative treatment options. Untreated patients with MIBC are at a very high risk of mortality, with five-year overall survival and cancer-specific survival of approximately 5% and 14%, respectively. Tri-modality therapy (TMT), incorporating maximal transurethral bladder tumor resection, radiotherapy, and CHT, is efficacious with a relatively low incidence of major toxicity for MIBC. As a result, TMT has been acknowledged as a viable alternative to RC, and an attractive option for elderly patients who often have major medical comorbidities and/or prefer bladder-preservation. The object of this review is to discuss the utility, rationale, and efficacy of TMT in elderly patients, which can offer a curative treatment for life-threatening MIBC but also safeguard the quality of life with organ-preservation.

Sex Differences in Differentiated Thyroid Cancer.

Background: Sex dimorphism strongly impacts tumor biology, with most cancers having a male predominance. Uniquely, thyroid cancer (TC) is the only nonreproductive cancer with striking female predominance with three- to four-fold higher incidence among females, although males generally have more aggressive disease. The molecular basis for this observation is not known, and current approaches in treatment and surveillance are not sex specific. Summary: Although TC has overall good prognosis, 6-20% of patients develop regional or distant metastasis, one third of whom are not responsive to conventional treatment approaches and suffer a 10-year survival rate of only 10%. More efficacious treatment strategies are needed for these aggressive TCs, as tyrosine kinase inhibitors and immunotherapy have major toxicities without demonstrable overall survival benefit. Emerging evidence indicates a role of sex hormones, genetics, and the immune system in modulation of both risk for TC and its progression in a sex-specific manner. Conclusion: Greater understanding of the molecular mechanisms underlying sex differences in TC pathogenesis could provide insights into the development of sex-specific, targeted, and effective strategies for prevention, diagnosis, and management. This review summarizes emerging evidence for the importance of sex in the pathogenesis, progression, and response to treatment in differentiated TC with emphasis on the role of sex hormones, genetics, and the immune system.

Potential Drug-Drug Interactions in Patients Using Warfarin, Heparin, and Enoxaparin

Background: Drug-drug interactions can often lead to preventable adverse drug events and hospitalization. However, the clinical outcome of a potential drug-drug interaction that may range from minor alterations to major toxicity or loss of effect is often unknown. Drugs with narrow therapeutic index are more susceptible to the outcomes of interactions. Anticoagulants are one of the drug groups prone to drug-drug interactions and have important side effects. in this retrospective study, the frequency of drug-drug interactions involving warfarin, heparin and enoxaparin was investigated. Methods: Overall, 300 patients (including 55% males with an average age of 50.75 years) participated in this study, and for each anticoagulant, 100 patient orders were randomly selected from the hospital system. Drug-drug interactions were evaluated using the Micromedex drug interaction checker. Results: A total of 1691 drug-drug interactions (306 major, 253 moderate, and 89 minor interactions) were recorded of which only 648 (average 2.16) involved warfarin, heparin, or enoxaparin. Most interactions were recorded in patients admitted to the cardiovascular surgery (n=312) and cardiology (n=119) wards. There was a significant relationship between the number of drugs and the frequency of interaction. warfarin had the highest number of interactions (n=388). Conclusion: The frequency of drug interactions is high in patients on anticoagulant therapy. The efficacy and safety of these drugs can be affected by drug interactions. Accordingly, these interactions should always be considered, especially in patients with multiple drug use. Efficient monitoring strategies should be employed to optimize treatment while reducing adverse effects.

Phase I Trial of Oral Yeast-Derived β-Glucan to Enhance Anti-GD2 Immunotherapy of Resistant High-Risk Neuroblastoma.

Simple SummaryBeta glucans, complex polysaccharides, can prime leukocyte dectin-1 and CR3-receptors and enhance anti-tumor cytotoxicity of monoclonal antibodies. In a phase I study (clinicaltrials.gov NCT00492167), we treated patients with intravenous 3F8 (fixed dose of 10 mg/m2/day × 10 days) and oral BG (dose-escalated from 10–200 mg/kg/day × 17 days in cohorts of 3–6 patients each). Forty-four patients completed 141 cycles of therapy with 3F8 + BG. One patient developed DLT: transient self-limiting hepatic transaminase elevation at a BG dose of 120 mg/kg/day. Overall, 1, 3, 12 and 24 evaluable patients had complete response, partial response, stable and progressive disease, respectively, at the end of treatment. Positive human anti-mouse antibody response and dectin-1 rs3901533 polymorphism were associated with better overall survival. BG dose level and serum BG levels did not correlate with response. BG lacked major toxicity and, in combination with 3F8, demonstrated anti-neuroblastoma activity against resistant disease. The recommended phase II dose was established at 40 mg/kg/day.Beta glucans, complex polysaccharides, prime leukocyte dectin-1 and CR3-receptors and enhance anti-tumor cytotoxicity of complement-activating monoclonal antibodies. We conducted a phase I study (clinicaltrials.gov NCT00492167) to determine the safety of the combination of yeast-derived beta glucan (BG) and anti-GD2 murine monoclonal antibody 3F8 in patients with relapsed or refractory high-risk neuroblastoma. Patients received intravenous 3F8 (fixed dose of 10 mg/m2/day × 10 days) and oral BG (dose-escalated from 10–200 mg/kg/day × 17 days in cohorts of 3–6 patients each). Forty-four patients completed 141 cycles. One patient developed DLT: transient self-limiting hepatic transaminase elevation 5 days after starting BG (120 mg/kg/day). Overall, 1, 3, 12 and 24 evaluable patients had complete response, partial response, stable and progressive disease, respectively, at the end of treatment. Positive human anti-mouse antibody response and dectin-1 rs3901533 polymorphism were associated with better overall survival. BG dose level and serum BG levels did not correlate with response. Progression-free and overall survival at 2 years were 28% and 61%, respectively. BG lacked major toxicity. Treatment with 3F8 plus BG was associated with anti-neuroblastoma responses in patients with resistant disease. Although the maximal tolerated dose for yeast BG was not reached, considering the large volume of oral BG, we recommended 40 mg/kg/day as the phase II dose.

Major Ambient Air Pollutants and Toxicity Exposure on Human Health and Their Respiratory System: A Review

Indoor and outdoor air pollution is causing environmental and health issues globally. It is more challenging mainly in developing countries like India, china, and others.According to recent World Health Organization (WHO) reports, nearly 4.2 million people die prematurely because of AAP (Ambient Air Pollution). Air pollution is made up of a variety of contaminants, including gases, liquids, heavy metals in the air, and particulate matter. Suspended particulate matter (SPM), surface ozone (O3), sulfur dioxide (SO2), nitrogen oxides (NO2), and other contaminants have become major environmental threats to plant health. These pollutants also have an effect on human health because they affect the consistency of the air we breathe. They usually cause inflammation in the upper respiratory tract, resulting in cough and shortness of breath. These are also significant contributors to the exacerbation of current respiratory conditions like asthma and chronic obstructive pulmonary disease. Epidemiological, toxicological, and clinical research all support the connection between air pollution and increased incidence and severity of respiratory and cardiovascular diseases. This pollution is a major public health problem in the locations where maximum pollution sources exist. To improve air quality and reduce the adverse effects of airborne toxicity due to AAP on human health, significant approaches are needed. The main objective of this review article is to provide evidence on the adverse effects of AAP on human health, as well as to make recommendations to policymakers on how to minimize exposure to this risk factor. Only public awareness combined with a multidisciplinary approach by scientific specialists will be able to handle this problem; national and international organizations must address the rise of this threat and suggest long-term remedies.

Association of advanced age and cancer history with autoimmune disease in melanoma patients: a cross-sectional study

BackgroundImmune-related adverse events (irAEs) are a major toxicity of immune checkpoint inhibitors. Studies have reported that pre-existing autoimmunity increases the risk of irAEs, but it remains unknown which clinical factors are linked to auto-immune disorders in cancer patients. This study aimed to evaluate if the prevalence of autoimmune diseases varied by specific cancer history and advanced age.MethodsOur cross-sectional medical record review consisted of 291,333 patients (age, ≥18 years) treated between 2000 and 2018. Patients were classified into four study groups (melanoma only, non-cutaneous solid cancer only, melanoma and non-cutaneous cancer, and no cancer history). Dependent variable was the presence of ≥1 autoimmune disorders based on 98 conditions using 317 ICD codes.ResultsNon-cutaneous cancer, in the absence or presence of melanoma, was associated with a higher prevalence of autoimmunity (16.5, 95% CI 16.1–16.9; 20.0, 95% CI 18.3–21.7, respectively) compared to the rates in patients with melanoma only and those without cancer history (9.3, 95% CI 8.6–10.0; 6.2, 95% CI 6.1–6.3, respectively). Among patients with metastases at initial presentation, those in the melanoma and non-cutaneous cancer group had a prevalence of 24.0% (95% CI 20.1–27.9) compared to 19.1% (95% CI 17.2–21.0) in those without metastases. Multiple logistic regression demonstrated that patients > 75 years exhibited the highest odds of autoimmunity relative to other age groups, with age 18–34 as the referent (OR, 1.78, 95% CI 1.67–1.89).ConclusionsAmong patients with melanoma, the greatest prevalence of autoimmunity occurred with advanced age and a history of non-cutaneous cancer.

Abstract P153: Claudin-1 is a therapeutic target for hepatocellular carcinoma

Abstract Introduction: Hepatocellular carcinoma (HCC) is the fastest rising and fourth leading cause of cancer death worldwide. While new therapeutic modalities have been recently approved, treatment response and survival in patients remain poor. Claudin-1 (CLDN1) is a cell membrane protein mediating cell-cell adhesion, fate and differentiation. While the function of CLDN1 within tight junctions is well characterized, the role of non-junctional CLDN1 in HCC remains unexplored. Aim and methods: Using humanized monoclonal antibodies (mAbs) targeting specifically the extracellular loop of human non-junctional CLDN1 and a large series of patient-derived cell-based and animal model systems we aimed to investigate the role of CLDN1 as therapeutic target for treatment of HCC. Results: Targeting non-junctional CLDN1 robustly suppressed tumor growth in a large series of patient-derived model systems, including multicellular tumorspheres and patient-derived xenograft (PDX) mouse models. In vivo and ex vivo studies further suggested synergistic efficacy in combination with sorafenib. Mechanistic studies revealed that CLDN1 mAbs suppressed tumor cell proliferation, invasion and stemness by interfering with Src, Wnt-β-catenin and STAT3 signaling. Treatment with humanized anti-CLDN1 mAbs is considered to be safe, as administration in non-human primates and mouse models did not reveal any major toxicity even when high doses largely exceeding the therapeutic need were repeatedly applied. Conclusion: Our results provide robust pre-clinical proof-of-concept for humanized CLDN1-specific mAbs for treatment of HCC. The unique and differentiated mechanism of action has the potential to break the plateau of limited response and survival offered by currently approved therapies. Citation Format: Natascha Roehlen, Marion Muller, Sara Cherradi, Frank Juehling, Francois H.T. Duong, Nuno Almeida, Fabio Del Zompo, Mirian Fernandez, Tobias Riedl, Hussein El Saghire, Antonio Saviano, Sarah Durand, Clara Ponsolles, Marine Oudot, Emanuele Felli, Patrick Pessaux, Irwin Davidson, Emilie Crouchet, Patrick Laquerriere, Mathias Heikenwälder, Roberto Iacone, Markus Meyer, Greg Elson, Tamas Schweighoffer, Catherine Schuster, Laurent Mailly, Joachim Lupberger, Thomas F Baumert. Claudin-1 is a therapeutic target for hepatocellular carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P153.

Remission is not maintained over 2 years with hematopoietic stem cell transplantation for rheumatoid arthritis: A systematic review with meta-analysis.

BACKGROUNDHematopoietic stem cell (HSC) transplantation (HSCT) is being accepted as a standard of care in various inflammatory diseases. The treatment of rheumatoid arthritis (RA) has been closely evolving with the understanding of disease pathogenesis. With the rising resistance to the traditional disease-modifying anti-rheumatic drugs and targeted biological therapy, researchers are in pursuit of other methods for disease management. Since the ultimate goal of the ideal treatment of RA is to restore immune tolerance, HSCT attracts much attention considering its reparative, paracrine, and anti-inflammatory effects. However, a systematic review of studies on HSCT in RA is lacking.AIMTo investigate the role of HSCT in the management of RA.METHODSA detailed search of PubMed, Scopus, EMBASE, Cochrane, and the Web of Science databases was made to identify the relevant articles till September 2020 following Cochrane and PRISMA guidelines. We extracted data including the number of patients, source of hematopoietic stem cells, their mobilization and conditioning regimens, results, and complications from the eligible studies. Results were dichotomized into success (ACR 50/70) and failure (ACR 20) based on the improvement from baseline characteristics. The methodological quality of the included studies was also assessed. Analysis was performed using OpenMeta[Analysis] software. RESULTSWe included 17 studies (1 randomized controlled trial, 11 prospective, and 5 retrospective studies) with 233 patients for analysis. HSCT provided a significantly beneficial overall improvement in the clinical grades of ACR criteria (Z = 11.309, P < 0.001). However, the remission was noted only till 24 mo and later on the significance of the result was lost (Z = 1.737, P = 0.082). A less than 1% treatment-related mortality was noted from the included studies. No major drug-related toxicities were noted in any of the included studies. All patients who underwent allogeneic HSCT received immunosuppression in the conditioning regimen to counteract the graft-vs-host reaction which made them vulnerable to infections. It is noted that the source of hematopoietic stem cells did not play a role in altering the functional outcome and both autologous (Z = 9.972, P < 0.001) and allogenic (Z = 6.978, P < 0.001) sources produced significant improvement in the outcome compared to the pre-operative state despite having a significant heterogeneity among the studies reporting them (I2 = 99.4, P < 0.001). CONCLUSIONAlthough the available literature is encouraging towards the use of HSCT in refractory cases with significant improvement from baseline till 2 years, the inclusion of HSCT into the standard of care of RA needs further exploration.

Abstract PO-054: A phase II trial of the super-enhancer inhibitor Minnelide in advanced refractory adenosquamous carcinoma of the pancreas (ASCP)

Abstract Background: Adenosquamous carcinoma of the pancreas (ASCP) is a very rare and highly aggressive variant of pancreatic ductal adenocarcinoma (PDA), accounting for 0.5-4% of all pancreatic cancer cases in the US. Current data indicates that epigenetic changes and Myc overexpression lead to squamous transdifferentiation of pancreatic tumor cells and development of ASCP. Minnelide is an oral anti-super-enhancer drug that inhibits Myc expression in preclinical models of ASCP. Oral Minnelide has been previously tested in the clinic where a Phase I study determined a recommended phase 2 dose of 2 mg/day. Major toxicities included neutropenia and sepsis. We hypothesize that Minnelide will be safe and effective in patients with advanced ASCP. Methods: This Phase II open label, single arm study being conducted at the NIH Clinical Center in Bethesda, MD (NCT04896073) will enroll up to 25 evaluable participants with advanced ASCP that has been previously treated. Eligibility criteria include: histologically confirmed ASCP (≥30% malignant squamous component), presence of metastatic, recurrent, or locally advanced unresectable disease, and progression or intolerance ≥1 prior systemic treatment for advanced disease. All participants will self-administer Minnelide at 2mg PO daily on days 1-21 of each 28-day cycle, for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Restaging scans will be performed every 8 weeks. Optional biopsies will be requested at baseline, mid-cycle 1 and at time of progression. The primary objective is to determine the antitumor activity of Minnelide by evaluating the disease control rate. Secondary objectives are determination of drug safety in this patient population, progression free survival, and overall survival. Exploratory objectives include assessment of Minnelide effect on tumor cell epigenetics, Myc expression and immune cell populations using on-treatment tumor biopsy tissues. Changes in circulating tumor DNA and circulating immune cell populations upon treatment will also be evaluated. A Simon optimal two-stage phase II trial design will be used. If 3 of the first 12 patients experience disease control, then enrollment will continue up to 25 evaluable participants. If ≥8 of 25 participants experience disease control this would rule out an unacceptably low clinical benefit of 20% in favor of 40% (α = 0.1, β = 0.2). This trial opened for accrual in July 2021. Citation Format: Nebojsa Skorupan, Mehwish I. Ahmad, Seth M. Steinberg, Jane B. Trepel, Derek Cridebring, Haiyong Han, Daniel D. Von Hoff, Christine Alewine. A phase II trial of the super-enhancer inhibitor Minnelide in advanced refractory adenosquamous carcinoma of the pancreas (ASCP) [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-054.

Carfilzomib: A Promising Proteasome Inhibitor for the Treatment of Relapsed and Refractory Multiple Myeloma.

The proteasome is crucial for the degradation of intracellular proteins and plays an important role in mediating a number of cell survival and progression events by controlling the levels of key regulatory proteins such as cyclins and caspases in both normal and tumor cells. However, compared to normal cells, cancer cells are more dependent on the ubiquitin proteasome pathway (UPP) due to the accumulation of proteins in response to uncontrolled gene transcription, allowing proteasome to become a potent therapeutic target for human cancers such as multiple myeloma (MM). Up to date, three proteasome inhibitors namely bortezomib (2003), carfilzomib (2012) and ixazomib (2015) have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with relapsed and/or refractory MM. This review mainly focuses on the biochemical properties, mechanism of action, toxicity profile and pivotal clinical trials related to carfilzomib, a second-generation proteasome inhibitor that binds irreversibly with proteasome to overcome the major toxicities and resistance associated with bortezomib.

Sequential Blinatumomab with Reduced Intensity Chemotherapy in the Treatment of Older Adults with Newly Diagnosed Ph Negative B-Precursor Acute Lymphoblastic Leukemia - Interim Analysis of the Australasian Leukemia and Lymphoma Group ALL08 Study

Sequential Blinatumomab with Reduced Intensity Chemotherapy in the Treatment of Older Adults with Newly Diagnosed Ph Negative B-Precursor Acute Lymphoblastic Leukemia - Interim Analysis of the Australasian Leukemia and Lymphoma Group ALL08 Study

All-in-one nanosponge with pluronic shell for synergistic anticancer therapy through effectively overcoming multidrug resistance in cancer

Overexpression of P-glycoprotein (P-gp) on cancer cells is a major hurdle to effectively treat tumors with multidrug resistance (MDR). The current study aimed to explore anticancer drug and P-gp inhibitor delivery as a promising strategy to efficiently treat colorectal cancer with MDR. To this end, a multidrug-loaded all-in-one nanosponge (ANS) was developed to simultaneously deliver doxorubicin (DOX), paclitaxel (PTX), and the P-gp inhibitor tetrandrine (TET), referred to as DOX/PTX/TET@ANS, without chemical conjugation. ANS with high loading content and efficiency facilitated a pH-dependent and controlled release with different profiles. Compared to free drugs and DOX/PTX@ANS, DOX/PTX/TET@ANS exhibited more effective anticancer effects on P-gp-overexpressing colorectal cancer cells and solid tumor mouse xenografts, without major toxicity. Notably, ANS composed of pluronic shell induced in vitro P-gp inhibition compared to TET, implying a synergistic anticancer effect. These findings suggest that ANS can encapsulate multiple drugs to efficiently deliver chemotherapy, particularly in MDR tumors.

Phase 1 Results of Novel Combination Therapy: BET Inhibitor PLX51107 with Azacitidine in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Phase 1 Results of Novel Combination Therapy: BET Inhibitor PLX51107 with Azacitidine in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)