Prolonged Surgical Interval Following Chemotherapy in a Patient With Idiopathic Subglottic Stenosis (iSGS): Case Report and Brief Review of Literature

Objective: To report a case of a patient with idiopathic subglottic stenosis (iSGS) who no longer required surgical intervention for her disease following a chemotherapy regimen of carboplatin and doxorubicin for ovarian cancer. A brief review of the literature and discussion on the possible mechanism of action of chemotherapy agents affecting fibrosis is included. Methods: Case report and review of literature. Results: A 71-year-old Caucasian woman with iSGS was managed with serial endoscopic excision and dilation (n = 5) from 2013 to 2017 with an average dilation interval of 12.3 months. After a course of doxorubicin and carboplatin to treat her ovarian cancer, we observed that her airway stenosis surprisingly stabilized, and has no longer required a surgical dilation for 45 months, which signifies an increase of 33 months when compared to her averaged dilation interval (12.3 months) prior to her second course of chemotherapy. Conclusion: We present an iSGS patient whose fibrosis was arrested following carboplatin/doxorubicin treatment. While a single case, a possible mechanism is carboplatin/doxorubicin’s inhibition of pathologic CD4 lymphocytes that propagate laryngotracheal fibrosis. Further investigation of like mechanisms may allow for translation of local agents with inhibitory effects on CD4+ cells and/or fibroblasts as a novel therapy for airway fibrosis.

FDA-Approved Drugs for Hematological Malignancies—The Last Decade Review

Hematological malignancies, also referred to as blood cancers, are a group of diseases involving abnormal cell growth and persisting in the blood, lymph nodes, or bone marrow. The development of new targeted therapies including small molecule inhibitors, monoclonal antibodies, bispecific T cell engagers, antibody-drug conjugates, recombinant immunotoxins, and, finally, Chimeric Antigen Receptor T (CAR-T) cells has improved the clinical outcomes for blood cancers. In this review, we summarized 52 drugs that were divided into small molecule and macromolecule agents, approved by the Food and Drug Administration (FDA) in the period between 2011 and 2021 for the treatment of hematological malignancies. Forty of them have also been approved by the European Medicines Agency (EMA). We analyzed the FDA-approved drugs by investigating both their structures and mechanisms of action. It should be emphasized that the number of targeted drugs was significantly higher (46 drugs) than chemotherapy agents (6 drugs). We highlight recent advances in the design of drugs that are used to treat hematological malignancies, which make them more effective and less toxic.

Versatile and Robust Method for Antibody Conjugation to Nanoparticles with High Targeting Efficiency

The application of antibodies in nanomedicine is now standard practice in research since it represents an innovative approach to deliver chemotherapy agents selectively to tumors. The variety of targets or markers that are overexpressed in different types of cancers results in a high demand for antibody conjugated-nanoparticles, which are versatile and easily customizable. Considering up-scaling, the synthesis of antibody-conjugated nanoparticles should be simple and highly reproducible. Here, we developed a facile coating strategy to produce antibody-conjugated nanoparticles using ‘click chemistry’ and further evaluated their selectivity towards cancer cells expressing different markers. Our approach was consistently repeated for the conjugation of antibodies against CD44 and EGFR, which are prominent cancer cell markers. The functionalized particles presented excellent cell specificity towards CD44 and EGFR overexpressing cells, respectively. Our results indicated that the developed coating method is reproducible, versatile, and non-toxic, and can be used for particle functionalization with different antibodies. This grafting strategy can be applied to a wide range of nanoparticles and will contribute to the development of future targeted drug delivery systems.

Mechanism of Action of the Sesquiterpene Compound Helenalin in Rhabdomyosarcoma Cells

Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in paediatric patients. Relapsed or refractory RMS shows very low 5-year survival rates, which urgently necessitates new chemotherapy agents. Herein, the sesquiterpene lactone, helenalin, was investigated as a new potential therapeutic agent against the embryonal RMS (eRMS) and alveolar RMS (aRMS) cells. We have evaluated in vitro antiproliferative efficacy of helenalin on RMS cells by the MTT and wound healing assay, and estimated several cell death pathways by flow cytometry, confocal microscopy and immunoblotting. It was shown that helenalin was able to increase reactive oxygen species levels, decrease mitochondrial membrane potential, trigger endoplasmic reticulum stress and deactivate the NF-κB pathway. Confirmation was obtained through the use of antagonistic compounds which alleviated the effects of helenalin in the corresponding pathways. Our findings demonstrate that oxidative stress is the pivotal mechanism of action of helenalin in promoting RMS cell death in vitro.

Combined Rothia dentocariosa and Streptococcus viridans Corneal Ulcer in an Immunocompromised Patient

Keratitis is a very common condition seen by ophthalmologists. However, many factors can complicate the treatment of this depending on the causative organism and other patient comorbid conditions. The objective of this clinical case report is to highlight the treatment of keratitis caused by Rothia dentocariosa. It also looks at the unique considerations in keratitis presentations for patients immunocompromised by chemotherapy agents. Our patient is a 58 yo female undergoing chemotherapy with folinic acid, fluorouracil, irinotecan, and panitumumab who presented with several days of a red, painful right eye with mucous discharge. Cultures were positive for Rothia dentocariosa and Streptococcus viridans. The patient ultimately underwent a conjunctival flap procedure as medical therapy with proper oral and topical antibiotics failed to resolve keratitis. This case is unique as previously, only a couple of cases of keratitis caused by Rothia dentocariosa have been reported and none of those patients were immunocompromised nor failed antibiotic therapy.

Exploiting convergent evolution to derive a pan-cancer cisplatin sensitivity gene expression signature

Precision medicine offers remarkable potential for the treatment of cancer, but is largely focused on tumors that harbor actionable mutations. Gene expression signatures can expand the scope of precision medicine by predicting response to traditional(cytotoxic) chemotherapy agents without relying on changes in mutational status. We present a novel signature extraction method, inspired by the principle of convergent evolution, which states that tumors with disparate genetic backgrounds may evolve similar phenotypes independently. This evolutionary-informed method can be utilized to produce signatures predictive of response to over 200 chemotherapeutic drugs found in the Genomics of Drug Sensitivity in Cancer Database. Here, we demonstrate its use by extracting the Cisplatin Response Signature, CisSig, for use in predicting a common trait (sensitivity to cisplatin) across disparate tumor subtypes (epithelial-origin tumors). CisSig is predictive of cisplatin response within the cell lines and clinical trends in independent datasets of tumor samples. This novel methodology can be used to produce robust signatures for the prediction of traditional chemotherapeutic response, dramatically increasing the reach of personalized medicine in cancer.

Novel Single Agents Are Equivalent to Conventional Chemotherapy Inpatients with Relapsed and Refractory Mature T-Cell Lymphomas: A Meta-Analysis

Background: Patients with advanced peripheral and cutaneous T-cell lymphomas (PTCL and CTCL) have an unfavorable prognosis . Primary refractoriness to traditional chemotherapy and relapse is common. Few FDA-approved "novel" single agents (SA) are available but their effectiveness as salvage agents relative to traditional multiagent cytotoxic chemotherapy (CC) regimens remains unknown. Therefore, we conducted a systematic meta-analysis to compare the response rates of approved and experimental single agents to conventional chemotherapy for patients with relapsed and refractory (R/R) PTCL and CTCL. Methods: This systematic review is reported in accordance with the PRISMA guidelines. Briefly a Harvard University Librarian (PB) systematically searched the publication libraries of: MEDLINE (through Ovid SP), Embase, Web of Science Core Collection, and Cochrane's Central Register for adult patients with R/R PTCL and CTCL enrolled in phase I, II, and III clinical trials of novel single and cytotoxic drugs. Agents determined as novel included antifolates, histone deacetylase inhibitors (HDACi), antibody-drug conjugates, therapeutic antibodies, hypomethylating agents, cereblon modulators, inhibitors of PI3K/AKT/mTOR, JAK/STAT, aurora kinase, farnesyl transferase and proteosome pathways, and CD4 CAR T- cells. Conventional chemotherapy agents included ifosfamide-, gemcitabine-, anthracycline-, and platinum-based treatments. Three researchers (NS, RS and LB) independently reviewed eligible studies and extracted data for baseline demographics, histological subtype, treatment characteristics including response rates, duration of response, overall and progression free survival, toxicity, and risk of bias assessment. Primary outcome was overall response rate (ORR), defined as the best reported partial response (PR) or better. Meta-analyses were conducted for ORR and the scale of logarithm of odd using the generic inverse variance method. The random effects model was used to pool the effect sizes for each study assuming a normal distribution of the random effects. Preplanned subgroup by therapy type and histological subtypes of lymphoma were treated as fixed effects and compared using Wald test. The degree of statistical heterogeneity was evaluated by inconsistency index (I2). Results: Our literature search identified 1873 articles, which after filtering for inclusion and exclusion criteria, ruling in only papers including T-cell lymphoma specific response, was narrowed to 128 studies for data extraction. Of these 128 studies, 35 were phase I trials, 70 phase II, 13 phase III, and 10 were combination. First, we divided all studies into upfront (n=33) versus R/R (n=100) based on timing of their treatments. We specifically focused on patients with R/R TCLs and subdivided those studies into the novel SA (n=84) and conventional chemotherapy (n=16) categories. The ORR for novel agents was lower at 37% (95% confidence interval [CI]: 34, 41) in comparison with 55% (95% CI: 40, 69) for standard chemotherapy agents (p=0.02). When stratified by histological subtype, patients with PTCL-NOS (n=751) had comparable ORR to novel agents (31%; 95% CI: 27, 35) and conventional chemotherapy (40%; 95% CI: 31,50; p=0.08). Similar results were seen with patients with AITL (n=296) who achieved equivocal ORR to single agents (45%; 95% CI: 38, 52) when contrasted with conventional chemotherapy (55%; 95% CI: 27, 80; p=0.52). Similar efficacy was seen for patients with CTCL (n=612) across SA (34%, 95% CI:29, 40) and CC (44%; 95% CI: 33, 56; p=0.11). Conclusions: Our meta-analysis highlights that for particular histological subtypes of PTCL such as PTCL-NOS and AITL, single agents are non-inferior to cytotoxic chemotherapy regimens in the R/R setting. These findings warrant serious consideration in the design and development of clinical trials for patients with R/R PTCL and the need for tailored treatments. Our meta-analysis also informs clinicians and patients about the benefits of single agents in comparison with standard chemotherapy while making clinical decisions for specified histologies. Disclosures Foss: Mallinckrodt: Honoraria; Kyowa: Honoraria; Kura: Honoraria; Seattle Genetics: Honoraria, Speakers Bureau; Acrotech: Honoraria, Speakers Bureau; Daiichi Sankyo: Honoraria. Jain: Trillium Therapeutics, Inc: Research Funding; Acro Biotech, Inc: Research Funding; Abcuro, Inc: Research Funding.

EXTH-76. DEVELOPING THE NOVEL COMBINATION THERAPY OPTIONS FOR CANCER THERAPY USING TUMOR TREATING FIELDS TOGETHER WITH THE CHEMO AGENTS TARGETING THE REPLICATION STRESS PATHWAY

Tumor Treating Fields (TTFields) as a component of cancer therapy has been shown to provide significant clinical benefit. The disruption of mitosis was identified as the first mechanism of action, however, a novel role for TTFields outside of mitosis where TTFields downregulates the Fanconi’s Anemia genes and proteins results in replication stress and reduced DNA repair capacity. Given these results we hypothesized that TTFields would increase the sensitivity of tumor cells to chemotherapy agents that increase replication stress. An analysis of agents that target replication stress in different ways was initiated. PARP1: Targeting PARP1 protects DNA breaks by recruiting DNA repair and checkpoint proteins to the sites of damage. Using the PARP1 inhibitor olaparib followed by radiation resulted in synergistic cell killing compared to radiation or olaparib alone or in combination. Etoposide: Etoposide forms a ternary complex with topoisomerase II and prevents re-ligation of DNA strands to elicit DNA strand breaks and replication stress. When combined with TTFields cell killing increased synergistically vs. etoposide alone. AZD6738: ATR is an essential kinase regulator of the replication checkpoint that plays a critical role in safeguarding genome integrity from replication stress. The advantage of combining TTFields with the ATR inhibitor-AZD6738 was tested for cell killing and the combination vs. AZD6738 was found to be synergistic. Irinotecan: Irinotecan traps topoisomerase I- DNA in a ternary cleavage complex and inhibits the initial cleavage reaction and re-ligation steps resulting in increased replication stress. Irinotecan and TTFields was tested and found to be highly effective at tumor cell killing. Collectively, our results suggest that it is likely of considerable clinical benefit to combine TTFields with chemotherapy agents that cause replication stress. This notion may explain the results of a number of clinical trials and suggests that there may be novel TTFields/replication stress-inducing chemotherapy agent combinations worth exploring.

Can antioxidants protect against chemotherapy in rat spermatogonial stem cell line?

LAY ABSTRACT: Boys administered chemotherapy to treat childhood cancer are at risk of damage to their healthy testicular tissue, which can lead to infertility in adulthood. Researchers are therefore investigating treatments to protect the testis during cancer treatment. Here, cells originating from the testicles of rats were cultured for four days and exposed to chemotherapy drugs with or without antioxidants for the final two days. Antioxidants can reduce cellular damage by inactivating toxic compounds. Here, the antioxidants melatonin or n-acetylcysteine were tested against chemotherapy agents’ cisplatin, doxorubicin, or vincristine. Cultures were repeated four times, with cell survival measured at the end of culture. The antioxidants themselves were not damaging to the cells and partially protected against cisplatin, although not against doxorubicin. Surprisingly, n-acetylcysteine was found to enhance the damage induced by vincristine. The results suggest that using antioxidants to try to protect the testis could have either beneficial or harmful effects when given alongside different chemotherapy drugs: this is important, considering that patients are often treated with multiple drugs which could react differently to protectants.