Development Of Secondary Malignancies Research Articles

Emerging Role of Natural Topoisomerase Inhibitors as Anticancer agents

Abstract: Topoisomerases I and II are the functionally two forms of DNA topoisomerase. In anticancer research, novel anticancer chemotherapeutical capable of blocking topoisomerase enzymes have been discovered. Most commonly, topoisomerase causes replication fork arrest and doublestrand breaks, and this is how a clinically successful topoisomerase-targeting anticancer medicines work. Unfortunately, this novel mechanism of action has been linked to the development of secondary malignancies as well as cardiotoxicity. The specific binding locations and mechanisms of topoisomerase poisons have been identified by studying the structures of topoisomerase-drug-DNA ternary complexes. Recent breakthroughs in science have revealed that isoform-specific human topoisomerase II poison could be created as safer anticancer drug molecules. It may also be able to develop catalytic inhibitors of topoisomerases by focusing on their inactive conformations. In addition to this, the discovery of new bacterial topoisomerase inhibitor molecules and regulatory proteins could lead to the discovery of new human topoisomerase inhibitors. As a result, biologists, organic chemists, and medicinal chemists worldwide have been identifying, designing, synthesizing, and testing a variety of novel topoisomerase-targeting bioactive compounds. This review focused on topoisomerase inhibitors, their mechanisms of action, and different types of topoisomerase inhibitors that have been developed during the last ten years.

Radiation-Induced Intraosseous Malignant Peripheral Nerve Sheath Tumor: A Case Report.

The significance of radiation therapy in cancer treatment comes with associated complications, including fibrosis, osteonecrosis, and the development of secondary malignancies, such as malignant peripheral nerve sheath tumors (MPNSTs). We emphasize the importance of understanding these complications for an effective patient management. We report a 47-year-old man with a history of squamous cell carcinoma of the tongue, treated with surgery, chemotherapy, and radiation therapy. The patient later presented with symptoms that led to the discovery of an intraosseous MPNST. Histopathological examination revealed characteristic features of MPNST, including spindle cells arranged is sweeping fascicles with contrasting hypercellular and hypocellular areas, producing a marble-like pattern, with atypical wavy, buckled, hyperchromatic nuclei, and brisk mitotic activity. Immunohistochemical analysis showed patchy positive staining for S100 and SOX10, and a complete loss of H3K27me3 expression. This report underscores the challenge of diagnosing secondary malignancies post-radiation therapy and the importance of careful histological examination to differentiate them from other conditions. In conclusion, radiation-induced secondary malignancies are a significant late side effect of radiation therapy that can profoundly impact treatment decision-making and requires a high index of suspicion during post radiation surveillance. Malignant peripheral nerve sheath tumor serves as a pertinent example, highlighting the importance of considering long-term risks when developing optimal management plans for cancer patients.

Clinical stage IIA/B seminoma - to do or not to do: the role of retroperitoneal lymphadenectomy

About 10% of patients with seminomatous testicuar germ cell tumors are diagnosed with clinical stage II/B. The current guideline recommended treatment options include systemic chemotherapy with 3 cycles PEB or radiation therapy with 30 Gy for CS IIA and 36 Gy for CS IIB. Despite a high cure rate of 90-94% and 82-90% for CS IIA and CS IIB, respectively, both options are associated with a high rate of treatment-associated long-term toxicities. A significantly increased risk for the development of secondary malignancies, cardiovascular and metabolic disease as well as an increased for treatment-associated mortality has been proven in various studies. Primary nerve sparing retroperitoneal lymph node dissection (nsRPLND) has been evaluated in 5 prospective and retrospective clinical studies and it has emerged as a valid treatment alternative. The relapse-rate after a median follow-up of 25-33 months is in the range of 11-30%, so that 70-90% of patients are cured without being subjected to chemotherapy and potential long-term toxicities. All relapsing patients have been cured with secondary salvage chemotherapy. The frequency of significant surgery-associated complications is low with 3-13%. Therapeutic success depends on the surgical experience of the various surgeons and the chosen template, so that this type of surgical interventions should only be performed in centres of excellence with dedicated surgeons. Preoperative evaluation of the new biomarker miR371 has been shown to predict the presence of metastatic disease with an accuracy of around 100% so that this marker might be used in daily routine prior to active treatment in CS IIA/B seminomas.

Secondary cancer risk assessment in healthy organs following craniospinal irradiation

Introduction Medulloblastoma is a central nerves tumor that often occurs in pediatrics. The main radiotherapy technique for this tumor type is craniospinal irradiation (CSI), through which the whole brain and spinal cord are exposed to radiation. Due to the immaturity of healthy organs in pediatrics, radiogenic side effects such as second cancer are more severe. Accordingly, the current study aimed to evaluate the risk of secondary cancer development in healthy organs following CSI. Materials and methods Seven organs at risk (OARs) including skin, eye lens, thyroid, lung, liver, stomach, bladder, colon, and gonads were considered and the dose received by each OAR during CSI was measured inside an anthropomorphic RANDO phantom by TLDs. Then, the mean obtained dose for each organ was used to estimate the probability of secondary malignancy development according to the recommended cancer risk coefficients for specific organs. Results The results demonstrated that the stomach and colon are at high risk of secondary malignancy occurrence, while the skin has the lowest probability of secondary cancer development. The total received dose after the treatment course by all considered organs was lower than the corresponding tolerable dose levels. Conclusions From the results, it can be concluded that some OARs during CSI are highly at risk of secondary cancer development. This issue may be of concern due to organ immaturity in pediatrics which can intensify the radiogenic effects of radiation exposure. Accordingly, strict shielding the OARs during craniospinal radiotherapy and/or sparing them from the radiation field through modern techniques such as hadron therapy is highly recommended.

Abstract 7449: Incidence of secondary malignancies in early onset colorectal cancer (EOCRC) patients

Abstract Introduction: The incidence of colorectal cancer in the younger population (20-49) continues to rise at a rapid pace. EOCRC patients are potentially at risk for developing additional secondary malignancies. There is a lack of reported data in the EOCRC space. In this analysis, we seek to examine the incidence, trends, and outcomes of secondary malignancies in EOCRC patients. Methods: The surveillance, epidemiology, and end-result (SEER) database was utilized to assess and compare the incidence and factors associated with development of secondary malignancies among EOCRC patients. Patient characteristics were summarized by secondary cancer status and compared using the Pearson chi-square test. Further OS was assessed using Kaplan- -Meier methods and compared across groups using the log-rank test. Multivariable Logistic regression models using backward selection approach were used to evaluate the association between patient characteristics and risk of secondary cancers. All statistics were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). Results: Of the 53,891 patients analyzed, 2578 (4.8%) patients with EOCRC developed a secondary malignancy in the SEER database from 2000-2019. The mean age for developing a secondary malignancy was 47.6 yo (median 48 yo; range 20-69). There was a higher likelihood of second cancers among men(56%), white patients (61.4%), those with stage II (25.5%). and III (32.8%) CRC. The patients who most commonly developed a secondary malignancy were in the age group 40-49(p <.001). Of the patients who developed a secondary malignancy, 1843 (71.5%) initially had a primary colon cancer compared to 920 (22.6%) having rectal cancer, with the remainder having a rectosigmoid cancer. Of the patients who developed secondary malignancies, a majority had received prior chemotherapy (58.5%), and a minority of patients received radiation therapy (20.6%) Patients who had a partner had a higher incidence of secondary malignancy (59.5%) and they were more likely to have resided in a metropolitan area compared to a nonmetropolitan area (86.6 versus 13.2% respectively). The most common sites of secondary malignancy were: an additional colorectal cancer (47.7%), followed by breast cancer (8.2%) urinary tract cancer (7.1%), thyroid cancer (7%) and prostate cancer (5%). Patients who developed a secondary cancer were found to have an improved disease specific survival (DSS) compared to those who did not develop a secondary malignancy (3 year mDSS 89% vs 74%; p <.001)The overall survival of patients who developed a secondary malignancy was worse than those who did not develop one (mOS 208 months vs 229 mos respectively). Conclusion: EOCRC patients are likely to develop secondary malignancies. Long-term screening should be recommended for these patients and integrated into their survivorship plans. Citation Format: Deepak Vadehra, Kristopher Attwood, Anthony George, Shailesh Advani, Sahithi Sonti, Sarbajit Mukherjee. Incidence of secondary malignancies in early onset colorectal cancer (EOCRC) patients [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 7449.

Treatment Outcomes of Retinoblastoma in Children Less than 6 Months of Age

Treatment Outcomes of Retinoblastoma in Children Less than 6 Months of Age

Radiation Exposure from GEP NET Surveillance.

Neuroendocrine tumors (NET) are neoplasms that secrete peptides and neuroamines. For gastroenteropancreatic (GEP) NET, surgical resection represents the only curative option. Ten-year imaging surveillance programs are recommended due to long time-to-recurrence following resection. We performed retrospective chart review evaluating radiation exposure and practice patterns from surveillance of completely resected GEP NET. We performed a retrospective cohort study of cases with well-differentiated GEP NET from January 2005 to July 2020. Location of primary, modality of imaging, and duration of follow-up were collected. Dosimetry data was collected to calculate effective dose. 62 cases were included with 422 surveillance scans performed. Cross-sectional imaging was used in 82% and functional imaging was used in 18% of scans. Mean number of scans per year was 1.25 (0.42-3). Mean total effective dose was 56.05 mSv (SD 45.56; 0 to 198 mSv) while mean total effective dose per year was 10.62 mSv (SD 9.35; 0 to 45 mSv). Over the recommended ten years of surveillance the estimated total effective dose was 106 mSv. Surveillance of completely resected GEP NET results in cumulative radiation doses in the range associated with secondary malignancy development. Strategies to minimize radiation exposure in surveillance should be considered in future guideline development.

Incidence and Risk of Secondary Malignancy in Patients with Waldenström Macroglobulinemia: A Population-Based Analysis.

Waldenström macroglobulinemia (WM) is a rare lymphoplasmacytic lymphoma which may predispose individuals to development of secondary malignancies (SMs). The Surveillance, Epidemiology, and End Results (SEER) database is a comprehensive registry of cancer patients in the United States reporting on a wide set of demographic variables. Using the SEER-18 dataset, analyzing patients from 2000 to 2018, we aimed to assess the incidence of SMs in WM patients. Patient characteristics such as gender, age, race, and latency were identified, and respective standardized incidence ratios (SIRs) and absolute excess risks (AERs) were calculated to compare to the general population. Of the 4,112 eligible WM patients identified, SMs were reported in 699 (17%) patients. The overall risk of developing SM, second primary malignancy, and secondary hematological malignancy was significantly higher in WM patients compared to the general population. Our findings show that WM patients had a 53% higher risk of SMs relative to the general population, and an AER of 102.69 per 10,000. Although the exact mechanism is unclear, the risk of SM development may be due to genetic predisposition, immune dysregulation, or treatment-induced immune suppression.

Retrospective Analysis of Adolescent Young Adult Patients with Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma Treated with the CALGB 10403 Regimen Since Completion of Trial Enrollment

INTRODUCTION The outcomes of adolescent and young adult (AYA) patients (ages 15-39 years) with acute lymphoblastic leukemia/lymphoma (ALL) have improved in part with the adoption of pediatric ALL regimens in the adult treatment setting. The Cancer and Leukemia Group B (CALGB) 10403 trial (C10403) was the largest prospective trial conducted in the United States (U.S.), demonstrating the safety and efficacy of delivering an intensive pediatric regimen utilizing asparaginase in the adult oncology treatment setting to AYAs with ALL, with 3-year event-free survival (EFS) and overall survival (OS) of 59% (95% CI, 54%-65%) and 73% (95% CI, 68%-78%), respectively (Stock et al., Blood 2019). Although this regimen is widely used in the U.S., outcomes for patients treated with C10403 outside of a clinical trial setting remain unknown. We thus conducted a multi-center retrospective study to examine the real-world, off-trial efficacy of the C10403 regimen delivered across U.S. cancer centers. METHODS AYAs ages 17-40 years with newly diagnosed Ph-neg B-ALL or T-ALL between October 1, 2012 and July 1, 2020 who received initial treatment with the C10403 regimen (off trial) across 5 U.S. centers were included. Patients were excluded if they had Ph+ or Burkitt-type ALL. Previously treated patients, except with hydroxyurea, steroids, or one dose of single-agent therapy were excluded; patients given rituximab for CD20+ B-ALL were included. Primary endpoints were induction response rate (IRR), 3-year EFS, and 3-year OS. Induction response was defined as achieving <5% blasts on bone marrow by end of induction or extended induction. Patients were censored for EFS at the time of change in regimen, the addition of another agent (eg blinatumomab) or if they proceeded to hematopoietic cell transplant (HCT). Patients with deviation from the C10403 regimen were included in the 3-year OS analysis. Events were defined as: 1) failure to achieve bone marrow response by the end of induction or extended induction, 2) failure to achieve metabolic response of lymphoma on PET-CT as determined by the clinician 3) death, 4) relapse at any site, or 5) development of second malignancy. RESULTS Among 101 included in the cohort, 54% were 20-29 years old, 69% were male, 55% were Caucasian and 31% identified as Hispanic. Of those with B-cell immunophenotype (70%), 49% had CD20 expression. The majority had normal karyotype (40%), while 3% were hypodiploid, 7% were KMT2a-rearranged, and 30% of the 27 patients assessed had Ph-like ALL. CNS involvement at diagnosis was documented in 20% (9% CNS2/11% CNS3) and 14% had a mediastinal mass. Of the B-ALL cohort (N=71), 16 (23%) received at least one dose of rituximab. Among the entire cohort, the IRR was 91% (54% MRD negative; threshold of at least 10 -4). Of the 101 patients who began induction with C10403, 72 (71%) completed induction and continued to consolidation; 51 (50%) continued beyond consolidation, and 31 (31%) completed the entire C10403 regimen through end of maintenance. Two patients (2%) died while in remission and still receiving treatment. Forty-four patients (44%) were taken off C10403 while in CR; 20 (20%) for allogeneic HCT, 23 (23%) for non-HCT alternative treatments including Hyper-CVAD or blinatumomab, and 1 (1%) for patient preference. The 3-year EFS and OS were 65% (95% CI, 53.8%-78.5%) and 82.7% (95% CI, 75.5%-90.5%), respectively (Figures 1 and 2). Conclusion In this multi-center, real world study of the C10403 regimen administered to newly diagnosed AYA ALL patients across adult U.S. centers, we demonstrate survival outcomes as favorable as the reported clinical trial results. While only 31% of patients completed the regimen through end of maintenance, a majority of patients who came off regimen either underwent consolidative HCT or alternative therapy while in CR. These data confirm the pediatric regimen as an excellent front-line option in AYA ALL.

Reverse Autologous Peripheral Blood Stem Cell Transplantation after Allogeneic Transplantation to Restore Immune Function and Pancytopenia

Despite advances in multiple myeloma treatment the disease remains challenging to treat with repeated relapses in most. For high-risk younger patients, allogeneic transplants are occasionally performed. While curative in some, complications can include the development of opportunistic infections and secondary malignancies. Furthermore, patients relapsing after an allogeneic transplant may have poor bone marrow reserve limiting the ability to use subsequent therapies. We describe two patients who underwent a “reverse” autologous peripheral blood stem cell rescue using stem cells banked prior to allogeneic transplantation. The outcomes were successful and led to full engraftment and correction of their immunodeficiencies and pancytopenia respectively. Case 1: A 37-year-old woman was diagnosed with multiple myeloma during routine testing for an in-vitro fertilization assessment. She had ISS stage 2 disease and was treated with CyBorD, followed by an autologous stem cell transplantation. Lenalidomide plus dexamethasone was used as maintenance. She relapsed after just one year then progressed through single agent carfilzomib and then bendamustine. After responding to 2 cycles of DCEP she had a 10/10 matched unrelated donor CD34-selected allogeneic transplant. The patient was EBV positive, but the donor was not. Four months post-transplant she developed tonsillar PTLD with a rising EBV DNA titer and was treated with rituximab. Her CD4 count was 46. Her multiple myeloma relapsed thereafter necessitating treatment with daratumumab. She then developed rituximab-resistant monomorphic PTLD which then responded to brentuximab-vedotin and donor lymphocyte infusions. The multiple myeloma relapsed again and was treated with daratumumab + pomalidomide + dexamethasone. After a rising EBV DNA titer, brentuximab-vedotin was restarted but the lymphoma progressed again with a 5 x 3 cm anterior mediastinal mass biopsy proven to be monomorphic PTLD. R-CHOP was given for 4 cycles but resulted in only a partial response. Due to subsequent rapidly symptomatic and progressive disease a decision was made to use high-dose melphalan (200 mg/m2) followed by a reinfusion of her previously collected autologous stem cells to restore her T-cell immunity and hopefully control her lymphoma. She engrafted uneventfully at Day + 12 with chimerism studies showing autologous hematopoiesis and a CD4 count of 856. Her post-transplant course was complicated by renal thrombotic microangiopathy treated successfully with eculizumab. After further myeloma relapses, she is currently alive and well and in remission while on teclistamab over 4 yrs after her 2 nd autologous PBSC transplant. Her lymphoma has resolved. Case 2: A 37-year-old-male with beta-thalassemia was noted to have an elevated total protein on routine blood testing for a life insurance policy. Work up revealed multiple myeloma with a t(4:14) abnormality and complex cytogenetics. After initial observation he was started on KRD for progressive anemia. A VGPR was obtained and consolidated with an autologous PBSC transplant. He was maintained on Ixazomib+lenalidomide+dexamethasone but relapsed 2 years later with a sacral mass. After progressions though daratumumab+pomalidomide+dexamethasone then carfilzomib and then XRT to a large chest mass followed by DCEP as salvage, he underwent a 9/10 mismatched allogeneic transplant. He developed Grade 2 skin GVH but had disease progression again after just 6 months. Salvage treatment with elotuzumab+pomalidomide+dexamethasone then DCEP and subsequently ciltacabtagene autoleucel were unsuccessful with progression after just 6 weeks from the latter. He was treated again with DCEP but became transfusion dependent after the 2 nd cycle and had progressive disease again. Due to symptomatic myeloma and pancytopenia he underwent a reverse autologous PBSC transplant using banked stem cells. He engrafted uneventfully on Day +11 and despite recurrent multiple myeloma, he is currently in remission while on talquetamab. His beta-thalassemia returned. These cases demonstrate the ability to reverse an allogeneic transplant successfully using previously stored autologous peripheral blood stem cells. The recovery allowed for resumption of effective anti-cancer treatment that became lifesaving. Whether this approach could correct patients with unrelenting GVH issues should be contemplated as well.

Radiation-associated secondary malignancies: a novel opportunity for applying immunotherapies.

Radiation is commonly used as a treatment intended to cure or palliate cancer patients. Despite remarkable advances in the precision of radiotherapy delivery, even the most advanced forms inevitably expose some healthy tissues surrounding the target site to radiation. On rare occasions, this results in the development of radiation-associated secondary malignancies (RASM). RASM are typically high-grade and carry a poorer prognosis than their non-radiated counterparts. RASM are characterized by a high mutation burden, increased T cell infiltration, and a microenvironment that bears unique inflammatory signatures of prior radiation, including increased expression of various cytokines (e.g., TGF-β, TNF-α, IL4, and IL10). Interestingly, these cytokines have been shown to up-regulate the expression of PD-1 and/or PD-L1-an immune checkpoint receptor/ligand pair that is commonly targeted by immune checkpoint blocking immunotherapies. Here, we review the current understanding of the tumor-immune interactions in RASM, highlight the distinct clinical and molecular characteristics of RASM that may render them immunologically "hot," and propose a rationale for the formal testing of immune checkpoint blockade as a treatment approach for patients with RASM.

Chromosomal Instability in Various Generations of Human Mesenchymal Stem Cells Following the Therapeutic Radiation.

Radiotherapy is a crucial treatment for most malignancies. However, it can cause several side effects, including the development of secondary malignancies due to radiation-induced genomic instability (RIGI). The aim of this study was to evaluate genomic instability in human mesenchymal stem cells (hMSCs) at different X-ray radiation doses. Additionally, the study aimed to examine the relative expression of certain genes involved in DNA repair, proto-oncogenes, and tumor suppressor genes. After extracting, characterizing, and expanding hMSCs, they were exposed to X-ray beams at doses of 0, 0.5, 2, and 6 Gy. Nuclear alterations were evaluated through the cytokinesis-block micronucleus (CBMN) assay at 2, 10, and 15 days postirradiation. The expressions of BRCA1, BRCA2, TP53, Bax, Bcl2, and KRAS genes were analyzed 48 hr after irradiation to evaluate genomic responses to different radiation doses. The mean incidence of micronuclei, nucleoplasmic bridges, and nuclear buds was 4.8 ± 1.6, 47.6 ± 6, and 18 ± 2.6, respectively, in the nonirradiated group 48 hr after the fourth passage, per 1,000 binucleated cells. The incidence of micronuclei in groups exposed to 0.5, 2, and 6 Gy of radiation was 14.3 ± 4.9, 32.3 ± 6.5, and 55 ± 9.1, respectively, 48 hr after irradiation. The expression levels of the BRCA2, Bax, TP53, and KRAS genes significantly increased after exposure to 6 Gy radiation compared to the control groups. However, there was no significant increase in BRCA1 and Bcl2 gene expression in our study. This study demonstrated significant nuclear alterations in the 10 days postirradiation due to the RIGIs that they inherited from their irradiated ancestral cells. While chromosomal instability is a prevalent event in malignant cells, so it seems necessary to optimize radiotherapy treatment protocols for tissues that contain stem cells, especially with IMRT, which delivers a low dose to a larger volume of tissues.

Risk prediction of second primary malignancies after gynecological malignant neoplasms resection with and without radiation therapy: a population-based surveillance, epidemiology, and end results (SEER) analysis

PurposeThe association between post-resection radiotherapy for primary gynecological malignant neoplasms (GMNs) and the development of secondary primary malignancies (SPMs) remains a subject of debate. This study represents the first population-based analysis employing a multivariate competitive risk model to assess risk factors for this relationship and to develop a comprehensive competing-risk nomogram for quantitatively predicting SPM probabilities.Materials and methodsIn our study, data on patients with primary GMNs were retrospectively collected from the Epidemiology, Surveillance and End Results (SEER) database from 1973 to 2015. The incidence of secondary malignant tumors diagnosed at least six months after GMN diagnosis was compared to determine potential risk factors for SPMs in GMN patients using the Fine and Gray proportional sub-distribution hazard model. A competing-risk nomogram was constructed to quantify SPM probabilities.ResultsA total of 109,537 patients with GMNs were included in the study, with 76,675 and 32,862 GMN patients in the training and verification sets, respectively. The competing-risk model analysis identified age, primary tumor location, tumor grade, disease stage, chemotherapy, and radiation as risk factors for SPMs in GMN patients. Calibration curves and ROC curves in both training and verification cohorts demonstrated the predictive accuracy of the established nomogram, which exhibited a good ability to predict SPM occurrence.ConclusionsThis study presents the nomogram developed for quantitatively predicting SPM probabilities in GMN patients for the first time. The constructed nomogram can assist clinicians in designing personalized treatment strategies and facilitate clinical decision-making processes.

Classical Hodgkin Lymphoma: From Past to Future-A Comprehensive Review of Pathophysiology and Therapeutic Advances.

Hodgkin lymphoma, a hematological malignancy of lymphoid origin that typically arises from germinal-center B cells, has an excellent overall prognosis. However, the treatment of patients who relapse or develop resistant disease still poses a substantial clinical and research challenge, even though current risk-adapted and response-based treatment techniques produce overall survival rates of over 95%. The appearance of late malignancies after the successful cure of primary or relapsed disease continues to be a major concern, mostly because of high survival rates. Particularly in pediatric HL patients, the chance of developing secondary leukemia is manifold compared to that in the general pediatric population, and the prognosis for patients with secondary leukemia is much worse than that for patients with other hematological malignancies. Therefore, it is crucial to develop clinically useful biomarkers to stratify patients according to their risk of late malignancies and determine which require intense treatment regimens to maintain the ideal balance between maximizing survival rates and avoiding late consequences. In this article, we review HL's epidemiology, risk factors, staging, molecular and genetic biomarkers, and treatments for children and adults, as well as treatment-related adverse events and the late development of secondary malignancies in patients with the disease.

Complications of Cancer Therapy in Children: A Comprehensive Review of Neuroimaging Findings.

Complications of cancer therapy in children can result in a spectrum of neurologic toxicities that may occur at the initiation of therapy or months to years after treatment. Although childhood cancer remains rare, increasing survival rates mean that more children will be living longer after cancer treatment. Therefore, complications of cancer therapy will most likely occur with increasing frequency.At times, it is very difficult to differentiate between therapeutic complications and other entities such as tumor recurrence, development of secondary malignancy, and infection (among other conditions). Radiologists often play a key role in the diagnosis and evaluation of pediatric patients with malignancies, and thus, awareness of imaging findings of cancer complications and alternative diagnoses is essential in guiding management and avoiding misdiagnosis. The aim of this review article is to illustrate the typical neuroimaging findings of cancer therapy-related toxicities, including both early and late treatment effects, highlighting pearls that may aid in making the appropriate diagnosis.

Breast malignancy after radioactive iodine ablation for thyroid pathology: A systematic review of the literature.

e22511 Background: Radioactive Iodine Ablation (RAI) is a procedure in which the administration of radioactive iodine is utilized to eradicate pathologic thyroid tissue. RAI is commonly used for thyroid malignancy and hyperthyroidism. Although RAI has been a mainstay of treatment for these diseases, there has been some controversy regarding the development of secondary primary malignancy after RAI. Breast cancer is a particular concern. As breast cancer is the second most common cancer for women in the United States, understanding its risk factors is a key component of public health. Methods: A systematic review was conducted following PRISMA guidelines. Inclusion criteria consisted of English language studies that evaluated the association between radioactive iodine ablation and secondary primary breast malignancy. The study was conducted from January 2023 until February 2023. Two independent researchers conducted the literature search utilizing PubMed, SCOPUS, JSTOR, and Wiley Library using standardized search terms. The titles and abstracts of these studies were independently screened, and further evaluated for relevancy. Qualitative data was then extracted and summarized. Results: Of the 386 manuscripts retrieved, 27 met inclusion criteria. These studies were published between 1983 – 2022. Of these, 15 articles reported no association between RAI and the development of secondary primary breast malignancy. Of the manuscripts which reported no association, 6 examined RAI for hyperthyroidism, and 9 examined RAI for thyroid malignancy. 12 studies reported an association between RAI and the development of secondary primary breast malignancy. Of the studies reporting an association, 1 examined RAI for hyperthyroidism, and the remaining 11 examined RAI for thyroid malignancy. For the single study that found an association in the case of hyperthyroidism, the researchers found a dose-dependent relationship. Conclusions: The literature surrounding secondary primary breast malignancy after RAI is controversial. This systematic review resulted in conflicting data regarding the association between radioactive iodine ablation for thyroid pathology and the development of secondary primary breast malignancy. The studies that suggested an association between RAI and secondary primary breast malignancy were overwhelmingly studies in which RAI was used for the treatment of thyroid malignancy. Some studies suggest a possible dose-dependent relationship between RAI and secondary primary breast malignancy, however this data is limited. Additional studies would be beneficial to address this gap in the literature.

Multiparametric analysis of etoposide exposed mesenchymal stem cells and Fanconi anemia cells: implications in development of secondary myeloid malignancy.

Secondary acute myeloid leukemia (sAML) may develop following a prior therapy or may evolve from an antecedent hematological disorder such as Fanconi Anemia (FA). Pathophysiology of leukemic evolution is not clear. Etoposide (Eto) is a chemotherapeutic agent implicated in development of sAML. FA is an inherited bone marrow (BM) failure disease characterized by genomic instability and xenobiotic susceptibility. Here, we hypothesized that alterations in the BM niche may play a critical/driver role in development of sAML in both conditions. Expression of selected genes involved in xenobiotic metabolism, DNA double-strand break response, endoplasmic reticulum (ER) stress, heat shock response and cell cycle regulation were determined in BM mesenchymal stem cells (MSCs) of healthy controls and FA patients at steady state and upon exposure to Eto at different concentrations and in recurrent doses. Expression of CYPA1, p53, CCNB1, Dicer1, CXCL12, FLT3L and TGF-Beta genes were significantly downregulated in FA-MSCs compared with healthy controls. Eto exposure induced significant alterations in healthy BM-MSCs with increased expression of CYP1A1, GAD34, ATF4, NUPR1, CXCL12, KLF4, CCNB1 and nuclear localization of Dicer1. Interestingly, FA-MSCs did not show significant alterations in these genes upon Eto exposure. As opposed to healthy MSCs DICER1 gene expression and intracellular localization was not altered on FA BM-MSCs after Eto treatment. These results showed that Eto is a highly potent molecule and has pleiotropic effects on BM-MSCs, FA cells show altered expression profile compared to healthy controls and Eto exposure on FA cells shows differential profile than healthy controls.

Adverse effects of hydroxyurea used for the treatment of myeloproliferative neoplasms

Background: Hydroxyurea is administered to control elevated blood counts in patients with myeloproliferative neoplasms (MPNs) to reduce the risk of thrombosis and mortality. We reviewed the side effects of hydroxyurea, development of secondary malignancies, and drug resistance observed in some patients.Current Concepts: The low incidences of malformed births, intrauterine deaths, and spontaneous abortions associated with hydroxyurea therapy suggest that adverse pregnancy and fetal effects are unlikely. However, animal studies have reported malformations; therefore, the use of hydroxyurea during pregnancy is not recommended. Low-grade adverse events associated with hydroxyurea therapy include gastrointestinal symptoms such as nausea, upper gastrointestinal discomfort, and diarrhea. These symptoms are usually resolved by dose adjustment or temporary discontinuation. Approximately 10% of patients with MPNs are resistant to hydroxyurea, and another 10% are unable to tolerate it owing to side effects. Drug intolerance and resistance are the most common causes of inadequate cytoreductive control in patients with MPNs. Second-line cytoreductive agents should be considered to overcome the high risk of thrombosis and poor survival. The evolution to secondary hematologic cancers is related to the duration of the disease, not hydroxyurea administration.Discussion and Conclusion: In pregnant patients accidentally exposed to hydroxyurea, the risk should be discussed with the patient to determine whether to continue the pregnancy. Hydroxyurea administration increases the risk of skin cancer but does not affect the incidence of other secondary hematologic or solid cancers. Ropeginterferon or Janus kinase (JAK) inhibitors, including ruxolitinib, are recommended as alternative treatments if the patient is intolerant or resistant to hydroxyurea, as this is associated with poorer survival.

Risk and prognosis of secondary thoracic cancers after radiation therapy for esophageal cancer.

Radiation therapy (RT) is a crucial modality for the local control of esophageal cancer (EC), but the effect of RT on the development of secondary thoracic malignancies is still unclear. This study aims to identify the association between RT for the treatment of primary EC and subsequent secondary thoracic cancer (STC). The primary EC patients were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Fine-Gray competing risk regression and standardized incidence ratio (SIR) were used to evaluate the radiotherapy-associated cancer risk. Overall survival (OS) was compared by Kaplan-Meier analysis. A total of 40255 EC patients from the SEER database were identified, of which 17055 patients (42.37%) did not receive radiotherapy (NRT) and 23200 patients (57.63%) had been treated with RT. After 12months of latency, 162 patients (0.95%) in the NRT group and 272 patients (1.17%) in the RT group developed STC. The incidences of the RT group were significantly higher than the NRT group. Patients who have primary EC were at an increased risk of developing STC (SIR=1.79, 95% CI: 1.63-1.96). The SIR of STC was 1.37 (95% CI: 1.16-1.60) in the NRT group and 2.10 (95% CI: 1.87-2.34) in the RT group. The OS of STC patients in the RT group was significantly lower than the NRT group (P=0.006). The RT for primary EC was associated with higher risks of developing STC than patients unexposed to radiotherapy. The EC patients treated with RT, especially young patients, require long-term monitoring of the risk of STC.

Virtual screening and multilevel precision-based prioritisation of natural inhibitors targeting the ATPase domain of human DNA topoisomerase II alpha

Human DNA topoisomerase II alpha (hTopIIα) is a classic chemotherapeutic drug target. The existing hTopIIα poisons cause numerous side effects such as the development of cardiotoxicity, secondary malignancies, and multidrug resistance. The use of catalytic inhibitors targeting the ATP-binding cavity of the enzyme is considered a safer alternative due to the less deleterious mechanism of action. Hence, in this study, we carried out high throughput structure-based virtual screening of the NPASS natural product database against the ATPase domain of hTopIIα and identified the five best ligand hits. This was followed by comprehensive validation through molecular dynamics simulations, binding free energy calculation and ADMET analysis. On stringent multilevel prioritization, we identified promising natural product catalytic inhibitors that showed high binding affinity and stability within the ligand-binding cavity and may serve as ideal hits for anticancer drug development. Communicated by Ramaswamy H. Sarma