Cancer
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Item Clinical significance of Annexin A2 expression in Bladder urothelial carcinoma.(2022) Guo, Christina; Chaudhary, Panka J.Purpose: Bladder urothelial carcinoma (BLCA) is a highly malignant cancer, representing the 8th most common cause of cancer death in the US. The unpredictable disease course of BLCA necessitates an accurate biomarker to guide screening, prognosis, and treatment. Our objective was to investigate AnxA2 expression in tumor tissues of bladder urothelial carcinoma patients to determine AnxA2 association with bladder urothelial cancer and implicate AnxA2 as a potential prognostic marker. Methods: We utilized data from The Cancer Genome Atlas (TCGA) to observe AnxA2 gene expression in BLCA and its association with overall survival. Additionally, we quantified AnxA2 protein expression in tumor tissues of BLCA patients via immunohistochemistry. Results: In our analysis of TCGA data, AnxA2 mRNA expression was significantly higher in BLCA tumor tissues compared to normal bladder tissues. In addition, AnxA2 expression was significantly associated with higher tumor stage and grade as well as non-papillary tumor subtypes. The high expression of AnxA2 in BLCA patients was significantly correlated to decreased survival [hazard ratio (HR), 1.78; 95% confidence interval (CI), 1.3-2.44] as compared to low expression. In addition, we found that AnxA2 was significantly upregulated in tumor tissues of bladder urothelial carcinoma patients compared with adjacent non-cancerous bladder tissues. Conclusion: AnxA2 is overexpressed in BLCA patients, which is related to the advanced clinicopathological variables and adverse prognosis of patients with BLCA.Item Racial disparities in the effectiveness of treatment of Her2 positive breast cancer as measured by pathological complete response(2022) Angell, Callie; Bullock, Jolonda; Diaz, Anna; Basha, Riyaz; Narra, KalyaniPurpose: Pathologic complete response (pCR) is a surrogate marker for long term survival that can be used to evaluate neoadjuvant chemotherapy. It has been shown in a previous study that black breast cancer patients have lower pCR rates than non-Hispanic white (NHW) patients, particularly in the hormone receptor (HR) negative Human epidermal growth factor receptor 2 (Her2) positive subtype. Because John Peter Smith Hospital (JPS) has a high proportion of black patients, making up about 30% of their breast cancer patients in particular, further research on racial disparities in the treatment of Her2 positive breast cancers is needed. Methods: This retrospective study was conducted to investigate the pCR rates of Her2+ breast cancer patients treated with neoadjuvant trastuzumab based regimens. Data was obtained from the institutional registry of the JPS Oncology and Infusion Center in Fort Worth, TX. Eligible patients were diagnosed with Her2 positive breast cancer between 1/1/2016 and 12/31/2019 and underwent neoadjuvant trastuzumab based chemotherapy. Information on treatment regimen, diagnostic stage, and ER and PR status were collected as well as demographic information. pCR was collected from pathology reports from the JPS Department of Pathology and was defined as ypT0/isypN0. Results: JPS had 45 eligible patients for this study: 12 NHW, 15 black, and 11 Hispanic. 40 of the 45 patients were treated with docetaxel, carboplatin, trastuzumab, and pertuzumab, of which 21 achieved pCR. 4 of the other 5 patients who received different combinations including trastuzumab achieved pCR. Of all 45 patients, 25 achieved pCR; 8 NHW, 7 Black, and 6 Hispanic. For HR negative patients, 3 of 4 NHW, 1 of 5 black, and 3 of 5 Hispanic patients achieved pCR, for a total of 9 out of 17 patients. Conclusion: This study was limited by the number of eligible patients and should not be extrapolated to larger populations, but it shows how disparity is present in this urban safety net hospital. At JPS, only 47% of black patients and 55% of Hispanic patients achieved pCR compared to 67% of NHW patients. For HR negative cases, black patients were even less likely to achieve pCR. More research on the treatment of breast cancer for different races is necessary because they are not experiencing the same results. Studies in this area are limited and earlier trials (NEOSPHERE and TRYPHAENA) had very low numbers of black patients and did not recruit Hispanic patients. Further investigations are warranted to understand the differences between ethnicities in treating Her2 positive breast cancer. The research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number ( R25HL125447).The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Item Pituitary Adenoma in a Cadaver: A Case Report(2022) Barrientos, Bryan; Eren, Savannah; Diokpa, Treasure; Chunda, Kurt; Deplaza, Maya; Fisher, Cara L.Background: Pituitary adenomas have a prevalence of 1 in 865 adults to 1 in 2688 adults. A study with the Swedish Cancer Registry found that in a 33-year period between 1958 and 1991, the incidence of pituitary adenoma went from 6 per million to 11 per million. These adenomas can be divided into microadenomas (< 10mm) and macroadenomas (>10mm) with half of the incidence being the former and the other half the latter. Pituitary adenomas can be further divided by immunohistochemistry and functional status. Functional status is determined by whether or not the adenoma has hormone activity. Non-functional adenomas are usually incidental findings through imaging studies or autopsies, and are asymptomatic or paucisymptomatic tumors known as incidentalomas. Less than one percent of incidental tumors found at autopsy are macroadenomas. Functional adenomas can present with a clinical syndrome based on the hormone they secrete. Both functional and non-functional pituitary adenomas may cause symptoms resulting from mass effects, including bitemporal hemianopia, headaches, hypopituitarism, and ophthalmoplegia. Case Information: During a routine cadaver dissection of an undernourished 82-year-old male, removal of the brain and subsequent hemisection of the skull revealed a pituitary adenoma in the area of the sella turcica. The following measurements were gathered with calipers. The measurements of strictly the pituitary adenoma were a width of 13.56 mm and a length (anterior to posterior) of 19.13 mm. The pituitary adenoma with the sella turcica from superior to inferior was 23.73 mm. The measurement of the pituitary gland itself in the sella turcica from anterior to posterior was 13.68 mm. The measurements indicated that the cadaver's pituitary adenoma can be classified as a macroadenoma. The donor had a history of dementia, with the cause of death being senile degeneration of the brain. There was no evidence of surgical procedures, and no other medical conditions were noted. Conclusions: Non-functioning and functioning pituitary adenomas are linked to damaged eyesight, hormonal imbalances, and impaired cognitive function. Functioning adenomas may have a more severe impact on cognitive function overall, as there is an apparent connection to neuroendocrine function. Due to the limited medical history of the cadaver, there is uncertainty regarding the type of pituitary adenoma and the effects it may have had. Various surgical methods have been proven effective for the treatment of pituitary adenomas themselves, including single nostril transsphenoidal microscopic and endoscopic surgery. Procedures are known to generally improve hormonal imbalances and not aggravate cognition. While patients' cognitive functioning post-surgery is not extensively tracked, procedures appear to have minimal effectiveness in improving cognitive function for patients with functioning pituitary adenomas and are nonsignificant for patients with non-functioning adenomas. Research determining the specific mechanisms by which pituitary adenomas affect cognitive functioning could be useful for clinicians and surgeons to determine whether surgical procedures would be effective at improving patients' quality of life. In this aspect, clinical case studies help add to the understanding and future literature of conditions, making them extremely important in the advancement of medicine.Item Targeting Sp1 in Ewing Sarcoma: A multi-approach method for the utilization of Mithramycin(2022) Lambring, Christoffer B.; Sankpal, Umesh; Basha, RiyazPurpose: Ewing Sarcoma (ES) is a bone and soft tissue cancer affecting young adults and children. ES mostly occurs in the bones or soft tissue of the arms, legs, and pelvis. Localized ES presents with 5-year survival rate of 70%, but metastatic 5-year survival rate is between 15% and 30%. Our laboratory is interested in combination treatments using less toxic agents to induce sensitization to chemotherapy in ES. The anti-cancer activity of an antineoplastic antibiotic, Mithramycin, against ES cells has been shown. Mithramycin inhibits Specificity protein 1 (Sp1) a marker associated with aggressive cancer cell growth and resistance to chemo/radiation therapies. However, its mechanistic effects on survivin, an anti-apoptotic protein associated with poor prognoses in multiple cancers, are continuing to be elucidated in ES. This studies purpose is to evaluate the effectiveness of Mithramycin and various combinations with other chemotherapeutics, Etoposide and Vincristine, to inhibit ES cell growth and effect various cancer related proteins. Methods: Anti-proliferative activity of Mithramycin and/or Vincristine and Etoposide against ES cell lines, TC205 and CHLA10, was evaluated using CellTiterGlo kit. Dose curves were plotted and IC50 values were determined by Sigma-Plot software. The expression of Sp1 and survivin was determined by Western blot analysis. Cell lines were obtained from Children's Oncology Group (COG). Results: Mithramycin significantly decreased ES cell line viability and showed the ability to reduce the expression of Sp1 and offer differing effects on survivin expression, indicative of anti-apoptotic mechanisms being implemented in the ES cell lines. IC50 values of both chemotherapeutics and Mithramycin were decreased by nearly 50% when used in combination and this effect was mirrored in Sp1 expression. Conclusions: Mithramycin may effectively sensitize certain ES cells and improve the response of chemotherapy while lowering necessary effective dosages. Studies to understand the mechanisms of action of Mithramycin on Sp1 and survivin are underway.Item Case Report: Patient with 3 Gastric Cancers Simultaneously (Adenocarcionma, NET, GIST)(2022) Jacobs, Benjamin; Ali, Arsalan; Logarajah, Shankar; Jeyarajah, RohanBackground: Cancer is the second leading cause of death in the world second only to heart disease. The top three cancers by incidence for men are Lung, Prostate, and Colorectal. For women, the top three cancers by incidence are Breast, Colorectal, and Lung. Although gastric cancer does not crack the top three for men or women by incidence, gastric cancer is the second most common cause of cancer death worldwide. Of the different types of gastric cancer, adenocarcinoma of the stomach comprises nearly 95% of all forms of gastric cancer. The other less common types of gastric cancer include primary gastric lymphoma, gastrointestinal stromal tumor (GIST), and neuroendocrine (carcinoid) tumors. Diagnosis of the specific type of gastric cancer comes from the analysis of the removed specimen under the microscope. Multiple gastric cancers in a single patient are extremely rare and few cases have been reported. We report a case of a patient with three distinct types of gastric cancer in one pathology specimen. Case Information: The patient is a 77-year-old female who underwent total gastrectomy and distal esophagectomy in 2011 for concerning imaging and EGD studies consistent with cancerous lesions in her stomach. Upon examination under the microscope, the pathology report revealed three distinct cancers: 1) Mucinous adenocarcinoma 2) Well-differentiated neuroendocrine and 3) Gastrointestinal stromal tumor. After surgery, this patient underwent adjuvant chemoradiation and has been in remission and cancer-free going on 10 years. Conclusions: We present an extremely rare and peculiar case of a 77-year-old female who is 10 years post-op total gastrectomy and distal esophagectomy revealing three separate, coexisting, gastric cancers. Coexisting gastric cancers are very uncommon; however, physicians shouldn't rule out the possibility of their patients' having more than one type of cancer in the pathology specimen report. Understanding the different types of gastric cancer can alter therapy and change the plan moving forward (post-op) to recheck scans for lesions elsewhere in the body and undergo genetic testing for inherited mutations.Item Intraparenchymal Brainstem Schwannomas in Pediatric Patients: Two Unusual Case Reports(2022) Deville, Haley; Cope-Yokoyama, Sandy; Bosemani, Madhan; Zhao, SiboBackground: A schwannoma is a tumor that originates from the myelin sheath of peripheral nerves. Intracranial schwannomas constitute 8-10% of primary brain tumors with many of these tumors associated with the vestibular nerve. Less than 1% of schwannomas are intraparenchymal with development unrelated to cranial nerves. Four pediatric cases have been previously documented in the English literature. Many developmental and non-developmental theories have been proposed to explain the histogenesis of these tumors; however, their origin is still largely unknown. This report details the cases of two children with intraparenchymal brainstem schwannomas both without neurofibromatosis and discusses the radiographic and pathologic characteristics of the lesions. Case Information: A previously healthy 8-year-old female presented with a history of ataxia, visual impairment, right hemiparesis, and school decline for approximately three months. Magnetic Resonance Imaging (MRI) revealed a fairly well-circumscribed lobulated mass arising from the right dorsal and lateral mesencephalon. The patient underwent a posterior fossa craniotomy with telovelar approach, and the intramedullary midbrain tumor was completely resected. Pathology best classified the tumor as schwannoma (WHO Grade I). Testing for neurofibromatosis was negative. There were no obvious immediate complications postoperatively; however, the following day the patient developed secondary hydrocephalus and later a right occipital ventriculoperitoneal shunt was internalized. Postoperatively, she had left hemiparesis, cranial nerve three and four palsies, aphasia, and hypertonia. Four years after the total resection, the patient had no evidence of residual tumor and remained with spastic hemiparesis, seizure disorder, and the presence of cerebrospinal fluid drainage problem. The second patient, a previously healthy 15-year-old female, arrived in the emergency department with diplopia and a headache which began the previous night. Anisocoria and ataxia were also noted; however, she did not present with a fever, vomiting, or history of a head injury. MRI revealed a complex partially cystic and partially enhancing posterior fossa lesion involving the midbrain and pons. The patient underwent a left subtemporal craniotomy with gross resection of the tumor and a small residual cyst remained deep in the fourth ventricle with no evidence of immediate complications. The tumor was best classified as schwannoma (WHO Grade I) and genetic work up for neurofibromatosis was negative. Postoperatively, she experienced right hemiparesis, dystonic tone in her neck, and was very somnolent and labile. Six months postoperative, MRI showed no evidence of disease recurrence with a stable decompressed cyst; however, she continued to experience ongoing right hemiparesis and neuropathic pain. Her muscle strength and diplopia gradually improved. Conclusions: Further investigation is necessary to determine the exact origin of these tumors and to explain their unusual location. Also, considering the rarity of these tumors, they should always be considered during workup. Furthermore, it is important to obtain an intraoperative frozen section to obtain good patient outcomes as gliomas appear similar to schwannomas on MRI and are more likely to be found in the brainstem. Lastly, complete resection is more difficult in the brainstem; therefore, a partial resection and intracapsular decompression also may obtain favorable outcomes.Item ASPARAGINASE ASSOCIATED INTRA-CARDIAC THROMBUS PRESENTING AS SEPSIS IN AN ADOLESCENT PATIENT DURING ALL INDUCTION THERAPY(2022) Wu, Kylie; Hamby, Tyler; Mohamed, AshrafBackground: The incidence of pegaspargase induced thrombotic complications in pediatric patients with acute lymphoblastic leukemia (ALL) is 5.2%, with the majority of thromboses induced by asparaginase occurring in the venous system. Drug-induced intracardiac thrombosis is very rare and, if noted, usually develops within the right atrium in relation to central lines. Case Presentation: A 14-year-old female was diagnosed with B-cell ALL. At the time of diagnosis, her echocardiogram revealed a mild congenital dysplastic mitral valve with underdevelopment of the posterior leaflet, but cardiac function was not affected. The patient was started on a 4-drug induction and received 2 doses of pegaspargase. She was readmitted to the hospital on induction day 25 with diffuse body aches, generalized weakness, mildly elevated lipase, hyperbilirubinemia, pancytopenia, and severe hypo-albuminemia (1.6 gm/dl). Her direct bilirubin measured 1.7 mg/dL and amylase measured 289 U/L. On induction day 38, the patient developed a fever of 39.2°C. She became very ill looking and pale, but was oriented and alert. She stated that breathing was harder than earlier that morning. A chest x-ray was ordered to assess increasing O2 requirement and bilateral opacities were found at the base of the lungs. Her heart rate was 130 bpm and blood pressure was 100/77 mmHg. After being transferred to intensive care, a stat echocardiogram was ordered due to suspected sepsis-induced cardiogenic shock. However, upon examination, the echocardiogram demonstrated an echo bright mass along the lateral wall of the left ventricle (LV), consistent with an LVT. The thrombus extended to the mitral valve causing severe acute mitral regurgitation leading to cardiogenic shock requiring pressors and inotropic support. The patient was initially started on heparin infusion to treat the LVT due to contraindications for surgical intervention including thrombocytopenia, neutropenia, and active cytomegalovirus infection. She later underwent LV thrombectomy and mitral valvuloplasty. She improved significantly after surgery and was transferred to the rehabilitation unit. Conclusion: This patient demonstrated a unique presentation to pegaspargase associated thrombus formation. Given the rareness of cardiogenic shock secondary to intra-cardiac thrombosis during pediatric ALL therapy, the clinical picture can be mistaken with septic shock. Having a high index of suspicion may prompt early evaluation with echocardiogram, which can make an immense difference in the management and outcome of a patient.Item A NEW ERA: TARGETED THERAPY FOR RECURRENT GLOMUS TUMOR(2022) Faisal, Annum; Ray, AnishBackground: Glomus tumors (GT) are rare, vascular, benign soft tissue neoplasms that are composed of cells resembling modified smooth muscle originating from glomus bodies. Glomus bodies are specialized forms of arteriovenous anastomosis found in the reticular dermis that serve as thermoregulators. These glomus bodies are highly concentrated in the hands and feet, and thus, GT typically present as solitary lesions in the subungual region but may also occur elsewhere in the skin and soft tissues. Classically, GT are diagnosed with the following triad of symptoms: focal tenderness, spontaneous pain, and temperature sensitivity. Total surgical excision remains the mainstay of treatment. Here, we describe an atypical case of multifocal GT resistant to surgical excision and discuss alternative treatment modalities for recurrent cases in a pediatric patient. The treatment of recurrent GT remains a challenge due to lack of literature supporting alternative options. Management is especially difficult following a series of failed surgical excisions. Our objective is to explore the efficacy of non-surgical targeted-therapy treatment for recurrent GT based upon molecular genetic findings. Case Information: A 16-year-old female with a history of multifocal GT status post prior extensive removal through medial and lateral incisions in 2012, 2013, and 2015 presented back in 2021 with significant pain and swelling of the right lower extremity. History and PET Scan imaging confirmed extensive recurrence where the prior neoplasms had been present. Specifically, PET Scan demonstrated multifocal uptake within numerous masses in the right calf and ankle. Molecular genetic testing of GT in this patient revealed genomic changes in the platelet-derived growth factor receptor gene (PDGFRβ- R561_E563>Q). This gene transcribes platelet-derived growth factor receptor beta (PDGFRβ), which is part of a family of proteins called receptor tyrosine kinases. Accordingly, the patient started Sunitinib, a multi-receptor tyrosine kinase inhibitor which decreases phosphorylation of PDGFRβ and subsequently inhibits proliferation and survivability. Initially, treatment was intermittently held due to side effects of syncope, rash and plantar erythrodysesthesia. Nevertheless, as a result of improvements in pain and size of the tumors, she resumed treatment at a lower dose. Following trials of two dose reductions, she tolerated the medication well with resolution of side effects. The patient continued to note a decrease in the size of her GT, confirmed by imaging and her ability to return to work successfully. Conclusions: This case highlights the insufficiency in current mainstay treatment options of GT with surgical excision. Our findings emphasize the significance of incorporating molecular genetic testing into the treatment and management of recurrent GT to prevent disease relapse. Further research into alternative gene therapies is warranted.Item An unusual presentation of metastatic colorectal cancer mimicking cholangiocarcinoma(2022) Thompson, Mallory; Mantry, Parvez; Mejia, Alejandro; Dyrved, Neils-JorgenBackground: While liver metastases are common in later-stage colorectal cancer (CRC), metastases that develop more than five years after a curative colectomy is extremely rare. Intrabiliary growth type of metastasis (IGM) is rare with a predicted annual incidence of 0.00067% in the United States. Case Presentation: A 67-year-old female was referred to hepatology by her primary care physician for management of elevated liver function tests in the setting of mixed hyperlipidemia. She had a history of Stage 1 CRC 10 years prior, which was treated with a hemicolectomy. Her most recent colonoscopy was performed five months prior. The initial workup included a liver biopsy and antimitochondrial antibody studies, both of which were normal and ruled out primary biliary cholangitis. Subsequent blood work revealed an elevated level of alkaline phosphatase. An MRCP was unremarkable and an MRI showed no biliary duct dilation or evidence of obstruction. In the setting of isolated ALP elevation and a negative workup for any other liver disease, a working diagnosis of an extrahepatic process for elevated ALP was assumed, and the patient was scheduled for follow up in six months. Six months later, the patient was admitted for an unrelated episode of gastritis. Serum studies taken during her admission showed elevated liver function tests. One month after discharge, she was seen in the office for follow-up and was complaining of abdominal pain; her liver enzymes remained elevated. A second MRCP revealed dilation of the right intrahepatic bile ducts which was highly concerning for underlying malignancy. A CEA and CA 19-9 were negative. An urgent endoscopic retrograde cholangiopancreatography (ERCP) with brush cytology was unremarkable and the cytology was negative for malignancy. The patient continued to have abdominal pain and elevated liver function tests, and a second ERCP with cytology was performed. The ERCP revealed a focal stricture in the right hepatic duct. The patient subsequently underwent a balloon dilatation with stent placement. The second brush cytology was positive for malignancy. The patient presented to the emergency department (ED) with complaints of upper abdominal pain and was admitted three days after her second ERCP. An abdominal computed tomography (CT) scan performed in the ED was negative for any obvious liver masses. The patient was discharged a few days later and was referred to surgery for a hepatectomy. A right hepatectomy was performed with no acute complications. On gross exam, the right liver lobe appeared slightly atrophic with no evidence of obvious masses. Histology revealed moderately differentiated adenocarcinoma (8.0 x 1.0 x 1.0 cm) with an intestinal phenotype, most consistent with colorectal adenocarcinoma. The patient underwent a colonoscopy and there was no evidence of recurrent colon cancer; CEA and CA 19-9 levels were within normal limits. Upon follow-up, the patient's ALP levels had improved and her liver enzymes were normalized. Conclusions: This case indicates that a new and unexplained biliary stricture could be a manifestation of metastasis even if no obvious mass is seen.Item Reprogramming of B16-F10 melanoma-educated macrophages by STING agonists loaded in mannose-decorated reconstituted high density lipoprotein nanoparticles.(2022) Dossou, Akpedje; Kapic, Ammar; Mamo, Lois; Sabnis, Nirupama; Lacko, Andras G.; Fudala, RafalPurpose: Representing a large portion of tumor-infiltrating cells, tumor-associated macrophages (TAMs) have the potential to mediate an immune response against the tumor. Instead, they are educated by the tumor microenvironment (TME) to display an immunosuppressive (M2) phenotype that favors tumor progression. The utilization of stimulator of interferon genes (STING) agonists to re-program TAMs to an immunostimulatory (M1) phenotype leads to tumor regression. However, the whole-body distribution of macrophages, the complex TME architecture, and low bioavailability at the TME are challenges to this therapeutic approach. The selective delivery of STING agonists by suitable nanoparticles can help address these challenges. Reconstituted high-density lipoprotein nanoparticles (rHDL NPs) are biocompatible, can penetrate the TME, and interact readily with macrophages. The scavenger receptor class B type 1 (SR-B1) mediates the intracellular delivery of rHDL NPs' payload. Since TAMs highly express scavenger receptors and the mannose receptor CD206, we hypothesize that mannose-decorated rHDL NPs will efficiently deliver STING agonists to TAMs for their repolarization to an M1 phenotype. Thus, the purpose of this study is to assemble and characterize mannose-decorated rHDL NPs and assess the ability of the formulation to deliver STING agonists and polarize B16F10 melanoma-conditioned macrophages to an M1 phenotype. Methods: DSPE-PEG-Mannose (DPM) was used to introduce a mannose moiety onto the rHDL NPs. Two STING agonists (DMXAA, MSA-2) were loaded separately in the rHDL-DPM to form rHDL-DPM-DMXAA and rHDL-DPM-MSA-2. Dynamic light scattering, absorbance- and fluorescence-based measurements were used to evaluate the chemical composition and characterize the formulations. Murine macrophages incubated in B16-F10 melanoma-conditioned media served as an in vitro TAM model. Lipopolysaccharide + interferon-gamma- and interleukin-4 -treated macrophages respectively served as M1 and M2 macrophage references. Western blots and ELISA were used to assess the expression of M1 markers (CXCL10, HLA-DR) and M2 markers (CD36). Results: Similar characteristics, including size, were found for rHDL-DPM-DMXAA and rHDL-DPM-MSA-2. In addition to CD206 expression, B16F10-conditioned macrophages show expression of M2 markers. M2 macrophages and B16-F10-conditioned macrophages showed a higher SR-B1 expression and higher uptake of the payload from rHDL-DPM NPs than M1 macrophages. Treatment with STING agonist-loaded rHDL-DPM diminished CD36 expression and induced HLA-DR and CXCL10 expression in B16F10-conditioned macrophages. Conclusions: The above findings show that the rHDL-DPM NPs can serve as a delivery vehicle for both DMXAA and MSA-2 and potentially can be extended to other TAM-repolarizing drugs. The expression of SR-B1 and payload uptake by the B16-F10-conditioned macrophages validate the utility of rHDL-DPM NPs to efficiently target TAMs. In addition, the induced expression of CXCL10 could be beneficial for the recruitment of CD8+ T-cells when rHDL-DPM NPs are used in combination with T-cell-based immunotherapies to improve treatment outcomes for cancer patients.Item Celiac Plexus Neurolysis: An Underutilized Palliative Therapy(2022) Oh, James; Smith, ScottBackground: Celiac plexus neurolysis is an image-guided, therapeutic procedure wherein a neurolytic agent is injected into the celiac plexus resulting in permanent loss of the nerve plexus and subsequent pain reduction. Although it has been demonstrated to be safe and effective, celiac plexus neurolysis is an underutilized tool for pain management in the setting of palliative care. Case Information: A 40-year-old female was found to have an extensive, infiltrative gastric cancer with metastatic spread to the peritoneum and bones, as well as retroperitoneal invasion along the course of the celiac artery with invasion of the celiac plexus. Given her severe intractable abdominal pain requiring high opioid narcotic use, interventional radiology was consulted for celiac plexus neurolysis. The patient was a candidate for the procedure following a thorough evaluation of the patient with a multidisciplinary team and she consented after a discussion of the risks and benefits. Based on the current literature, a posterior paravertebral approach was deemed the most appropriate. Guided by computed tomography (CT), two 20-gauge Chiba needles were placed using a bilateral posterior paravertebral antecrural approach. Test injections were used to confirm needle position and satisfactory spread of the injection into the antecrural space. A 10 mL mixture of a 2 mL dilute contrast (1 mL Isovue-370 mixed in 20 mL normal saline) and 8 mL 1% lidocaine was made. The mixture was injected through both 5 mL Chiba needles. Ideally 25-30 mL of 95-100% ethanol is recommended, however due to a nationwide shortage of ethanol associated with the COVID-19 pandemic, 20 mL of 75% ethanol was injected instead through each needle. Post-procedure imaging confirmed dispersed spread of the neurolytic agent within the preaortic space. Conclusion: Following the procedure, the patient achieved temporary abdominal pain relief. However, her pain eventually returned to similar pre-procedure level. Factors that may have contributed to the ineffectiveness include her advanced disease status and tumor invasion into the celiac plexus, multifactorial pain associated with metastatic disease, and the dilution of ethanol. In an ideal situation, percutaneous celiac plexus neurolysis has been shown to improve pain in 70-90% of patients with abdominal cancer with low complication rate, decrease the need for daily analgesic medications, and improve patient survival rate. Therefore, the shortcoming of our case study should not discourage physicians to consider the procedure for palliative care.Item Leading Predictors and Their Associations with Combination Pain Therapy in Older Adults with Cancer: Application of Machine Learning Approaches(2022) Manning, Sydney E.; Madhavan, Suresh; Rasu, Rafia; Sambamoorthi, UshaOBJECTIVES: Opioid combination therapy is frequently prescribed in older adult cancer survivors despite negative outcomes. The objective of this study was to identify the leading predictors and their associations with opioid combination therapy prescribing after cancer diagnosis using interpretable machine learning approaches. METHODS: This is a retrospective longitudinal cohort of older (> 66 years old) cancer survivors (N = 2,673) diagnosed with primary and incident cancer in 2014 using the Surveillance, Epidemiology, and End Results (SEER) cancer registry linked with Medicare claims. Recursive feature elimination with random forest was used to extract the optimal number of predictors out of 119 likely ones for predictive modeling. eXtreme Gradient Boosting (XGBoost), SHapley Additive exPlanations (SHAP), and global feature importance were used to identify the leading predictors and their associations with opioid combination therapy. SAS 9.4 was used for data management and Python 3.9.7 was used for machine learning model calibration and tuning. RESULTS: Specificity (0.858), sensitivity (0.843), and area under the curve (AUC, 0.85) of our predictive model were high. Thirty-four features were included in the final predictive model. Baseline use of NSAIDs, opioids, benzodiazepines, and gabapentinoids, and chemotherapy, surgery, Complex relationships were observed between zip code percent of Hispanic and Native American residents living below poverty, care fragmentation (FCI), age at diagnosis, and opioid combination therapy. CONCLUSIONS: 1 in 3 older cancer survivors were prescribed opioid combination therapy. Patient-level baseline medication use, biological factors, cancer treatment, and zip code level social determinants were leading predictors of opioid combination therapy. Although observed relationships were complex, further analysis of predictors may help compute individual risk of patients on combination therapy, which in turn may help clinicians and policy makers utilize targeted interventions at the outset and prevent long-term effects of combination pain therapy such as prolonged and inappropriate use.Item Automated evaluation of p16 immunohistochemistry for diagnosis of cervical precancer(2022) Tao, Amy; Wentzensen, Nicolas; Clarke, Megan; Darragh, Teresa; Miranda, Felipe; Grabe, Niels; Lahrmann, BerndPurpose: Cervical cells transformed by high-risk strains of Human Papilloma Virus (HPV) overexpress the p16 protein, a cyclin-dependent kinase inhibitor that indicates activation of the E6 and E7 oncogenes. The Lower Anogenital Squamous Terminology (LAST) Standardization Project for HPV-Associated Lesions recommends the adjunctive use of p16 immunohistochemistry (IHC) in cervical biopsies to support diagnosis of Cervical Intraepithelial Neoplasia (CIN), which in some cases progresses to cervical cancer. However, evaluation of p16 expression is subjective. Development of automation that can quantify p16 expression in biopsies offers efficiency, accessibility, and objectivity in guiding clinicians in their management of women with suspected cancer precursors. We sought to evaluate the performance of artificial intelligence in assessing biopsies based on level of p16 expression. Methods: 251 biopsy specimens were collected from women with abnormal cervical cytology screening. These biopsies underwent p16 IHC and evaluation by a pathologist and were used to train and validate an initial deep-learning algorithm. After epithelial segmentation and p16 quantification, different thresholds of p16 expression were evaluated and correlated with disease status. Results: A threshold of 15 or more segments that demonstrate p16-staining in 70% or greater of the vertical extension of the epithelium produced a sensitivity of 82.26% and a specificity of 86.00% in identifying CIN2 or more pathogenic lesions. Conclusions: Current efforts are being made to further refine the algorithm and select the optimal threshold of p16 expression that correctly identifies CIN2+ biopsies. Artificial intelligence provides a reliable and promising avenue in the assessment of cervical biopsies, especially in low-resource settings where there is not ready access to pathologists and cervical cancer is a more prevalent phenomenon.Item Exosomal Proteins as Potential Markers for Breast Cancer Disparity(2022) Kandukuri, Prathima; Sankpal, UmeshPURPOSE: Breast cancer is the most common non-cutaneous malignancy and the second most lethal form of cancer among women in the United States. However, the mortality differs among different races, with Black women having significantly higher mortality rates than White women, even when factors like socioeconomic status are controlled. One explanation for this is the fact that Black women are diagnosed at higher rates with a particularly aggressive subtype known as triple-negative breast cancer (TNBC), which lacks the receptors that chemotherapy drugs classically target. It is important to recognize the various biological factors that contribute towards this health disparity. The overarching goal of this research is to identify differentially expressed exosomal proteins as potential makers to understand this disparity. Proteins under investigation include anti-apoptotic proteins and transcription factors. The specific goal for this project is to optimize protocol for exosome isolation and characterization. METHODS: MDA-MB-231 and MDA-MB-468 metastatic TNBC cell lines were cultured in media supplemented with exosome-depleted serum. After 24h, the culture media was centrifuged to remove cell debris and processed for exosome isolation using ExoQuick-TC kit (System Biosciences). The protocol involves precipitation of exosomes using the ExoQuick reagent. The exosomal pellet was resuspended in PBS and used for Western blot to analyze proteins and Nanoparticle Tracking Analysis (NTA) for determining exosomes size and concentration. The NTA calculates the size of the particles based on their movement. For Western blotting the antibodies used were against standard exosomal markers. RESULTS: Western blot analysis for exosomes showed that all samples were positive for standard exosomal protein markers such as Flotillin, CD54 and EpCAM and negative for non-exosomal marker GM130. The average size of the exosomes isolated from the MDA-MB-231 and MDA-MB-468 were 147.8 nm, and 146.6 nm respectively as determined by NTA. The concentration of exosomes from the two cells lines was determined to be 3.01e+8 ± 7.96e+6 particles/mL for MDA231 and 1.61e+8 ± 8.35e+6 particles/mL for MDA468. CONCLUSIONS: This research project streamlined a method to isolate and characterize exosomes from TNBC cell lines using the ExoQuick kit. The next step would be to isolate exosomes from a panel of breast cancer cell-lines as well from serum or plasma derived from White and Black breast cancer patients. Exosomes from these racial groups will be probed to investigate the differential expression of any potential biomarker. Such markers can be developed into novel diagnostic tools or as potential therapeutic targets, which will help clarify and reduce the current mortality gap between the two populations.Item One-Pot Synthesis of Novel 2-Imino-5-Arylidine-Thiazolidine Analogues and Evaluation of Their Anti-Proliferative Activity against MCF7 Breast Cancer Cell Line(2022) Iskander, Amany; Aziz, MarianAn efficient surface-mediated synthetic method to facilitate access to a novel class of thiazolidines is described. The rationale behind the design of the targeted thiazolidines was to prepare stable thiazolidine analogues and evaluate their anti-proliferative activity against a breast cancer cell line (MCF7). Most of the synthesized analogues exhibited increased potency ranging from 2-15-fold higher compared to the standard reference, cisplatin. The most active thiazolidines contain a halogenated or electron withdrawing group attached to the N-phenyl ring of exocyclic 2-imino group. However, combination of the two substituents did not enhance the activity. The anti-proliferative activity was measured in terms of IC50 values using an MTT assay.Item Molecular Tumor Boards in Pediatric Oncology: An Argument for a Multidisciplinary Approach(2022) Liu, Angela; Vicenzi, Paige; Sharma, Ishna; Teller, Christa; Koentz, Micha; Trinkman, Heidi; Vallance, Kelly; Ray, AnishPurpose: Although precision oncology has been shown to improve patient outcomes, it remains challenging to apply results from molecular tumor profiles to clinical decision making, since accurate interpretation of these complex molecular findings requires expertise from various fields of medicine. To aid in interpretation of increasingly complex biomarkers, molecular tumor boards (MTBs) have been established across the nation. This study provides a convincing argument for a multidisciplinary approach toward MTBs. Methods: Molecular profiling of tumor specimens was accomplished through Foundation One Medicine, Inc. to detect genomic alterations in DNA and RNA, microsatellite status, tumor mutation burden (TMB), and programmed death ligand-1 (PDL-1) expression. Cases were evaluated by a multidisclipinary MTB consisting of pediatric oncologists, pathologists, clinical pharmacists, geneticists, and nurse coordinators. If targetable mutations were present, clinical pharmacists led in weighing treatment options and exploring the logistics and feasibility of drug access. Results: From March 2016 to September 2021, 115 cases were evaluated by the MTB. In 85% of cases, the MTB recommended targeted therapy based on evaluation of patient history and genetic alterations detected by Foundation One testing. Treatable alterations most frequently occurred in the cell cycle/DNA processing pathway, specifically involving the genes TP53 (21, 11%) and MLL (21, 11%). The MTB was able to provide treatment recommendations based on detected genomic mutations for the majority of cases. However, only three patients received MTB-recommended targeted therapy, one of whom experienced improved clinical outcomes. Conclusion: The most common reason that MTB-recommended treatment was not administered was that the molecular profiling was not performed until late disease stages. For the three patients who received MTB-recommended therapy, it was not administered until months after diagnosis, demonstrating a deviation from MTB recommendations in favor of physician preference. Educating providers on demonstrated clinical benefit of molecular-matched precision therapy may increase acceptance of these novel targetable therapies, improving patient survival and quality of life.Item Surveying the mental health of adolescent and young adult cancer survivors with treatment derived late effects(2022) Mitchell, William A.; Howe-Martin, Laura; Orlino, Angela; Jetelina, Katelyn; Berry, Emily; Argenbright, KeithPurpose: Survival has steadily improved for adolescent and young adult (AYA) cancer survivors over the last 25 years, yet more information is still needed to understand the unique challenges facing AYA cancer survivors resulting from the development late effects due to treatment, and how it may impact mental health in this population. As an example, occurrence of cardiotoxicity, one of the most severe treatment-based side effects, could be expected to have a larger impact on mental health than less severe side effects, like peripheral neuropathy, osteopenia, or gonadal dysfunction. Our aim is to describe the impact of these late effects on patient mental health using semi-structured interviews completed with patients receiving care through the After the Cancer Experience (ACE) program at Children's Medical Center in Dallas. Methods: English-speaking patients who were between 15 and 55 years of age with a documented diagnosis of cancer treatment related late effect, were eligible to participate in the study. To date, three patients have completed the necessary study questionnaires, including the Personal Health Questionnaire - 9 (PHQ-9) for depression, Generalized Anxiety Disorder Scale (GAD-7), Quality of Life Patient/Cancer Survivor Version (QOL-CSV), and the Healthcare System Distrust Scale, and the corresponding semi-structured interview. Results: Participants were primarily female (n = 2) and the average age at diagnosis was 16 years. At time of study participation, patient age ranged from 24 to 52 years. All participants received chemotherapy as their primary course of treatment, with two of three also undergoing surgery as part of their treatment plan. Late effect diagnoses include peripheral neuropathy, foot drop, and cardiotoxicity. Conclusion: AYA cancer survivors have a unique set of circumstances when diagnosed with cancer specific to their age demographic. This population is receiving a cancer diagnosis during an integral time of forming individual identity and social growth. The challenging themes highlighted in these patient interviews include identity formation and need for social and emotional independence, some of the most impactful challenges in the AYA population; these findings are consistent with literature. While prior societal norms and structural challenges previously made addressing mental health difficult, patients now seem to have greater access to mental health resources, including consistent therapy, which appears to have lessened the impact of a subsequent late effect diagnosis on the patient's overall mental health. These interviews highlight the importance of individually tailored multimodal care to address the unique needs and distinct circumstances specific to this age demographic. Specifically, neglecting mental health during treatment, can trigger previously unrecognized or repressed emotions to resurface with the emergence of a diagnosis related to cancer treatment, whereas, the early detection of mental health concerns in cancer patients may not only address the immediate mental health needs, but also better equip a patient to maintain long term positive mental health when faced with subsequent challenges and diagnoses related to cancer treatment.Item MIEN1 derived peptides exhibit anti-cancer activities by inhibiting the key pathways viz. epithelial-mesenchymal transition (EMT) and NF-kB signaling in MDA-MB-231 breast Cancer Cells(2022) Tripathi, Amit K.; Desai, Priyanka; Vishwanatha, JamboorPurpose MIEN1 is a tumor-specific target protein that promotes cancer cell migration and invasion. MIEN1 is overexpressed in human breast, prostate, colorectal, gastric, ovarian, squamous cell carcinoma and non-small cell lung cancer (NSCLC) with minimal or no expression in normal cells, which makes it an excellent therapeutic target The overall goal of this project is to identify small inhibitory or interference peptides (iPeps) from the native MIEN1 protein, which could achieve the high selectivity for the native MIEN1 protein as well as being able to enter cells and inhibit the intracellular targets Methods Online tools like CASTp server were used to identify pockets or empty concavities on the MIEN1 protein surface into which solvent and other potential inhibitory molecules can gain access. Peptides were designed from the primary sequence of MIEN1 protein using various biophysical parameters and peptide designing tools such as AntiCp and Cancer PPD. Chimera program was used to check if these peptides can bind to MIEN1 protein. The peptides were synthesized and correct molecular weights were ascertained. Biological experiments like MTT and scratch assays were performed. RT-PCR was done to check the ability of the small inhibitory or interference peptides (iPeps) to inhibit the key pathways like the epithelial-mesenchymal transition (EMT) by which epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells. Western blot experiments were done to study the inhibition of the NFκB signaling pathway which is involved extensively in cancer development and progression. To show the specificity of these peptides for MIEN1 protein, circular dichroism (CD) experiments were performed. Results Two peptides designed based on MIEN1 protein sequence showed inhibition of MDA-MB-231 breast cancer cell proliferation in the MTT assay. Wound healing and transwell invasion assays show that these peptides inhibited the migration and invasion of MDA-MB-231 cells in a dose-dependent manner. RT-PCR results showed that the key molecules of epithelial-mesenchymal transition (EMT) were inhibited which can inhibit the migratory capacities of the cells. The nuclear translocation of p50 and p65 subunits of NFκB were also inhibited. The bio-active peptides attained a β-sheet structure in MIEN1 protein environment, in the circular dichroism (CD) experiments indicating the specific interaction with MIEN1 protein while the non-active peptides remained random coiled. Conclusions This work is the first report of the inhibitors designed for targeting MIEN1 protein. The peptides inhibitors were able to inhibit the key epithelial-to-mesenchymal transition transcription factors (EMT-TFs) like SNAIL, SLUG and TWIST1 which play a vital role in the metastatic process of breast cancer. Besides this the also downregulated nuclear factor-κB (NF-κB) activation. By inhibiting these two key processes aggressiveness and metastatic potential of MDA-MB-231 breast cancer cells were decreased.Item Targeted delivery of α-Mangostin to Prostate Cancer Cells Utilizing Reconstituted High-Density Lipoprotein Nanoparticles(2022) Kapic, Ammar; Dossou, Akpedje; Lacko, Andras G.; Sabnis, Nirupama; Petty, Roland; Fudala, RafalPurpose: Androgen deprivation therapy remains the primary treatment for inhibiting the progression of prostate cancer (PCa). However, depletion of systemic androgens enhances the development of androgen independence resulting in the highly malignant castration-resistant phenotype. Interest has grown in utilizing cell cycle checkpoint inhibitors to induce cellular arrest and apoptosis. A natural compound, α-Mangostin, possesses selective anti-cancer effects against PCa by inhibiting CDK4-CyclinD complex activity, thus restricting the progression of the cell cycle. However, the employment of α-Mangostin as a chemotherapeutic is limited due to its poor oral bioavailability and hydrophobicity, making delivery difficult. Reconstituted High-Density Lipoproteins nanoparticles (rHDL-NPs) are biocompatible targeted nanoparticles capable of encapsulating various compounds. Drug delivery is mediated through a non-endocytic mechanism via the Scavenger Receptor Class B Type-1 (SR-B1). Significant overexpression of SR-B1 has been documented in PCa, which enhances cholesterol accumulation thus fuels growth, proliferation, and intertumoral androgen synthesis. This increased expression of the SR-B1 makes it a primary target for the rHDL-NPs. Because of its lipophilic characteristics, we hypothesize that the α-Mangostin can be successfully encapsulated in the rHDL-NPs, retain its biological effects, and be delivered via the SR-B1. Methods: The rHDL formulations were prepared using a modified protocol utilizing sodium cholate and sonication. The physical characteristics of the rHDL were determined using Dynamic Light Scattering (DLS), which include the polydispersity index (PDI) Zeta Potential particle diameter. The absorbance of the samples was measured using a spectrophotometer for the concentration of α-Mangostin and used to calculate the encapsulation efficiency. The anisotropy was calculated to compare the degree of molecular rotation between the free and encapsulated drug. The fluorescence lifetime (FLT) was used to detect changes in the local environment of the drug. Cytotoxicity studies were conducted using three cell lines: PZ-HPV as the normal cell line, DU145, and 22RV1 as the PCa cell lines. Different concentrations of free and rHDL encapsulated α-Mangostin were administered to 2D cell cultures to determine if there was a difference in cytotoxicity. Vehicle and empty particles were used as controls. A CCK-8 assay was used to determine the cell viability after administering the treatments. Results: The rHDL nanoparticles were produced to meet the standards of the NIH criteria for lipid-based nanoparticles. The drug was found in the same fraction as the rHDL, with an average encapsulation efficiency of 55%. There was a significant increase in anisotropy when compared to the free drug. The FLT decreased by more than half. The drug loading study found the maximum amount of drug encapsulated without decreasing the particle quality. Finally, the α-Mangostin rHDL-NPs continued to produce a cytotoxic effect comparable to the free drug. Conclusion: This study produced and characterized a stable α-Mangostin rHDL-NP formulation. The changes in the anisotropy and FLT suggest that encapsulation of the α-Mangostin has occurred. Furthermore, the encapsulation of the α-Mangostin did not block the cytotoxic effects against the PCa cell lines and decreased cell viability.Item Minimally Invasive Lower Anterior Resections - Better Than Open But Not All The Same(2022) Brant, Nicholson; Lim, Joseph; Apple, Drue; Stadler, Ronney; Downs, Marcus; Jeyarajah, RohanPurpose: The optimal approach for lower anterior resection (LAR) has been closely debated. The relatively new addition of the robotic approach adds a layer of complexity to this topic. The majority of the literature has compared the possible approaches 2 at a time; however, only a few studies have comprehensively compared all 3 approaches at the same time. Methods: This is a retrospective cohort study of a prospectively maintained database at a non-university tertiary care center. A total of 130 patients underwent open, laparoscopic, or robotic oncological lower anterior resection from 2014 to January 2020. Results: Statistical significance of length of stay (LOS) was noted between the three approaches (p< 0.005) with the mean LOS for open being 8.08 days, laparoscopic being 7.04 day, and robotic being 4.96 days. No statistical significance was noted for estimated blood loss, operating time, or postoperative complications including anastomotic leak, ileus, pneumonia, pulmonary embolism, surgical site infection, and urinary tract infection. Conclusions: No one particular LAR approach demonstrates superiority in regards to perioperative outcome. Post-operatively, robotic LAR has a shorter LOS and appears to be a safe alternative to open and laparoscopic LARs, further bolstering the advocacy of robotic LAR over its counterparts.