Cancer

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/30804

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3D TUMOR MODELING TO IMPROVE BIOMARKER IDENTIFICATION AND CANCER OUTCOMES.
(2022) Mylabathula, Preteesh Leo; Ranade, Payal; Trivedi, Rucha; Vishwanatha, Jamboor
Purpose: Cancer-associated proteins annexina2 (ANXA2) and MIEN1 are overexpressed in various cancers including triple negative breast cancer, prostate, and colorectal cancers. Therefore, these proteins are being investigated as potential biomarkers and therapeutic targets. We will use a 3D tumor model to mimic in vivo tumor growth and evaluate changes in tumor characteristics after silencing ANXA2 and MIEN1 to understand their correlative/causal relation to tumor behavior. Methods: Ultra-low attachment 3D culture plates were used to culture tumor spheroids in breast cancer cells(MDA-MD-231) with ANXA2 knock-down using sh-RNA and colorectal cancer cells(HT29) with MIEN1 knock-out (KO) using CRISPR-Cas9. Changes in spheroid growth, migration and invasion, drug sensitivity, and immune cell killing will be evaluated. Boyden chambers with Matrigel inserts were used to evaluate migration and invasion. Spheroids were imaged using confocal microscopy for size estimation. Results: Optimal initial seeding density was 5000 cells and spheroids were grown for 7-days. Average tumor spheroid size was 1360±420µm with no differences in spheroid size with MIEN1 KO. 50% reduction in migration and invasion potential were observed after MIEN1 KO in colorectal cancer cells in a 96-hour time-course experiment. Experiments with ANXA2 knock-down are ongoing with spheroid sizes averaging 1700±260µm. Future experiments include evaluating changes in protein expression, drug sensitivity, immune cell killing as a result of knockout of MIEN1. Conclusion: We expect the results to identify functional role of cancer-associated proteins ANXA2 and MIEN1 in tumor spheroid growth, metastasis, drug sensitivity, and susceptibility to immune cell killing. Funding: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number R01CA220273 (JKV).
A Drug-Loaded Nanoparticle to Target Bone-Metastatic Prostate Cancer
(2022) Lampe, Jana B.; Desai, Priyanka; Tripathi, Amit K.; Ranjan, Amalendu; Vishwanatha, Jamboor
Treatment for localized prostate cancer (PCa) has a tremendous success rate. However, the fact that the five-year overall survival rate drops from 100% to 30.2% when tumor cells metastasize to distant sites, represents an unmet medical need. In 90% of metastatic cases, bone is the primary metastatic site. Our objective is to co-load a poly(lactic-co-glycolic) (PLGA) nanoparticle (NP) with Cabazitaxel (CBZ) and Bortezomib (BTZ) and to conjugate a bone-targeting moiety, Alendronate (ALN), to the outside of the nanoparticle to facilitate targeting to bone tumors and to ameliorate the resulting bone damage. We hypothesize that this targeted nanomedicine will affect genes and proteins that contribute to invasion and migration, anti-apoptotic signaling, and ultimately lead to tumor-cell apoptosis. Furthermore, we predict that the nano-delivery system will help ameliorate bone lesions inflicted by the tumors. Methods: Nanoparticles were engineered using an Emulsion-Diffusion-Evaporation Technique in which PLGA is dissolved in dichloromethane, 5% polyvinyl alcohol, and Bis(sulfosuccinimydyl)suberate (BS3) crosslinker. For targeting, Alendronate (ALN) is later conjugated to the outside of the nanoparticle via this crosslinker. Results: Our average NP size was around 240 nm in diameter, a PDI of < 0.2, with a Zeta Potential (ZP) of -28 mV. Our drug loading capacity (DL) for CBZ was 11.97% and for BTZ 0.9%. Encapsulation efficiency (EE) for CBZ was 25.26% and 8.9% for BTZ. The IC50 for the CBZ NPs is 5.6 nM and BTZ NPs is 15.6 nM. We have successfully shown that the gene expression for various migration and invasion markers as well as cell signaling proteins have been affected by the nanoparticles. Conclusions: Our nanoparticles have a desirable size, PDI, ZP, DL, and EE for our intended therapeutic purpose. Furthermore, we have shown alterations in the cell signaling and gene expression responsible for Epithelial-to-Mesenchymal Transition-Transcription Factors (EMT-TFs), indicating that our nanotherapeutic has significant potential to treat metastatic PCa and to mitigate the damage done by metastatic tumors.
A NEW ERA: TARGETED THERAPY FOR RECURRENT GLOMUS TUMOR
(2022) Faisal, Annum; Ray, Anish
Background: 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.
A Novel Method to Characterize Invasive Ductal Carcinoma Tumor Biopsies Using Contact Angle Measurements
(2022) Rincon, Julio; Mishra, Ina; Kastellorizios, Michail
Purpose: The goal of this work is to develop a preclinical method to characterize human breast cancer biopsies of different racial origin. Contact angle measurements are used to assess the biopsies' surface properties and examine possible correlation with race/ethnicity, tumor type, and cancer grade. This method enables us to study differences in interaction of drugs directly in tumor tissues based on available covariate data of the obtained samples. Here, we present a study of 80 invasive ductal carcinoma tumor samples compared against their matching normal and/or cancer adjacent tissues. Methods: To obtain contact angles of tumor tissues, we developed a contact angle instrument capable of delivering a ~45 nL drop on top of a 1.5 mm biopsy using a modified goniometer with added custom components (DataPhysics Instruments USA Corp.). The system allows us to measure contact angles from 3 different positions (0°, -45°, 90°), and viewing the tumor tissue through an inverted microscope to determine drop position and quality. For this study, breast cancer tissues were obtained as tumor micro arrays (TMA) and as FFPE tissues with matching normal adjacent tissue. For TMA slides, two drops per tissue were delivered and the test was repeated with a subsequent section of the same TMA, unless the TMA included duplicate cores. For FFPE samples, tissues were processed with a microtome at a thickness of 15 µm, a minimum of 6 drops were delivered per tissue. Results: Aggregated data showed normal adjacent tissue (NAT) had an average contact angle (CA) of 51.4° ± 6.5° n=19, cancer adjacent tissue (CAT) had an average CA of 62.8° ± 8° n=59, grade 1 tumors had an average CA of 71.1° ± 7° n=13, grade 2 tumors had an average CA of 67.4 ± 9.1° n=49, and grade 3 tumors had an average CA of 64.6° ± 10.3° n=11. When comparing normal adjacent tissue against any other tissue, p-values ≤ 0.05 and power ≥ 0.80 were observed. When comparing cancer adjacent tissue, only CAT vs NAT and CAT vs grade 2 tumors had p-values ≤ 0.05 and power ≥ 0.80. Individually, 37 cases reached p-values ≤ 0.05 and power ≥ 0.80, were tumor tissue showed contact angles greater than their NAT or CAT. An additional 7 cases met p-values ≤ 0.05 and power ≥ 0.80, however, tumor contact angles were lower than their NAT or CAT. Finally, ignoring type 2 errors, then an additional 11 cases reached p-values ≤ 0.05. Conclusions: Higher contact angles of deionized water were observed in tumor tissues when compared to matching normal or cancer adjacent tissue. It is clear that breast cancer tumors exhibit surface energy differences from normal adjacent tissues, with cancer tissue being more hydrophobic compared to normal tissue. Future work includes the determination of contact angles of Doxil-like liposomes in these tumors and the determination of surface energy of the tissues.
Adrenal Incidentaloma in a 72-year-old Male with History of Prior Exploratory Laparotomy
(2022) Burgon, Mackay
Background: Adrenal incidentalomas are adrenal masses greater than 1 centimeter in diameter that have been found unexpectedly on radiographic imaging. Theses incidentalomas are found on 2.3% of abdominal radiographic images. The differential diagnosis of an adrenal mass is broad and includes adenoma, myelolipoma, cyst, lipoma, pheochromocytoma, adrenal cancer, metastatic cancer, hyperplasia, and tuberculosis. Case information: A 72-year-old Caucasian male presents for evaluation of a left adrenal mass that has increased in size over the past year. The mass was found on a CT scan showing a left adrenal mass with heterogenous enhancements with small low-density areas that could be cystic or necrotic. The patient did not present with any signs or symptoms. The patient has a history of hyperlipidemia, diabetes mellitus, hypertension, and is a hepatitis C carrier. He has allergies to penicillin, does not drink, and has a 10-pack year smoking history despite quitting 5 years ago. The patient's labs show elevated glucose at 137, elevated hemoglobin A1c at 5.8 and a decreased HDL at 37. All his other labs were within normal limits. He has a surgical history of exploratory laparotomy for a perforated gastric ulcer, appendectomy, and right finger amputation. A 24-hour urine study was done to measure the patients total metanephrines. His total metanephrine level was 305 mcg/24 hours which is in the normal range for the patient's age. Due to the increasing size a robotic left adrenalectomy was the treatment decided upon between the patient and physician. The increased risk of conversion to an open operation due to prior exploratory laparotomy was thoroughly discussed. Due to difficulty dissection, visual impediment, and proximity of the mass to the splenic artery and vein, the procedure is converted to an open surgery. The pathology report for the left adrenal mass reveals a 7 by 4.5 by 4 cm lesion positive for pheochromocytoma. The mass stains positive for chromogranin, synaptophysin and pancytokeratin while staining negative for GATA 3, inhibin and S100. The mass also shows a high potential for malignancy with 2+ periadrenal adipose tissue, 2+ necrosis, 2+ cellular spindling, 1+ capsular invasion, and 1+ vascular invasion. Conclusion: This patient and his case illustrate a distinct presentation of pheochromocytoma in an atypical age group, with no accompanying signs or symptoms.
An unusual presentation of metastatic colorectal cancer mimicking cholangiocarcinoma
(2022) Thompson, Mallory; Mantry, Parvez; Mejia, Alejandro; Dyrved, Neils-Jorgen
Background: 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.
ASPARAGINASE ASSOCIATED INTRA-CARDIAC THROMBUS PRESENTING AS SEPSIS IN AN ADOLESCENT PATIENT DURING ALL INDUCTION THERAPY
(2022) Wu, Kylie; Hamby, Tyler; Mohamed, Ashraf
Background: 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.
Association of Specificity Proteins with Hepatocellular Carcinoma Patients Survival
(2022) Iloani, Nwamaka Amy; Dulemba, Victoria; Hafeez, Areeba; Bao, Serena; Basha, Riyaz
Presenter: Nwamaka Amy C. Iloani Authors: Nwamaka Iloani, Victoria Dulemba, Areeba Hafeez, Serena Bao and Riyaz Basha Title: Association of Specificity Proteins with Hepatocellular Carcinoma Patients Survival Background: Liver cancer is one of the most diagnosed cancers worldwide and ranks third in cancer mortality, leading to over 700,000 deaths per year. Of these liver cancers, the most common is hepatocellular carcinoma (HCC), accounting for nearly 80% of all liver cancer diagnoses. Since the current treatment options have limited improvement in prognosis over the years, identifying novel targets to induce therapeutic efficacy and reduce resistance to current therapeutic option is urgently needed. Specificity protein (Sp) transcription factors Sp1 and Sp3 are associated with incidences and poor prognosis of several cancers. Sp1 is implicated in the development and metastasis of HCC by binding to GC-rich sequences of the promoter region. Sp1 influences genetic transcription of the oncogenes encoding for the HCC by binding to gene regions such as RING1 and YY1 Binding Protein (RYBP), Ras guanine nucleotide-releasing protein 1 (RasGRP1) and many others to regulate their genetic expression. Sp3 works in a similar fashion and binds to GC and GT rich sequences in regulatory genes to affect HCC cell expression. The objective of this study is to ascertain the association of Sp1 and Sp3 expression with the survival of HCC patients using publicly available data bases. Method: Information regarding the expression levels of Sp1, Sp3, RYBP, RasGRP1 and Kaplain-Meier curves were obtained from accessing the data in the public data basses, R2 genomics visualization platform and The Cancer Genome Atlas (TCG). These data used to assess the probabilities of HCC patients with high vs low expression of Sp1 or Sp3. Results: The analysis of these data indicated significant findings. When comparing normal liver cell lines and HCC cell lines, HCC cell lines showed increased expression of both Sp1 and Sp3. The high expression of Sp1 or Sp3 is associated with decreased probability and chance of survival in comparison to individuals with decreased expression (Sp1: p< 0.027; Sp3: p< 0.0087). The survival curves of RYBP and RasGRP1 also following similar patten, however the relevance to Sp1 and Sp3 has higher impact and poor prognosis. Conclusion: Higher expressions of Sp1 and Sp3 are typically associated with poorer patient survival rates. These results suggest that the therapeutic interventions that focus on targeting Sp1, Sp3 and their downstream mechanisms have the chance for impeding HCC tumorigenesis. We are investigating the association of Sp1 and Sp3 regulated oncogenes with HCC. Investigational agents with inhibitory effect against Sp1 and Sp3 are also currently being tested against HCC proliferation. 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.
Automated evaluation of p16 immunohistochemistry for diagnosis of cervical precancer
(2022) Tao, Amy; Wentzensen, Nicolas; Clarke, Megan; Darragh, Teresa; Miranda, Felipe; Grabe, Niels; Lahrmann, Bernd
Purpose: 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.
Case Report: Patient with 3 Gastric Cancers Simultaneously (Adenocarcionma, NET, GIST)
(2022) Jacobs, Benjamin; Ali, Arsalan; Logarajah, Shankar; Jeyarajah, Rohan
Background: 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.
Celiac Plexus Neurolysis: An Underutilized Palliative Therapy
(2022) Oh, James; Smith, Scott
Background: 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.
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.
Exosomal Proteins as Potential Markers for Breast Cancer Disparity
(2022) Kandukuri, Prathima; Sankpal, Umesh
PURPOSE: 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.
HIV-1 Nef-mediated acceleration of HPV-associated cancer through differential ubiquitination of cellular proteins
(2022) Park, Inwoo
While the emergence of combination anti-retroviral therapy (cART) has reduced AIDS-defining cancer in individuals with HIV-1, the morbidity and mortality of non-AIDS defining cancers such as those caused by HPV remain high. However, the molecular mechanism by which coinfection of HIV-1 and HPV accelerates HPV-mediated cancer in coinfected individuals is unknown, as they infect distinct target cells using disparate receptor molecules. Our transduction experiment using pseudotyped HIV-1 indicates that HIV-1 cannot enter HeLa cells, human cervical cells, suggesting that viral protein generated by infected cells, not HIV-1 infection, may be responsible for accelerating HPV-associated cancer in coinfected individuals. Specifically, our study shows that HIV-1 Nef could be the major culprit. Proteomic analysis in the presence or absence of Nef indicated that ubiquitination was up-regulated in 93 cellular proteins and down-regulated in 232, highlighting that Nef plays a key role in regulating cellular protein stability through ubiquitination and the UPS-mediated proteasomal degradation pathway. Western blot analysis demonstrated that differential ubiquitination was not caused by differential protein expression, validating our analyses. Computational analysis classified the majority of identified proteins as metabolite interconversion enzymes or nucleic acid metabolism proteins, with most being responsible for binding or catalytic activity, functioning in cellular and metabolic processes, and localizing to cellular anatomical entities and intracellular regions. Additionally, several proteins directly interact with Nef (23), the UPS (15), P53 (28), and E6, E6-BP, and E6-AP (1 each). Taken together, our data show that HIV-1 Nef plays a pivotal role in acceleration of HPV-mediated cancer progression in coinfectees.
Incidental finding of gallbladder adenocarcinoma in the 2nd trimester of an otherwise healthy pregnant woman.
(2022) Cushen, Spencer; Logarajah, Shankar; Kabbani, Wareef; Osman, Houssam; Jeyarajah, Rohan
Background Pregnancy causes an increased production of steroid sex-hormones resulting in more cholesterol laden bile and decreased gallbladder emptying. This results in greater incidence of gallbladder disease in pregnant women with 10% of pregnant women developing gallstones or sludge and a further 1% of these developing symptomatic disease. In addition to simple gallstone disease, multiple pregnancies increase the risk of gallbladder in cancer. In this Case Report, we present what is, to our knowledge, the first report of incidental gallbladder adenocarcinoma in an otherwise healthy pregnant woman. Case Presentation A 36-year-old woman presented to the emergency department with right upper quadrant abdominal pain at 16 weeks of gestation. A clinical picture of acute cholecystitis was developed and confirmed by ultrasound demonstrating sonographic Murphy's sign, gallbladder containing gallstones, 2 mm thick gallbladder wall, and pericholecystic fluid. This patient then underwent laparoscopic cholecystectomy. Routine pathologic assessment of the gallbladder demonstrated a 3.9 cm calculus, 2.5 cm wide high-grade dysplasia, and a 1.0 cm invasive, moderately differentiated adenocarcinoma. This malignant lesion extended through the wall of the gallbladder, giving it a tumor classification of pT2a. The patient was then referred to the hepatopancreaticobiliary (HPB) surgery service for completion of an extended cholecystectomy as indicated to stage the cancer and remove additional disease. After this surgery no lymph nodes, cystic duct margins, or liver sections collected for pathology demonstrated malignancy, giving the final TNM classification of pT2aN0M0R0, Stage IIA. On 6 month follow up patient had received chemotherapy and was free of evidence of malignancy on MRI. Conclusions To our knowledge this is only the second case report demonstrating a pregnant woman being diagnosed with gallbladder cancer. In the other report, the woman had Crohn's disease and gallbladder changes consistent with Crohn's disease. Therefore, this is the first presentation of an otherwise healthy pregnant woman being incidentally diagnosed with gallbladder cancer after acute gallstone disease. This report adds to the current understanding of pregnancy induced gallstone disease by providing a rare end point to such disease processes.
Intraparenchymal Brainstem Schwannomas in Pediatric Patients: Two Unusual Case Reports
(2022) Deville, Haley; Cope-Yokoyama, Sandy; Bosemani, Madhan; Zhao, Sibo
Background: 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.
Investigational Agents to Target Specificity Protein1 Transcription Factor and Survivin for Inhibiting Medulloblastoma Cells Growth
(2022) Bao, Serena; Kishinchandani, Sachi; Lambring, Christoffer B.; Basha, Riyaz; Sankpal, Umesh; Nwamaka, Iloani
Abstract Presenter: Serena Bao Authors: Serena Bao, Sachi Kishinchandani, Briggs Lambring, Umesh Sankpal, Iloani Nwamaka, Riyaz Basha Title: Investigational Agents to Target Specificity Protein1 Transcription Factor and Survivin for Inhibiting Medulloblastoma Cells Growth Background: Medulloblastoma (MB) is a brain cancer predominantly arising in children. It accounts for 20% of all childhood brain tumors. The treatment for MB includes a combination of surgery and radiation therapy. Although around 70% of the patients have shown remission with treatment today, these therapies are associated with significant morbidity, especially in the youngest patients. Therefore, widespread interest is shown to develop more successful treatments. One potential target of cancer treatment is a protein known as survivin. Survivin inhibits cell death and is upregulated in most cancers, including MB. A transcription factor known as Sp1 upregulates survivin by binding to its promoter region. Therefore, suppressing Sp1 activities indirectly down-regulates survivin and can serve as a target for MB therapy. Our aim is to find and test appropriate investigational agents that inhibit Sp1, thereby inhibit survivin and cancer cell growth. In addition, we want to use an in silico analysis to determine the expression of Specificity protein1 (Sp1) and survivin in MB patients, and see how it correlates with the survival of these patients. It has been previously determined that the investigational agents Tolfenamic acid (TA) and its derivative copper-tolfenamic acid (CuTA) are effective at inhibiting Sp1 in some cancer cells. In this project, we investigated the growth inhibitory effect of TA and CuTA using DAOY cell line. Method: DAOY cell lines (purchased from a commercial source, American Type Culture Collection, Manassas, Virginia; IBC-2016-0038) were cultured and seeded (2,000 cells per well) in a 96 well plate. Cells were treated using increasing concentrations (0, 10, 20, 40, 80 µM) of TA or Cu-TA. After a 48-hour incubation, the viability of the sample was measured via a luminance assay using the CellTiterGlo. Dose curves were generated, and the dose required to inhibit 50% of the viability (IC50 value) was determined using Graphpad Prism Software. Data from the R2 genomics visualization platform was used to generate Kaplain-Meier curves. The presented curves compare survival probabilities in Medulloblastoma patients with high vs. low expression of Sp1 and survivin. Results: The in silico analyses using R2 genomics visualization platform demonstrated MB patients who express higher levels of Sp1 is associated with low survival time(p = 0.033). Similarly, MB patients with higher levels of survivin expression show poor prognosis (p = 0.049) As per the IC50 values, Cu-TA is 3.6 times more effective against MB cells without affecting non-cancerous cells than TA Conclusion: Higher expression of Sp1 or survivin is associated with low survival time in medulloblastoma patients. Both TA and Cu-TA are inhibiting DAOY cell growth, however, Cu-Ta is more effective than TA against MB cell line. With increased resistance to standard therapies, TA and Cu-TA potentially enhance the therapeutic efficacy of chemotherapy and radiation.
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, Usha
OBJECTIVES: 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.
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, Jamboor
Purpose 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.
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, Rohan
Purpose: 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.

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