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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with over 50,000 new cases in the United States annually. Major risk factors for HNSCC include chronic smoking and/or alcohol consumption, and more recently infection with human papillomaviruses (HPVs). HNSCC comprises a diverse collection of tumors, of which the oral cavity is the most affected site. Most HNSCC patients will die within the first 30 months of disease, an abysmal statistic largely reflecting a lack of effective treatment strategies. This challenge highlights the current unmet need to identify 1) distinct molecular subgroups of HNSCC and 2) prognostic biomarkers that can inform subgroup-specific treatment plans. The Lu Lab has identified a previously unappreciated HNSCC subgroup defined by alteration in NSD1, a histone methyltransferase enzyme mutated in up to 15% of HPV- HNSCC. NSD1 has specific di-methylase activity targeting histone H3 lysine 36 (H3K36). The formation of methylated H3K36 is associated with open chromatin and transcriptional activation. There are several distinct features of NSD1-mutant HPV- HNSCC tumors, including a) increased patient smoking history and mutational burden; b) a significantly better prognosis; and c) reduced immune cell infiltration in the tumor. These correlative findings may suggest a tumor-suppressive role of NSD1, yet the impact of NSD1-loss in HNSCC pathogenesis and the underlying mechanisms remain unclear. The scope of my thesis work aims to address this gap in knowledge through investigating the consequences of impaired NSD1 in normal epithelial tissue and in the setting of HNSCC tumors. In Chapter 2, we employed both a syngeneic tumor implantation model and a physiologic mouse model of HNSCC carcinogenesis to establish and characterize Nsd1-KO tumors. We found that mice harboring Nsd1-KO tumors are comparatively immune- ‘cold,’ a phenotype that persisted in human HNSCC patient samples. Our in vitro data suggests that depletion of NSD1 epigenetically silences the interferon response, an effect that was rescued through inhibition of epigenetic machinery that limits NSD1-deposited H3K36me2. These studies provide novel insight into the molecular underpinnings of observed immune-‘coldness’ in NSD1-mutated HNSCC. They also prompted us to probe the impact of NSD1-loss at early stages of tumor development. In Chapter 3, I describe a lingual-derived organoid system to assess unbiased transcriptional changes that occur upon Nsd1-loss during homeostasis, premalignancy, and overt tumor formation. Interestingly, we found that Nsd1-KO organoids harvested from stages preceding HNSCC featured downregulation in gene expression related to epithelial barrier formation and wound healing. Furthermore, organoids derived from Nsd1-KO tumors showed reduced expression of epithelial-to-mesenchymal transition (EMT) signature genes, potentially signifying a role of NSD1 in modulating cell adhesion and mobility. Several additional studies are needed to establish the functional basis of how NSD1 participates in these processes. Taken together, this body of work expands upon our current understanding of NSD1-loss in HNSCC development and presents a conceptual scaffold framing NSD1 as a multi-faceted player in the homeostatic maintenance and neoplastic events of the oral epithelium.

MicroRNAs (miRNAs) function as key regulators in immune responses and cancer development. In the contexts of infection with oncogenic viruses, miRNAs are engaged in viral persistence, latency establishment and maintenance, and oncogenesis. In this review, we summarize the potential roles and mechanisms of viral and cellular miRNAs in the host-pathogen interactions during infection with selected tumor viruses and HIV, which include (i) repressing viral replication and facilitating latency establishment by targeting viral transcripts, (ii) evading innate and adaptive immune responses via toll-like receptors, RIG-I-like receptors, T-cell receptor, and B-cell receptor pathways by targeting signaling molecules such as TRAF6, IRAK1, IKKε, and MyD88, as well as downstream targets including regulatory cytokines such as tumor necrosis factor α, interferon γ, interleukin 10, and transforming growth factor β, (iii) antagonizing intrinsic and extrinsic apoptosis pathways by targeting pro-apoptotic or anti-apoptotic gene transcripts such as the Bcl-2 family and caspase-3, (iv) modulating cell proliferation and survival through regulation of the Wnt, PI3K/Akt, Erk/MAPK, and Jak/STAT signaling pathways, as well as the signaling pathways triggered by viral oncoproteins such as Epstein-Barr Virus LMP1, by targeting Wnt-inhibiting factor 1, SHIP, pTEN, and SOCSs, and (v) regulating cell cycle progression by targeting cell cycle inhibitors such as p21/WAF1 and p27/KIP1. Further elucidation of the interaction between miRNAs and these key biological events will facilitate our understanding of the pathogenesis of viral latency and oncogenesis and may lead to the identification of miRNAs as novel targets for developing new therapeutic or preventive interventions.

Primary gastrointestinal lymphoma is the most common type of extra-nodal lymphoma, representing about 30-50% of all extra-nodal involvement. The stomach is the most common site, with the colon and rectum accounting for a minority of occurrences. Primary colorectal lymphoma is uncommon, representing only 0.3% of all large intestinal malignancies and approximately 3% of GI lymphomas with the majority of these being B-cell non-Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL) being the most common subtype. We present a case of an 85-year-old male who presented with symptoms suggestive of bowel obstruction, who after further evaluation was diagnosed with primary non-Hodgkin lymphoma of the colon, DLBCL subtype.

One of the most pressing global health concerns is the impact of cancer, which remains a leading cause of death worldwide. The timeliness of detection and diagnosis is critical to maximizing the chances of successful treatment. Radiomics is an emerging medical imaging analysis proposed, which refers to the high-throughput extraction of a large number of image features. Radiomics generally refers to the use of CT, PET, MRI or Ultrasound imaging as input data, extracting expressive features from massive image-based data, and then using machine learning or statistical models for quantitative analysis and prediction of disease. Feature reduction is very critical in Radiomics as a large number of quantitative features can have redundant characteristics not necessarily important in the analysis process. Due to the immense features obtained from radiological images, the main objective of our research is the application of machine learning techniques to reduce the number of dimensions, thereby rendering the data more manageable. Radiomics involves several steps including: Imaging, segmentation, feature extraction, and analysis. Extracted features can be categorized in the description of tumor gray histograms, shape, texture features, and the tumor location and surrounding tissue. For this research, a large-scale CT dataset for Lung cancer diagnosis (Lung- PET-CT-Dx) which was collected by scholars from Medical University in Harbin in China is used to illustrate the dimension reduction techniques, which is a main part of radiomics process, via R, SAS and Python. The proposed reduction and analysis techniques in our research will entail; Principal Component Analysis, Clustering analysis (Hierarchical Clustering and K-means), and Manifold-based algorithms (Isometric Feature Mapping (ISOMAP).

Myelodysplastic syndrome (MDS) is a group of clonal bone marrow disorders characterized by bone marrow dysplasia with myeloblasts <20%, typically seen in older patients. MDS has a significant risk of transformation to Acute Myeloid Leukemia (AML). We report a case of MDS transformed to AML, with sustained Complete Remission and incomplete count recovery (CRi) with treatment. A 78-year-old male with a 2-year history of leukopenia had a workup including bone marrow biopsy (BMBX) revealing intermediate- risk MDS with 13% blasts (Refractory Anemia Excess Blasts II), deletion 20 on cytogenetics and normal MDS FISH panel. He was categorized as revised IPSS score 4.5 on risk stratification. Patient initiated treatment with hypomethylating agent Azacytidine with subsequent improved BMBX with 7% blasts. He continued Azacytidine with dose reductions due to cytopenia only to develop 14% blasts on another follow up BMBX. He continued successful treatment for over 3 years before developing with 40-50% CD 34+/CD117+ blasts in the bone marrow consistent with transformation to AML. He commenced salvage treatment with Venetoclax and full dose Azacytidine as advanced age and performance status precluded transplant options. Repeat BMBX 4 weeks following Venetoclax showed hypocellular marrow, blasts percentage less than 2% indicating a CRi. Two other subsequent marrow exams have demonstrated sustained CRi twelve months after transformation with continued Venetoclax and Azacytidine administration. Around 30% of MDS patients eventually transform to secondary AML. Azacytidine therapy has significantly improved survival and time to AML transformation in intermediate-2 and high-risk MDS patients. Venetoclax, a BCL-2 inhibitor, in treating AML. Based on the results of the VIALE-A trial, the incidence of CR (complete remission) was higher around 36.7% with Azacytidine-Venetoclax (A-V) compared to 17.9% with Azacytidine. The composite CR (CR+ Cri) was higher in the A-V group, 66.4% compared to 28.3% with Azacytidine group. The median overall survival was 14.7 months in the A-V group compared to 9.6 months in the Azacytidine group. Our patient achieved a CRi with A-V treatment and has demonstrated a durable response beyond 16 months in secondary AML which has a bleak prognosis indicating the promise of this new combination treatment.

We describe a patient who developed hemolysis and methemoglobinemia due to rasburicase (RBU) and was found to have glucose-6-phosphate dehydrogenase (G6PD) deficiency. This is a rare clinical scenario that provides valuable insight into complex diagnosis and management of these life-threatening complications. A 59-year-old male presented to the VA Medical Center with 11 days of epigastric abdominal pain radiating to the back and flank, associated with bloating and lower extremity edema. He was transferred to our facility for percutaneous nephrostomy tube (PCN) placement for renal dysfunction (creatinine 5.5). Computed tomography (CT) scan of the abdomen and pelvis revealed 17 cm retroperitoneal mass engulfing major vessels, involving right renal hilum and ureter with moderate-severe right hydronephrosis. CT guided biopsy of the mass showed intermediate-large malignant cells that were CD20, CD23, BCL2 and BCL6 positive; CD10 and MUM1 negative. Fluorescent in-situ hybridization resulted after discharge to reveal no MYC rearrangement, confirming a diagnosis of diffuse large B-cell lymphoma. Positron-emission tomography CT revealed extensive retroperitoneal lymphadenopathy with pelvic extension into internal and external iliac vessels, encasing aorta, inferior vena cava and anteriorly displacing pancreas and bowel and contiguous involvement of the right kidney with hypermetabolic activity. Moderate right sided pleural effusion was also seen. Creatinine improved with PCN. Uric acid was 10.3 with lactate dehydrogenase (LDH) 953. The patient received RBU for tumor lysis syndrome (TLS). However, pulse oximetry showed an oxygen saturation of 70-80%, though the patient had only mild dyspnea. CT pulmonary embolism (CTPE) showed segmental PE. Therapeutic lovenox was initiated. He underwent thoracentesis with symptomatic improvement but continued to desaturate on pulse oximetry. Arterial blood gas on 100% oxygen via non-rebreather revealed methemoglobin of 4.5% without hypoxemia. LDH worsened to 1668 with low haptoglobin and direct hyperbilirubinemia, suggestive of hemolysis. G6PD was deficient at 0.8 U/g. Treatment was conservative with cautious use of red cell transfusions and supplemental oxygen. Due to hyperbilirubinemia, chemotherapy was started with dose-adjusted etoposide, prednisone, oncovin, cyclophosphamide, and rituximab - with adriamycin withheld upfront. As hemolysis improved the patient received dose-reduced adriamycin. RBU is a recombinant urate oxidase used in managing TLS. It converts uric acid to allantoin, producing hydrogen peroxide, which oxidizes hemoglobin to methemoglobin. G6PD deficiency decreases cellular ability to reduce glutathione and thus detoxify hydrogen peroxide. This causes life-threatening methemoglobinemia and hemolysis. Methylene blue is contraindicated due to the risk of worsening hemolysis in G6PD deficiency. Methemoglobinemia is typically treated in such cases with exchange transfusion or hyperbaric oxygen therapy.

Rhabdomyosarcomas (RMS) are the most common type of soft tissue neoplasm in children. They typically arise from primitive skeletal muscle and are usually observed in either the head and neck or the genitourinary region. We report a rare case of an embryonal rhabdomyosarcoma lung malignancy and a formulated histopathological process to differentiate these lesions from its main differentials. We aim to bring attention to this case in an effort to assist physicians in making the correct diagnosis, should they be presented with a similar case. Here we present a case of a 56-year-old female with a past medical history of COPD and a 30-pack-year smoking history who was referred to a Regional Cancer Center clinic due to newly diagnosed lung cancer. The patient presented with anorexia, weight loss, cough, dyspnea for two months, and a 30-pound weight loss over the last month. CTA of the chest on 7/26/2021 revealed a 14 cm confluent mass extending throughout the mediastinum and the left hilum with associated narrowing of the left-sided pulmonary arteries and bronchi consistent with neoplasia. Several cavitary nodules in the left lung are present, consistent with metastatic disease. CT-guided biopsy on 8/2/2021 revealed a high-grade neoplasm with neuroendocrine features, and frequent mitotic figures, and tumor necrosis. Immunohistochemical staining was positive for synaptophysin, and CD56. Negative stains include cytokeratin TTF-1, AE1/AE3, CAM 5.2, CK 34 beta E12, CK5/6, CK7, CK20, p40, mart 1, SOX10 and CD45. The patient was then diagnosed with pulmonary embryonal rhabdomyosarcoma. In this case report the patient was diagnosed with pulmonary embryonal rhabdomyosarcoma, which characteristically has cells that show variable degrees of skeletal muscle differentiation with spindled morphology and differentiated rhabdomyoblasts. Desmin, myoD1, and myogenin are the key immunohistochemical stains that should be utilized to confirm the suspected diagnosis of a RMS. The staining pattern varies between different RMS subtypes, as the pulmonary subtype staining pattern is more focal compared to the others which tend to stain diffusely. CD56 staining can also be used to identify an alveolar RMS, however, is nonspecific. In this patient's case, CD56 was positive but the FISH analysis confirmed embryonal RMS as the final diagnosis. Previous studies have indicated that RMS can metastasize to the lung, thus this strain can prove to be a useful tool in rare cases such as this one, where the etiology of the cancer is unclear but has progressed to the lung. This unique case report highlights the diagnostic approach and aims to provide a differential diagnosis for a pulmonary embryonal rhabdomyosarcoma as well as an effective workup. Future research into the origin of the pulmonary embryonal rhabdomyosarcoma is indicated to provide comprehensive treatment for the patient and further understand the pathophysiology of the disease discussed.

<p>miRNAs therapeutics have emerged as a potential cancer therapeutics due to their unique ability to target multiple genes, allowing a single miRNA to act as a multi-drug cocktail. However, toxicity associated with current delivery vehicles as well as the sensitivity of the miRNA to serum nucleases are critical hurdles that stand against their clinical utility. Ligand-targeted delivery approaches such as small molecules, aptamers, antibodies or glycoconjugates provide a promising strategy to achieve specific delivery of the therapeutic cargo to the intended targeted cells without any toxicity. We hypothesized that combining both ligand targeted approach along with modifying the miRNA would provide a perfect delivery system which does not only achieve specific delivery but also reduce the therapeutic dose. The data presented in this dissertation shows (i) that miR-34a delivered using a combination of targeting ligand (DUPA) and an endosomal escape agent (nigericin) enables selective delivery of miR-34a to prostate cancer cells, (ii) that the use of full chemical modification approach enhances miR-34a stability and activity both in vitro and in vivo. Overall, these results provide an advancement in the miRNA delivery field and will help the development of miRNA based therapeutics against cancer.</p>

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