Oral squamous cell carcinoma (OSCC), or oral cancer, accounts for the majority of head and neck cancers. Resistance to therapy is a challenge, and 5-year survival rate remains at ~50 percent. Lysine-specific demethylase 1 (LSD1) plays a crucial role in controlling cell homeostasis in health and disease. LSD1 is elevated in oral cancer and promotes metastasis and correlates with poor prognosis. LSD1 is a nuclear histone demethylase that has been implicated in maintaining the undifferentiated state of cancer-initiating stem cells and promoting OSCC. Large dataset analysis showed that genetic alterations, including upregulation of LSD1, are seen in clinical cancers including OSCC. This study aims to evaluate the unknown mechanism of LSD1 and determine if pharmacologic inhibition of LSD1 has preventative and/or therapeutic applications for OSCC. This study used the 4NQO mouse model to induce OSCC in mice and split the mice into 8 treatment groups. Each group received a different immunotherapy treatment (SP2509, Verteporfin, anti PD-1 and anti PD-L1 alone and in combination). Our results have shown that LSD1 inhibition reduces the development of gross pathologic lesions. LSD1 inhibition has also shown to cause differences in gene expression in preneoplasia and OSCC, attenuating many genes that are part of the pro-oncogenic gene network (LSD1, YAP, EGFR), immune checkpoints (PD-1 and PD-L1), and Hippo signaling effectors (YAP, TAZ). Interestingly, LSD1 has shown a role in regulating the immune microenvironment and promoting antitumor immunity, which led us to investigate LSD1 in combination with immune checkpoint antibodies (anti PD-1 and anti PD-L1). Our results show that LSD1 sensitizes to anti-PD-1 and anti-PD-L1 antibodies to treat mouse tongue OSCC. Thus, we showed for the first time that blocking LSD1 inhibits preneoplasia and OSCC feed-forward loop, which could have implications in OSCC prevention, chemo- and immunotherapeutic combinations.

Fibrillary glomerulonephritis (FGN) is a rare disease identified in less than one percent of native kidney biopsy. FGN is characterized by hematuria, edema, renal insufficiency, and high-grade proteinuria. Renal biopsy results typically demonstrate deposition of randomly-arranged fibrils within the capillary wall or mesangium. Positive staining with DnaJ Heat Shock Protein Family Member B9 (DNAJB9) is considered diagnostic. Associations include malignancy, hepatitis C, dysproteinemia, autoimmune disorders, and diabetes mellitus. To our knowledge, this is the first case demonstrating association between fibrillary glomerulonephritis and vulvar squamous cell carcinoma. A 66-year-old year old Caucasian female presented to the emergency department for worsening renal injury. She was diagnosed with vulvar squamous cell carcinoma 5 years prior and underwent radical excision with inguinal lymphadenectomy and CO2 laser treatment. Over the years, she had multiple relapses and received wide local excision and adjuvant radiation, with the last treatment involving radiation being 2.5 years before admission. The patient had a recently identified non-malignant vulvar lesion at the time of admission, which was found to be lichen sclerosus et atrophicus. She was found to have renal dysfunction and nephrotic range proteinuria; her creatinine was 2.84 mg/dL (normal range 0.60–1.10 mg/dL), BUN 33 mg/dL (normal range 6–20 mg/dL), urine protein:creatinine ratio 3.9 mg/g (normal range < 0.15 mg/g). She was started on pulse dose methylprednisolone of 500 mg daily, but her creatinine worsened, necessitating renal biopsy. Renal biopsy findings indicated mesangial expansion and randomly-arranged non-branching fibril deposition. Glomerular immunofluorescence indicated positive staining for IgA, IgG, and DNAJB9. These findings confirmed the diagnosis of fibrillary glomerulonephritis. Screening for associations – coexistent malignancies, hepatitis C, multiple myeloma, and autoimmune disorders – was negative. The patient was started on rituximab and prednisone therapy after confirming the absence of underlying infection. One month after initial hospitalization, she was re-hospitalized for worsening kidney function and required initiation of dialysis, on which she remains dependent. FGN is rapidly progressing and results in end-stage-renal-disease within two years in 50% of individuals. It should be considered as a differential diagnosis in patients with a history of malignancy, especially vulvar squamous cell carcinoma. There is no definitive treatment for FGN. Rituximab can be used in conjunction with steroid therapy, but further research is needed to determine the proper treatment for FGN at various stages of disease manifestation. The original case is published in Cureus, and permission has been received to present this case.

Purpose: Cancers of the sinonasal tract are rare, comprise a diverse group of histologies and are known for their poor prognostic outcomes. The primary aim of this study was to evaluate the 2- and 5-year overall survival (OS) rates in patients treated with radical and palliative intent for sinonasal squamous cell carcinoma (SNSCC). Methods: A retrospective review of medical records of all patients presenting to Cape Town's Groote Schuur Hospital between January 2003 and December 2013 was carried out. All patients with histologically proven squamous cell carcinoma (SCC) of the maxillary sinus and nasoethmoidal complex who underwent treatment at Groote Schuur Hospital and/or iThemba LABS (Laboratory for Accelerator Based Sciences) were included. Fifty-five patients with cancers of the sinonasal tract were identified from the electronic patient system; 23 were excluded either because of different histologies, lack of histology or having initiated treatment outside of Groote Schuur Hospital. The medical records of 32 patients were utilised for final analysis. 2- and 5-year OS was calculated using Kaplan-Meier analysis. Results: The majority (75%) of patients had an ECOG performance status of 1 with facial asymmetry secondary to tumour mass or swelling being the most common presenting symptom (present in 68,75% of cases). 62,50% of cases originated within the maxillary antrum and 56,25% of cases were classified as keratinizing SCC. Twenty-six (81,25%) patients presented with stage IV disease; nodal disease was seen in 13 (40,63%) patients and distant metastasis in 4 (12,50%) patients. Most patients underwent palliative intent treatment with only 11 (34,38%) having radical treatment. The cumulative 2- and 5-year OS from the date of treatment initiation was 26% and 19% respectively. Median OS for the entire cohort was 7,7 months and was statistically significant between intent groups at 5,19 months (95% CI:3.43– 6.95) for palliative compared to 35,45 months (95% CI: 0.00–138.52) for radical patients (c2 = 7.80, p = 0.005). Conclusion: Despite a decline in incidence of disease over the last 30 years and the improved diagnostic and therapeutic modalities available today, the prognosis and survival outcomes for SNSCC remains poor.

Estimates for 2017 indicate that 20% of cancers globally are gastrointestinal tract (GIT) cancers, with oesophageal cancer being the 8th most common cancer. Oesophageal squamous cell carcinoma (OSCC) occurs in the upper to mid oesophagus and is present at high incidence in developing countries including South Africa. There are no early symptoms, resulting in late diagnosis and poor prognosis. In this study, tumour and blood DNA was obtained from 35 OSCC patients and subjected to whole genome sequencing (WGS). Bioinformatics analysis pipelines were designed to identify the possibility of novel viral insertions, investigating Human Endogenous Retroviruses (HERV's) insertions alongside the presence of somatic mutations in patient samples. The aims being to identify integration of any foreign DNA, to investigate if there is any linkage between HERV insertion and somatic mutations, and to identify any somatic mutations of potential interest in the OSCC cohort. The novel virus investigations however, proved to be inconclusive and there appeared to be no link between HERV insertions and somatic mutations present in the patients. Very significantly, it was determined that numerous somatic mutations were present in the MUC3A gene of the patient cohort, an interesting observation as no such previous association with OSCC has been recorded. MUC3A is a membrane-bound glycoprotein component of mucous gels, and its aberrant expression has been correlated with invasion and metastasis in a variety of other cancers. However, due to the complexity of the particular gene sequence and the known inconsistencies of variant calling performed on complex data sets, these mutations should be viewed with extreme caution as they are likely to be false positives. Analysis of RNA-seq data showed a 4.6 log2 fold increase in MUC3A expression in the tumour samples of these OSCC patients, with a P-adjusted value of 7.05e-06, suggesting highly significant differential gene expression. Functional enrichment analysis further showed that MUC3A was significantly associated with one of the top 5 gene ontologies (extracellular matrix structural constituent) for molecular function ontology class together with a number of collagen (COL) and MMP genes known to play a role in oncogenic progression and membrane stiffness. GSEA and KEGG analysis indicated predominantly chemokine/cytokine pro-inflammatory enriched pathways. Immunohistochemistry staining showed 10 out of 13 of the samples had no detectable levels of MUC3A protein, suggesting that the production of a non-functional truncated protein may lead to the upregulation of MUC3A expression that could possibly play a role in downstream pro-oncogenic signalling.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24840号 / 医博第5008号 / 新制||医||1068(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 藤田, 恭之, 教授 松田, 道行, 教授 柳田, 素子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Cancer is a major cause of morbidity and mortality with increasing incidence worldwide. Early detection of cancers and better treatments would improve the outcome for patients. The overall 5-year survival rates of head and neck squamous cell carcinoma have not improved in the past several decades due to diagnosis at advanced stages and recurrent disease. Early detection and improved chemotherapy drugs are two key areas that are required to help to improve the prognosis for this disease. This thesis focuses on the enzyme telomerase which is known to contribute to one of the hallmarks of cancer (immortality). Elevated telomerase activity has been observed in the majority of cancer cells but not in most normal human cells so there is an opportunity to use telomerase as a biomarker for disease. This first part of this study assessed telomerase activity in saliva and tissues of head and neck squamous cell cancer patients. The Telomerase PCR-ELISA kit was used to assess telomerase activity in the saliva of patients with confirmed oral carcinomas and its expression was analysed in paraffin embedded tissue using immunohistochemistry (IHC). Whilst telomerase was detected in cell lines, no telomerase activity was detected in saliva samples from patients but was detectable in IHC specimens. The second part of the study focused on the pharmacological evaluation of a series of small molecule G–quadruplex DNA binding agents as potential telomerase inhibitors. A total of 19 telomerase inhibitors were identified but of these, only 4 were specific inhibitors of telomerase. These compounds also caused toxicity to cell lines following a 2 hour drug exposure at doses that also inhibit telomerase activity. Further studies are required to explore these compounds further. In conclusion, the results of this study have demonstrated that detection of telomerase activity I the saliva of patients with oral cancers is unlikely to be useful in terms of detecting oral cancers before symptoms of the disease are clinically manifest. A series of novel and specific inhibitors of telomerase have been identified and further studies are required to develop these compounds further.

Squamous cell carcinoma (SCC), the most common oral neoplasm of cats, demonstrates aggressive local invasion and has a poor prognosis. In humans, mutation of the p53 gene, crucial in cell cycle arrest and induction of apoptosis in damaged cells, is common in neoplasms. Survivin, an inhibitor of apoptosis, is frequently overexpressed in many types of human cancer. Studies suggest that wild-type p53 inhibits survivin expression, while mutated p53 does not. The purposes of this study included immunohistochemical examination of survivin and p53 expression in feline oral SCC and determination of a correlation between p53 mutation and survivin overexpression, as well as comparison with survival time. Survivin expression was noted in 80% (24/30) of cases, while 43.3% (13/30) of cases were positive for p53. No statistically significant correlation was noted between p53 and survivin expression, even when corrected for age, breed, and sex; and survival time was not affected.

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