No description available.

Diagnosis of two distinct malignant entities existing concurrently and at the same location (synchronous malignancy) by fine-needle aspiration (FNA) is unusual but may occur. Small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) in particular is associated with an increased incidence of secondary tumor, likely due to associated immunodeficiency. Co-occurrence of some carcinomas such as squamous cell carcinoma (SCC), may show especially aggressive behavior. A 57-year-old Caucasian male presented with recurrent upper extremity lymphedema and diffuse lymphadenopathy ofthe axillary and cervical regions. FNA ofa large cervical lymph node was diagnostic for both atypical lymphocytic proliferation and SCC. Flow cytometric analysis showed the atypical lymphocytic proliferation to be positive for CD5, CD23, CD19, CD20, HLA-DR, CD38, and the population was kappa light chain restricted. These cells were negative for CD-10 and FMC-7 antigens, suggesting a phenotype of B-cell SLL/CLL. We report a rare occurrence of metastatic SCC to a lymph node infiltrated by SLL/CLL. The diagnosis was achieved by a combination of cytomorphologic examination of FNA smears, immunohistochemical staining of cell block material, and flow cytometry on the sample obtained by FNA. To the best of our knowledge, only three cases of SCC metastasis to SLL/CLL diagnosed by FNA have been reported in the English literature. Though rare, awareness of such a possibility and careful cytological examination under the appropriate clinical conditions is warranted.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21417号 / 医博第4407号 / 京都大学大学院医学研究科医学専攻 / (主査)教授 羽賀 博典, 教授 小川 誠司, 教授 万代 昌紀 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医科学) / 甲第21699号 / 医科博第103号 / 新制||医科||7(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 妹尾 浩, 教授 渡邊 直樹, 教授 松原 和夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Early investigations of the urokinase type plasminogen activator (uPA) receptor (uPAR) and its ligand, uPA, were limited to their role in degradation of the extracellular matrix (ECM) and invasion. Emerging evidence revealed that uPAR and its relationship with uPA and/or transmembrane proteins, such as the integrins, affects cell-ECM adhesion events and proliferation. These events are tightly coordinated and essential for epithelial tissue development. However, unregulated expression of molecules involved in cell adhesion and proliferation plays a significant role in tumour development and metastasis. The overexpression of uPAR is linked to several cancer types, including human oesophageal squamous cell carcinoma (HOSCC). This study examines the contribution of uPAR, and its communication with extracellular components, to cell-ECM adhesion and/or proliferation of HOSCC cells. The confirmation of the uPAR and 1-integrin expression as well as uPA secretion in the HOSCC cells lines, established these lines as excellent models for further investigation. In all the HOSCC cell lines, uPAR associated with integrin-linked kinase, a scaffolding protein in cell-ECM adhesion events. Data presented in this investigation confirmed that the interaction of uPAR with uPA or 1-integrin contributed to adhesion of the HOSCC cell lines on collagen type I and vitronectin. It was clearly established that uPAR also played a part in the proliferation of all the HOSCC cell lines. The uPAR role in proliferation is influenced by: a) The absence or presence of collagen type I or vitronectin substrates; b) The activation of uPAR by endogenous uPA; c) The uPAR/1-integrin interaction; d) the presence of transforming growth factor  and epidermal growth factor. In the current study, it was successfully demonstrated that uPAR, and its relationship with the ECM and growth factors, contributes to adhesion and proliferation during the progression of HOSCC. This gives uPAR a considerable value as a therapeutic target for HOSCC.

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.

We report two cases of combined cutaneous tumors composed of melanoma and carcinoma. The first tumor presented as a 5-mm pink-blue macule over the right zygomatic arch in an 85-year-old man. Shave biopsy and immunohistochemical studies revealed that the tumor was composed of melanoma (highlighted by SOX10 and MART-1, with high Ki-67 proliferative index) intermixed with nodular basal cell carcinoma (highlighted by pan-cytokeratin and Ber-EP4). The neoplastic melanocytes were confined to the basal cell carcinoma nodules, and a diagnosis of combined melanoma in situ and basal cell carcinoma was rendered. After therapeutic excision, the patient was disease-free at 9 months after the initial diagnosis. The second tumor presented as a 6-mm pink-brown crusted papule on the right forehead in an 89-year-old man. Shave biopsy and immunohistochemical studies revealed that the tumor was composed of malignant melanoma (MM) (highlighted by S100 and MART-1) intermixed with squamous cell carcinoma (SCC) (highlighted by cytokeratin and p63), and a diagnosis of combined MM-SCC was rendered. These two cases highlight the importance of recognizing these rare types of melanocytic-epithelial cutaneous neoplasms to arrive at an accurate diagnosis that may inform appropriate disease stage and therapy.

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.