Introduction: Testicular microlithiasis is an uncommon condition characterized by calcifications within the seminiferous tubules. The true prevalence in a normal population has not been defined. Methods: A review of the literature with emphasis on the connection between testicular microlithiasis and testicular malignancy was carried out. Results: Testicular microlithiasis is associated with different testicular pathologies, including testicular cancer. However, a direct causative connection between testicular microlithiasis and testicular pathologies is not supported by the literature. Conclusions: Patients with testicular microlithiasis should be followed up regularly. Further investigations concerning the etiology of testicular microlithiasis remain to be done. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Skeletal metastasis is a lethal component of many advanced cancers including prostate, the second most common cancer among men. Patients whose prostate cancer is localized and detected early benefit from multiple treatment options ranging from active surveillance to radiation and surgery, resulting in a 5-year survival rate of nearly 100%. Unfortunately, the prognosis and survival for patients with advanced metastatic disease is much worse due to the highly aggressive nature of the disease and a paucity of treatment options. Understanding the mechanisms and interactions that occur between metastatic cancer cells and the bone will enable the future treatment landscape for bone metastatic prostate cancer to expand, thereby improving patient outcomes. Our current knowledge of how metastatic prostate cancer cells interact with the bone is summarized in a model known as the “vicious cycle.” Numerous fundamental vicious cycle factors have been identified, including parathyroid hormone-related protein (PTHrP), while additional elements, such as matrix metalloproteinases (MMPs), are progressively being discovered and added to the model. PTHrP is a critical regulator of bone resorption and augments osteolysis in skeletal malignancies. In Chapter 2, we report that the mature PTHrP1-36 hormone is processed by MMPs to yield a stable product, PTHrP1-17. PTHrP1-17 retains the ability to signal through PTH1R to induce calcium flux and ERK phosphorylation but not cyclic AMP production or CREB phosphorylation. Notably, PTHrP1-17 promotes osteoblast migration and mineralization in vitro, and systemic administration of PTHrP1-17 augments ectopic bone formation in vivo. Further, in contrast to PTHrP1-36, PTHrP1-17 does not affect osteoclast formation/function in vitro or in vivo. Finally, immunoprecipitation-mass spectrometry analyses using PTHrP1-17-specific antibodies establish that PTHrP1-17 is indeed generated by cancer cells. Thus, MMP-directed processing of PTHrP disables the osteolytic functions of the mature hormone to promote osteogenesis, indicating important roles for this mechanism in bone remodeling in normal and disease contexts. MMPs have traditionally been associated with cancer progression based on their extracellular matrix degrading activities. However, it has become evident that their regulation of non-extracellular matrix substrates can exert both contributive and protective effects during tumorigenesis. Previous studies of matrix metalloproteinase-3 (MMP-3) have demonstrated tissue dependent pro- and anti-tumorigenic effects, but despite elevated expression, its roles have not been explored in bone metastatic prostate cancer. In Chapter 3, we show that tumor-derived MMP-3 contributes to prostate tumor growth in bone. In vitro, we observe that silencing MMP-3 reduces prostate cancer cell proliferation. Further, we found increased levels of IGFBP3, a known MMP-3 substrate, and decreased IGF-1R, ERK, and AKT phosphorylation in the MMP-3 silenced cells. Notably, we also observe reduced tumor growth and proliferation in in vivo intratibial models when tumor-derived MMP-3 expression is silenced. These data suggest that increased MMP-3 expression by prostate cancer cells contributes to their proliferation in bone by regulating the activity of the IGF/IGF-1R signaling axis. Taken together, our studies indicate that MMPs possess important functional roles in bone metastatic prostate cancer. We believe that elucidation of these mechanisms and their contributions to the vicious cycle of bone metastasis will offer novel opportunities to design effective therapeutic treatment options.

>Magister Scientiae - MSc / Aim: The aim of this study was to report on the frequency of and radiographic features of non-odontogenic malignancies of the jaws as seen on panoramic images, stored in the radiological achieves over an eleven year period.

Spirocerca lupi is a nematode that infects the dog’s oesophagus and promotes the formation of an inflammatory fibroblastic nodule that progresses to sarcoma in approximately 25% of cases. Differentiating neoplastic from non-neoplastic cases ante-mortally is challenging and has major therapeutic and prognostic implications. More importantly, spirocercosis-associated oesophageal sarcoma is an excellent and under-utilized spontaneous model of parasite-associated malignancy and the pathogenesis of the neoplastic transformation is poorly understood. The current study objective was to investigate potential clinical, clinicopathological, radiological and tissue biomarkers for the malignant transformation and an attempt to use these biomarkers to gain a deeper understanding of the pathogenesis of the neoplastic transformation. Our central hypothesis was that the parasite produces excretory product(s) which diverts the immune response from a T helper 1 (Th1) to Th2 cell response, typical of many nematode infections, and further to an immunoregulatory (immunosuppressive), FoxP3+ regulatory T cell-predominated response which then facilitates neoplastic transformation. The following parameters were studied and compared between cases with non-neoplastic and neoplastic spirocercosis: clinical presentation, haematology, serum albumin and globulin, thoracic radiology, haematoxylin-eosin (H&E) histology, Immunohistochemistry for expression of vascular endothelial growth factor (VEGF)-A, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), MAC387 (myeloid cells), CD3 (T cells), Pax5 (B cells) and FoxP3 (T regulatory cells) and plasma cytokine concentrations including IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, GM-CSF and MCP-1. Hypertrophic osteopathy showed 100% specificity for neoplastic transformation but relatively poor sensitivity (40%). Female gender, anaemia, leukocytosis, thrombocytosis, spondylitis and bronchial displacement were significantly more common in neoplastic cases, but appeared in non-neoplastic cases as well. The H&E study revealed 2 stages in the non-neoplastic nodules: early inflammation, characterized by fibrocytes and abundant collagen, and a pre-neoplastic stage, characterized by activated fibroblasts and reduced collagen. The neoplastic cases were all sarcomas, primarily osteosarcoma with very aggressive features comparable to other appendicular osteosarcoma in the dog. The inflammation in spirocercosis is characterized by pockets of pus (MAC387+ cells) surrounded by organized lymphoid foci (CD3+ and to a lesser degree Pax5+ cells). There was no evidence of a local accumulation of FoxP3+ cells, unlike many previous studies which have reported an increase in Foxp3+ T cells in both malignancies and parasite infections. Interleukin-8 plasma concentration was higher in the neoplastic group compared to the non-neoplastic and the control groups. Interleukin-18 concentration was higher in the non-neoplastic group followed by the control group and finally the neoplastic group. As with most similar studies, no ideal biomarker with high sensitivity and specificity was identified. However, if examined together, a panel of the biomarkers that were identified more commonly in the neoplastic cases should substantially increase the index of suspicion for neoplastic transformation in a diagnosed spirocercosis case. The inflammatory response showed features of increased myeloid (innate) response and lymphocytic response with pro-inflammatory cytokines. This was not our initial hypothesis and the question remains whether the response is secondary to the worm infection, or to a symbiotic bacterium that is carried by the worm. The role of such a reaction in neoplastic transformation remains to be elucidated. / Thesis (PhD)--University of Pretoria, 2012. / Companion Animal Clinical Studies / unrestricted

Case Report: Krukenberg tumor is a metastatic adenocarcinoma of the ovary that classically arises from the gastrointestinal tract, most often as a metastasis from the stomach as the primary origin, followed by colon. Krukenberg tumors are very rare malignant tumors of the ovary, only accounting for 1-2% of all ovarian malignancies. They tend to present with bilateral involvement. The most common presenting symptoms are abdominal pain, distention, and ascites, secondary to the large ovarian masses. Postmenopausal vaginal bleeding is a rare presenting symptom of a Krukenberg tumor. The diagnosis is commonly delayed until late in the disease progression. We present a case of a 77-year-old woman with stage IV metastatic adenocarcinoma of lower GI with mesenteric involvement and pulmonary nodules. Her disease was confirmed by mesenteric mass biopsy and was histologically CK20 positive, CDX positive, and CK7 negative. She underwent eighteen rounds of palliative chemotherapy with oral capecitabine (Xeloda) over the course of fifteen months. Sixteen months after the initial diagnosis, imaging uncovered a new cystic pelvic mass measuring 15x13x12 cm, decreased mesenteric mass, increasing liver lesion, metastasis to the left adrenal gland, and minimal ascites. She has had vaginal bleeding. Patient underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy and small bowel resection by gynecological oncologist. The left ovary was involved by metastatic adenocarcinoma, 15 cm, consistent with small bowel origin. The small bowel resection showed adenocarcinoma, 3.3 cm in size with serosal invasion arising in an adenoma. Patient is planned for chemotherapy with irinotecan in palliation. Our case demonstrates a rare case of small bowel adenocarcinoma later presenting as a Krukenburg tumor.

Thesis (Ph.D. (Biochemistry)) -- University of Limpopo, 2021 / Breast cancer is the leading cause of female deaths in the world. Varying types of therapy options are available, yet these conventional treatments for the malignancy are known to have numerous side effects. Similar to other diseases, herbal remedies are being explored as alternative treatment options as well as starting points for development of new drugs to treat breast cancer. Bidens pilosa is a weed distributed throughout the world with known medicinal properties. Its anti-cancer activity has been established in various cancers. This study aimed to investigate the epigenetic patterns affected by a bioactive extract of B. pilosa in breast cancer. A crude methanol extract of B. pilosa was fractionated with n-hexane, chloroform, ethyl acetate, n-butanol, 65% methanol and water. Healing properties of plants are often an attribute of the presence of phenolic compounds within the plant and the sub-fractions of the methanol extract of B. pilosa were, therefore, assayed for these compounds. The water sub-fraction showed the highest content of total phenolic compounds, however, when the sub-fractions were analysed for the presence of two classes of specific phenolic compounds, the butanol sub-fraction boasted the highest concentration of flavonoids and tannins, affording it superior antioxidant activity in a quantitative DPPH assay. Distribution of the antioxidant compounds in TLC-DPPH analysis also supported this finding. Despite its high antioxidant compound content, cytotoxicity of the butanol sub-fraction in MCF-7 breast cancer cells was not impressive in the MTT viability assay. Treatment with varying concentrations of the chloroform sub-fraction resulted in a better dose- and time-dependent decrease in cell viability of MCF-7 cells than all the other sub-fractions as well as the crude methanol extract. Analysis of breast cancer genes affected by the chloroform sub-fraction on the Human Breast Cancer RT2 Profiler PCR array showed repression in BRCA1 and BRCA2, genes classified as tumour suppressors. Bisulfite pyrosequencing showed no significant modification in methylation of selected CpG islands within the promoter regions of both genes. Results of the array also showed decreased expression of CDH1 which is associated with invasiveness and aggression of tumours. Its investigated CpG island was also shown not to be differentially methylated by treatment of the cells with the chloroform sub-fraction of the extract. As a well-appreciated biomarker for breast cancer risk, BRCA1 protein expression was further investigated. Western blot analysis showed parallel findings to those of the PCR array, with down-regulation of BRCA1 within 24 hours of treatment of MCF-7 cells with the sub-fraction. Repression of the BRCA genes is strongly linked to arrest of cells at the G2/M phase of the cell division cycle, and this was therefore also assessed. Treatment of MCF-7 cells with the chloroform sub-fraction effected a dose-dependent accumulation of cells at the G2/M phase of the cell cycle as determined by flow cytometry. Results of global DNA methylation analysis showed an increase in chromosomal instability by a significantly reduced level of methylation of the genome. This hypomethylation also supports arrest of the cells at the G2/M phase of the cell cycle, as cells accumulate at this checkpoint, awaiting repair to prevent segregation of broken chromosomes during mitosis. However, the lack of BRCA1 suggests that repair proteins were not recruited to the sites of repair and the cells were consequently directed to apoptosis. Analysis of the effect of the chloroform sub-fraction of the methanol extract of B. pilosa in the Mitopotential assay showed an increase in the number of dead cells with depolarised mitochondrial membranes, alluding to the intrinsic mode of apoptotic cell death in MCF-7 cells treated with the sub-fraction. Down-regulation of BRCA1 is further associated with telomerase inactivation in cancer cells. Treatment of MCF-7 cells with the chloroform sub-fraction reduced telomerase activity within 24 hours of treatment, with an absence of activity following treatment with 100 and 125 μg/ml of the sub-fraction. This lack of telomerase activity resulted in shortened telomeres which limit proliferative ability of the cells. Characterisation of the six sub-fractions of the methanol extract of B. pilosa with GC-MS showed an abundance of fatty acids in the chloroform sub-fraction, specifically α-linolenic acid, palmitic acid and linoleic acid. Palmitic acid is alleged to play a role in down-regulation of BRCA1 and its abundance in this sub-fraction leads to the conclusion that palmitic acid may be responsible for the decreased expression of BRCA1 in MCF-7 breast cancer cells. The down-regulation results in hypomethylation of the genome leading to cell cycle arrest at the G2/M checkpoint and subsequent apoptosis as a result of this repression of BRCA1. Repression of BRCA1 also leads to inactivation of telomerase, inhibiting cell proliferation. Taken together, the observed antioxidant activity and pro-apoptotic potential attributed to epigenetic modifications validate B. pilosa as an anticancer agent. Our findings merit the plant for use in development of potential breast cancer drugs. / SAMRC and University of Limpopo (UL)

Patients can develop malignancies due to various reasons including genetic factors, chemical carcinogens, radiation, and defects in their immune system. The immune system is postulated to carry out routine surveillance for malignancy. Patients who have defective immune responses may be susceptible to malignancies due to complicated underlying mechanisms. These include defective immune response to cancer-causing bacteria, transforming viruses, and concomitant molecular, cellular and immunoregulatory defects. Common variable immune deficiency (CVID) is characterized by hypogammaglobulinemia, impaired antibody responses and an increased susceptibility to infections. A disorderly immune response, or immune dysregulation, may also lead to autoimmune complications and possibly to malignancy. The treatment of CVID involves infusion of replacement doses of immunoglobulin, either intravenously (IGIV) or subcutaneously (SCIG). However, it is unclear whether adequate replacement of immunoglobulins is sufficient to prevent the increased risk of malignancy seen in this disease. We present two cases of unusual solid tumors complicating CVID treated with adequate doses of intravenous immunoglobulins. In this study we review the occurrence of malignancy in patients with CVID and postulate mechanisms that may be involved indigent to this disease. We will also review the role of replacement immunoglobulin and discuss cancer screening in these high risk individuals.

No description available.

Background: Lynch syndrome is a hereditary disorder, with a very high risk of the developing colorectal cancer (CRC) and a predilection to develop other cancers, including upper tract urothelial carcinoma (UTUC) that has an estimated lifetime risk of 0.2-25%, above that of the general population. Our aim was to assess the prevalence of UTUC in a Lynch syndrome cohort undergoing screening for CRC, to determine the need for a UTUC screening program. Methodology: Lynch syndrome patients were screened with urine dipstix for microscopic haematuria. Patients with confirmed microhaematuria were offered urine cytology, microscopy and culture, ultrasound (US) of their upper tracts and flexible cystoscopy. Results: Of the 89 patients screened, 86 had an MLH1 mutation and 2 had an MSH2 mutation. Eleven of the 12 patients who had microscopic haematuria were female. 10 patients had urinary tract infections. One patient had follicular cystitis and another had a simple renal cyst. No patients had hydronephrosis on ultrasound. All urine cytology specimens were negative for malignancy. Conclusion: No cases of UTUC were detected in our cohort during this study. A more rational screening protocol in this group may be to screen patients for UTUC with known MSH2 mutations at an earlier age (over 35).

No description available.