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Deep venous thrombosis is a common and potentially life-threatening condition that is often associated with various risk factors including underlying malignancy. In this case report, we present a male patient who presented with deep venous thrombosis as the earliest presenting feature of metastatic gallbladder carcinoma. This case report emphasizes the importance of thorough evaluation of patients presenting with unprovoked deep venous thrombosis to early detection of underlying malignancy.

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Introduction. In contrast to colorectal carcinoma, the significance of tumor budding in breast carcinoma is not established. The X20 objective which is used to assess tumor budding in colorectal carcinoma, is not widely available in countries with limited resources. This study aimed to determine the prevalence of tumor budding and its associations with pathological prognostic factors in invasive breast carcinoma-no special type (IBC-NST), and to assess the correlation between the tumor budding observed using ×20 and ×40 objectives. Methods. A total of 349 excision specimens of IBC-NST were studied. Tumor budding was defined as a single cell/cluster of up to 4 cells at the invasive front and was assessed in hotspots at the advancing edge of the tumor using ×20 and ×40 objectives. Tumor budding was categorized into low (<5/0.785 mm2), intermediate (5-9/0.785 mm2), and high budding (≥10/0.785 mm2) for ×20 objective and low (≤4/0.196 mm2) and high (≥5/0.196 mm2) for ×40 objective based on the number of buds per hotspot. The association between tumor budding and prognostic factors was analyzed with Mann-Whitney U test, Kruskal-Wallis test, χ2 test, and logistic regression. Correlation between tumor budding in ×20 and ×40 objectives was analyzed with Pearson correlation test. Results. The prevalence of tumor budding was 72.5%. There was a significant correlation between the number of buddings observed in ×40 objective and ×20 objective (0.958). High tumor budding observed in both objectives was significantly associated with size (P < .001), lymphovascular invasion (P < .001), perineural invasion (P < .001), lymph node status (P < .001), number of lymph nodes (P < .001), T stage (P < .001), and N stage (P < .001) on univariate analysis, but only lymph node positivity (P < .001) showed significant association on multivariate analysis. Conclusion. Tumor budding assessed with ×20 and ×40 objectives showed a significant correlation and was significantly associated lymph node metastasis on multivariate analysis.

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BACKGROUND: Characterization of the host response in cutaneous leishmaniasis (CL) through proteome profiling has gained limited insights into leishmaniasis research compared to that of the parasite. The primary objective of this study was to comprehensively analyze the proteomic profile of the skin lesions tissues in patients with CL, by mass spectrometry, and subsequent validation of these findings through immunohistochemical methods. METHODS: Eight lesion specimens from leishmaniasis-confirmed patients and eight control skin biopsies were processed for proteomic profiling by mass spectrometry. Formalin-fixed paraffin-embedded lesion specimens from thirty patients and six control skin specimens were used for Immunohistochemistry (IHC) staining. Statistical analyses were carried out using SPSS software. The chi-square test was used to assess the association between the degree of staining for each marker and the clinical and pathological features. RESULTS: Sixty-seven proteins exhibited significant differential expression between tissues of CL lesions and healthy controls (p < 0.01), representing numerous enriched biological processes within the lesion tissue, as evident by both the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases. Among these, the integrated endoplasmic reticulum stress response (IERSR) emerges as a pathway characterized by the up-regulated proteins in CL tissues compared to healthy skin. Expression of endoplasmic reticulum (ER) stress sensors, inositol-requiring enzyme-1 (IRE1), protein kinase RNA-like ER kinase (PERK) and activating transcription factor 6 (ATF6) in lesion tissue was validated by immunohistochemistry. CONCLUSIONS: In conclusion, proteomic profiling of skin lesions carried out as a discovery phase study revealed a multitude of probable immunological and pathological mechanisms operating in patients with CL in Sri Lanka, which needs to be further elaborated using more in-depth and targeted investigations. Further research exploring the intricate interplay between ER stress and CL pathophysiology may offer promising avenues for the development of novel diagnostic tools and therapeutic strategies in combating this disease.

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Diagnosing neoplastic fever requires excluding identifiable causes, making it a diagnostic challenge. Fever as a primary manifestation of pancreatic adenocarcinoma is uncommon with few cases reported in the literature. Here we present an unusual case of metastatic pancreatic adenocarcinoma primarily manifesting as pyrexia of unknown origin. A 63-year-old Sri Lankan male, a non-smoker who was diagnosed with diabetes, hypertension and dyslipidaemia presented with a history of fever, anorexia and weight loss for 2 months. Despite the completion of treatment for positive serology for paratyphi, his symptoms and inflammatory markers remained elevated while the rest of the infectious screening was negative. On further evaluation, the patient was found to have a hypodense distal pancreas with ring-enhancing multiple liver lesions on imaging. Histology confirmed pancreatic adenocarcinoma with liver metastasis. Atypical liver metastases may present with evidence of ring enhancement in computed tomography imaging; thus, the biopsy is mandatory for diagnosis and decision-making. Usually, tumours of the pancreatic tail are resectable but if they are associated with liver metastatic disease, surgical resection is not recommended because it is not potentially curative. Therefore, in the context of metastatic pancreatic adenocarcinoma, palliative chemotherapy and pharmacological management of fever are required.

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Characterization of the host response in cutaneous leishmaniasis (CL) through proteome profiling has gained limited insights in leishmaniasis research, in comparison to that of the parasite. The primary objective of this study was to comprehensively analyze the proteomic profile of the skin lesions tissues in patients with CL, by mass spectrometry, and subsequent validation of these findings through immunohistochemical methods. Sixty-seven proteins exhibited significant differential expression between tissues of CL lesions and healthy controls (p<0.01), representing numerous enriched biological processes within the lesion tissue, as evident by both the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases. Among these, the integrated endoplasmic reticulum stress response (IERSR) emerges as a pathway characterized by the up-regulated proteins in CL tissues compared to healthy skin. Expression of endoplasmic reticulum (ER) stress sensors, inositol-requiring enzyme-1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6) in lesion tissue was validated by immunohistochemistry. In conclusion, proteomic profiling of skin lesions carried out as a discovery phase study revealed a multitude of probable immunological and pathological mechanisms operating in patients with CL in Sri Lanka, which needs to be further elaborated using more in-depth and targeted investigations.

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[This corrects the article DOI: 10.1016/j.ekir.2021.03.898.].

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BACKGROUND: The multistep molecular model of breast carcinogenesis is based on the oestrogen receptor(ER) status of the tumour. Its two main arms comprise ER-positive and ER-negative breast carcinomas(BCa), which are associated with Nottingham grade(NG) of the tumour and different proliferative epithelial changes. According to the model, columnar cell lesions(CCL), lobular carcinoma in-situ(LCIS) and atypical ductal hyperplasia(ADH), low-grade ductal carcinoma in-situ (LG-DCIS) are associated with low grade ER-positive tumours and microglandular adenosis (MGA), pleomorphic LCIS(PLCIS), high-grade DCIS(HG-DCIS) are associated with ER-negative high grade tumours. This study aims to describe the association between proliferative epithelial changes in breast tissue adjacent to tumour, in relation to the ER status and NG of the tumour. METHODS: This descriptive cross-sectional study included 420, wide local excision and mastectomy specimens of BCa from National Hospital of Sri Lanka, between 2017-2019. The histopathological features of the tumour and proliferative epithelial changes in tumour adjacent tissue within 10 mm distance from the tumour-host interface were evaluated independently by two pathologists. The ER, PR(Progesterone receptor) and HER2 status assessed by immunohistochemistry(IHC) was reviewed. The associations between above epithelial lesions and ER status and NG{categorised as low grade (NG1 and NG2) and high grade (NG3)} of the tumour were analyzed. RESULTS: ER positive BCa showed significant associations with CCH (p = 0.04), FEA (p = 0.035) and LGDCIS (p < 0.001). Although PLCIS was more frequent in ER positive tumours, the association did not attain statistical significance. ER negative BCa showed a significant association with HGDCIS (p = 0.016). CCLs as a whole (p = 0.005) and also CCC (p = 0.006) and FEA (p = 0.048) and LGDCIS (p < 0.001) showed significant associations with low NG tumours. High NG tumours showed a significant association with HGDCIS (p < 0.001). Microglandular adenosis was not identified in our study population. CONCLUSION: These morphological findings support the multistep molecular based pathogenetic pathways of breast carcinoma in the studied setting in South Asia. Identification of these proliferative epithelial components in a core biopsy that is negative for BCa, should prompt for close clinicoradiological correlation, and if necessary re-biopsy of women suspected of harbouring a BCa.

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Usual type necrosis (UN) and infarct like necrosis (ILN) occur in CRLMs. ILN is a rare form of necrosis in colorectal liver metastases which is usually seen following chemotherapy. De novo occurrence of ILN is a very rare phenomenon. ILN in CRLM without adjuvant chemotherapy following colorectal resection was not described previously. We describe the presence of complete ILN in a solitary metachronous liver metastasis from right colonic adenocarcinoma without prior chemotherapy.

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Introduction and objectives: Leishmania donovani is the causative organism of leishmaniasis in Sri Lanka. Studies on the immunopathology of leishmaniasis due to L. donovani are limited. The objective of this study was to describe the immunopathological characteristics of cutaneous leishmaniasis in a cohort of Sri Lankan patients. Methodology: Fifty skin biopsies of cutaneous leishmaniasis confirmed by detection of organisms by histology, culture, slit-skin smear, and/or polymerase chain reaction were reviewed. The inflammatory infiltrate was characterized by immunohistochemical staining for CD4, CD8, CD20, and CD68. Associations and correlations between immunohistochemical staining pattern and the parasitic load, and patterns of inflammation were determined. Results: The majority of biopsies showed a CD8+/CD4- T lymphocyte predominant infiltrate (84%, n = 42). A CD68 predominant infiltrate was seen in 16%(n = 8). The mean percentage of CD8+, CD4+, CD20+, and CD68+ inflammatory cells in the biopsies were 56.1% (SD = 16.5%), 2.6% (SD = 4.5%), 12.3% (SD = 10.9%), and 25.7% (SD = 15.8%) respectively. There was no association between the predominant inflammatory cell and the degree of inflammation (P = .173), presence of high RPI (P = .922), MRI(P = .367) or presence of granuloma (P = .247).The percentage of CD4+ cells showed a positive correlation with granuloma formation (Correlation coefficient = .411, P = .03). The percentage of CD20+ cells in the infiltrate showed a positive correlation with the degree of inflammation (Correlation coefficient = .491, P = .02) and the RPI (Correlation coefficient = .334, P = .018). Discussion and Conclusion: Skin biopsies from cutaneous leishmaniasis due to L. donovani infection showed a CD8+/CD4- predominant infiltrate. This is similar to the findings of studies on cutaneous leishmaniasis due to some other species and suggests that the cytotoxic T cell response plays a role in infections due to L. donovani.

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Introduction: Adenosquamous carcinoma (ASC) is a rare subtype of the conventional adenocarcinoma of the bile duct. The clinico-pathological characteristics of this entity are poorly understood partly due to its rarity. Case Summary: A 67-year-old ASA II male presented with obstructive jaundice subsequently complicated by cholangitis. CT abdomen showed dilatation of the intra and extrahepatic biliary tree. Endoscopic retrograde cholangiopancreatography revealed a stricture with a mucosal growth at the ampulla of Vater. He had a pancreaticoduodenectomy and the distal common bile duct tumour identified in the specimen was on histology an adenosquamous carcinoma (ASC) of the extrahepatic bile duct. Discussion: ASCs are considered to have more aggressive tumour biology compared to adenocarcinomas. The presence of a squamous component at the invasive front relates to its poor prognosis. Surgery is the curative option, but with a high propensity for early recurrence and distant metastases. The scarcity of reports on the clinicopathological course of ASC have resulted in a lack of standardised care pathways. Conclusion: A better understanding of the clinicopathological characteristics, biological behaviour and disease progression of ASC will aid therapeutic options and prognostication.

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Giant cell urothelial carcinoma is a rare variant of bladder cancer recognized by the current World Health Organization classification of urologic tumours. It is an aggressive tumour with a poor prognosis that usually presents at an advanced stage. It is characterized histologically by pleomorphic giant cells. We discuss a case of giant cell urothelial carcinoma presenting at an early stage in a previously well 62-year-old woman. Histology showed a tumour comprising pancytokeratin positive bizarre mononuclear and multi-nuclear giant cells admixed with areas of conventional urothelial carcinoma and carcinoma in situ. Three-month follow-up cystoscopy and magnetic resonance imaging showed no evidence of recurrence or pelvic lymphadenopathy.

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INTRODUCTION: Despite much research on chronic kidney disease of uncertain etiology (CKDu) in Sri Lanka and the Mesoamerican nephropathy, the etiology and pathogenesis of this disease remains elusive. The pathology has broadly been described as chronic tubulointerstitial nephritis and no specific signature lesions have been identified. METHODS: A scoping review was conducted through MEDLINE and Google Scholar databases for peer-reviewed publications on biopsy studies related to CKDu - Sri Lanka and Mesoamerican nephropathy to develop a comparative and critical analysis of the renal pathology found in these patients. RESULTS: Thirteen studies met the selection criteria. Interstitial fibrosis was the predominant lesion in all the studies. Tubulointerstitial and glomerular abnormalities showed a more variable distribution. No characteristic histopathological feature was reported other than a proximal tubular lysosomal inclusion body which was claimed to indicate a toxic etiology. Three main pathogenetic mechanisms were postulated: repeated acute insults leading to scarring, low-grade chronic insults leading to non-inflammatory fibrosis, and tubulointerstitial damage in combination with glomerular injury. The main limitations in the interpretation and comparative analysis of these studies were the heterogeneity in case selection and biopsy reporting. CONCLUSIONS: Although no characteristic histopathological feature could be found in CKDu-Sri Lanka or Mesoamerican nephropathy, there are noticeable differences between these two groups in the frequency and severity of the glomerular and tubulointerstitial changes which warrant more explorative studies preferably on kidneys in early stages of the disease. Future strategies should ensure that more uniform selection criteria and reporting methods are used.

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BACKGROUND: Androgen receptor (AR) expression is emerging as a prognostic biomarker in breast carcinoma (BCa). The study aimed to determine the prevalence of AR expression by immunohistochemical analysis among a cohort of Sri Lankan women with early BCa and to evaluate its association with clinicopathological features including immunohistochemical molecular subtype and early survival. METHOD: We studied the clinical and pathological features and immunohistochemical profile of 141 women undergoing primary surgery for early BCa, followed by standard adjuvant therapy. AR status was assessed by immunohistochemistry in all cases. Overall survival (OS) and disease-free survival (DFS) was determined. The relationship between AR expression and clinical and pathological parameters and immunohistochemical molecular subtype was analyzed using Student T test and chi-square tests. Cox regression analysis was used to analyze the prognostic impact of AR expression. RESULTS: AR expression was seen in 40.8%(95%CI 33.10-49.07%) of the BCa study cohort. None of the clinical data studied showed a significant association with the AR status(p > 0.05). Ductal carcinoma in situ(p = 0.003), oestrogen receptor (ER) (p = 0.001) and progesterone receptor (PR) (p = 0.001) positivity and luminal IHC molecular subtype(p = 0.016) were significantly associated with AR-positive status. AR-negative status was significantly associated with tumour necrosis > 50%(p = 0.031), moderate to extensive lymphocytic infiltrate at the tumour margin(p = 0.025) and basal triple negative breast carcinoma(p = 0.016). The mean duration of patient follow-up was 46.70(95% CI 46.495-46.905) months (3.89 years). On univariate analysis, AR-positivity was associated with better OS among ER-positive tumours(p = 0.047), specifically in postmenopausal women (p = 0.030). In ER-negative tumours, AR positivity was associated with worse DFS (p = 0.036). On multivariate analysis, TNM stage and ER/AR status were predictive of survival. ER-positive/AR-positive (ER+/AR+) tumours demonstrated better OS than ER-positive/AR-negative (ER+/AR-) tumours(p = 0.015). ER-negative/AR-positive (ER-/AR+) tumours (p = 0.014) had a worse DFS than ER-negative/AR-negative (ER-/AR-) tumours. CONCLUSIONS: AR prevalence obtained was low. AR positivity was associated with positivity for ER and PR. On multivariate analysis, apart from TNM stage only ER/AR status were predictive of OS and DFS, with concordant expression of ER/AR demonstrating a better, early survival.

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BACKGROUND: Triple negative breast carcinoma (TNBC) and basal-like breast carcinoma (BLBC) are subtypes of breast carcinoma (BCa) that are associated with poor survival. AIMS: To study the prevalence, clinicopathological profile and survival of TNBC among a Sri Lankan patient cohort and to determine the proportion and predictive histological features of BLBC among TNBCs. STUDY SETTING AND DESIGN: A cohort of 221 women undergoing primary surgery for BCa at a tertiary-care center in Sri Lanka was studied. MATERIALS AND METHODS: Clinicopathological and follow-up information were collected by patient interviews and review of slides and clinical records. Estrogen, progesterone, HER2 receptors, and basal markers (CK5/6, CK14, EGFR, 34ßE12) were evaluated immunohistochemically. STATISTICAL ANALYSIS: Data was analyzed with Chi-square test, multinomial logistic regression, and Cox regression using SPSS20.0. RESULTS: Fifty-three (24%) tumors were triple-negative (95%CI = 18.37%-29.63%). On multivariate analysis, young age (P = 0.002), high Nottingham grade (P = 0.005), moderate to severe tumor necrosis (P = 0.004), absent ductal carcinoma in situ (DCIS) (P = 0.04), reduced vascular density at tumor edge (P = 0.016) and distinct cell margins (P = 0.047) predicted TNBC over luminal subgroups, whereas reduced vascular density (P = 0.004) and low TNM stage (P = 0.011) distinguished TNBC and HER2. BLBC accounted for 45.28% (95%CI 32.66%-58.55%-24/53) of TNBC. The presence of extensive necrosis in TNBC correlated significantly with BLBC (P = 0.03). The survival among the TNBC subgroup did not differ significantly from other subgroups. CONCLUSION: Twenty four percent were TNBCs by immunohistochemical analysis, comparable to studies in the Indian subcontinent, however higher than the West. TNBC status correlated with younger age, high tumor grade, necrosis, absent DCIS, reduced vascular density at tumor edge, and distinct cell margins. The presence of moderate to extensive necrosis in TNBC was predictive of BLBC.

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BACKGROUND: The 30-year-old armed conflict in Sri Lanka resulted in a general breakdown of civil administration in the Northern and Eastern provinces, leading to mobilisation of many armed forces personnel to assist with reconstruction and resettlement. This occupational group has been identified as a priority risk group for leishmaniasis. METHODS: Individuals enlisted at all military establishments in Mullaitivu and Kilinochchi districts, Northern Province of Sri Lanka were included. Five thousand individuals were screened for skin lesions between September 2018 and August 2019. Persons with lesions suspected as cutaneous leishmaniasis (CL) were further investigated. Information on sociodemographic/other potential risk factors was obtained through an interviewer-administered structured questionnaire. The diagnosis was confirmed by microscopic visualization of parasitic stages from different samples obtained (skin scraping, lesion aspirate and tissue impression smears), histopathology and polymerase chain reaction DNA amplification. RESULTS: Among 5000 individuals screened, 74 individuals were suspected of having CL. Of these, 67.6% (n = 50) patients were confirmed for CL by microscopy. Around two third of both males (67.6%; n = 48) and females (66.6%; n = 2) were positive for Leishmania. The soldiers belonging to 26-35-year age group reported the highest susceptibility (83.3%; OR: 4.83, 95% CI: 3.49-6.20%). Of the sociodemographic factors, age, wearing short-sleeved upper body clothing as the uniform and non-use of insect repellents were identified as significant risk factors. Most of the CL patients had a single lesion (86.0%; n = 43) of an ulcerative type (34.0%; n = 17), mostly on their upper limb (67.9%; n = 34). Lesions were mostly 5-10 mm diameter (59.9%; n = 30) in size with poorly defined margins (72.0%; n = 36). Amongst the diagnostic techniques, microscopic examination of slit skin smear and tissue impression smear were able to discriminate the majority of patients (92.1%; n = 46) for CL. CONCLUSIONS: In order to highlight the true burden of leishmaniasis in the military personnel, cases of leishmaniasis from military institutes should be recognized as a different entity per say and be included in the national figures so as to depict the real magnitude of the disease burden amongst this high-risk group.

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Cutaneous leishmaniasis (CL) is a neglected tropical disease that is gaining importance in Sri Lanka and internationally. The clinical presentation, pathology, and method of parasite elimination in CL vary according to the species. Leishmania donovani is the causative organism for leishmaniasis in Sri Lanka. This collaborative cross-sectional study describes the clinicopathological features of cutaneous leishmaniasis among personnel of the tri-forces serving in the North and East of the country. The histology of fifty cases of CL confirmed by at least two methods (slit skin smear, lesion aspirate, tissue impression, and histology) was reviewed. The parasitic load was assessed semiquantitatively. The histological features were correlated with the clinical presentation and organism load. The majority (89.8%; n = 44) presented with a single lesion mostly located in the upper limb (69.4%). The lesion types included papule (34.7%), nodule (32.7%), and an ulcer (30.6%). The evolution time of lesions averaged 31.55 weeks. Epidermal changes were observed in 49 of the biopsies and included hyperkeratosis (90.0%; n = 45), acanthosis (44.0%; n = 22), atrophy (34.0%; n = 17), and interface change (66%; n = 33). Dermal changes were seen in all cases and were characterized by a lymphohistioplasmacytic inflammatory infiltrate of variable intensity with ill-formed granuloma in 19 cases (38%) and well-formed epithelioid granulomas in 22 cases (44%). Focal necrosis was present in 20% (n = 10). Leishmania amastigote forms were observed in 88% (n = 44). Transepidermal elimination (P = 0.025), granuloma (P = 0.027) formation, and type of lesion (P = 0.034) were significantly associated with the organism load. Granuloma formation was associated with a reduction in organism load, indicating that the macrophage activation played an important role in the control of the organism.

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BACKGROUND: Breast carcinoma (BCa) is the commonest malignancy among women worldwide and in Sri Lanka. Several prognostic indices are described for BCa. AIMS: To assess clinicopathological features and prognostic indices derived from routine clinical, histopathological and immunohistochemical (IHC) data, in a cohort of patients undergoing primary surgery for BCa and to determine their prognostic impact on short-term disease free survival. SETTING AND DESIGN: : This is a bidirectional cohort study of 208 women undergoing primary surgery for BCa at the National Hospital of Sri Lanka, from 2012-2014, excluding post-neoadjuvant chemotherapy cases. MATERIAL AND METHODS: Clinical details, tumor size and nodal status were obtained from histopathology reports. Histopathology and estrogen/progesterone receptor and HER2 status were reviewed. Molecular subtype based on IHC was determined. Nodal ratio (number of positive nodes/total number retrieved) and Nottingham prognostic index were calculated. Follow up information was obtained by patient interviews and record review. STATISTICAL ANALYSIS: Data was analyzed by univariate and multivariate Cox regression using SPSS19.0. RESULTS: Mean follow-up duration was 27.16 months (0.5-52 months, s = 9.35 months). 174 (82.9%) remained disease free with 19 (9%) deaths. Thirteen (6.2%) survived with metastasis and 4 (1.9%) with recurrences. On univariate Cox regression, tumor, nodal and TNM stages, nodal ratio and lymphovascular invasion (LVI) were predictive of disease free survival (DFS) (P = 0.001, P = 0.021, P = 0.022, P = 0.002, P = 0.018). On multivariate analysis TNM stage and LVI were predictive of DFS. CONCLUSION: TNM stage and LVI were the most important predictors of short-term disease free survival in this study population, confirming that early detection of BCa at a lower stage has a significant impact on short-term outcomes.

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A healthy postnatal woman succumbed to fulminant iatrogenic Aspergillus infection of the central nervous system, following accidental inoculation into the subarachnoid space at spinal anesthesia, during an outbreak of Aspergillus meningitis in Sri Lanka. Autopsy revealed extensive Aspergillus meningitis and culture confirmed Aspergillus fumigatus. The thalamic parenchyma in the brain was invaded by fungal hyphae producing necrotizing angitis with thrombosis, thalamic infarcts and fungal abscesses. The directional growth of fungal hyphae from the extra-luminal side of blood vessels towards the lumen favored extension from the brain parenchyma over hematogenous spread. The spinal parenchyma was resistant to fungal invasion in spite of the heavy growth within the spinal meninges and initial inoculation at spinal level. Modulation of the immune response in pregnancy with depression of selective aspects of cell-mediated immunity probably contributed to rapid spread within the subarachnoid space, to involve the brain parenchyma leading to clinical deterioration and death.

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