Prognostic significance of estrogen, progesterone and HER2 receptors' status conversion following neoadjuvant chemotherapy in patients with locally advanced breast cancer: Results from a tertiary Cancer Center in Saudi Arabia.

BACKGROUND: The prognostic impact of neoadjuvant chemotherapy (NAC) on the receptor expression status in patients with locally advanced breast cancer (LABC) is still not fully understood. We aimed to evaluate the changes in hormone (estrogen and progesterone) receptor (HR) and human epidermal growth factor receptor 2 (HER2) status post-NAC and their correlation with survival. METHODS: Patients with LABC who have received NAC between 2008 and 2015 and have been followed up till December 2019 at the Oncology Center, King Saud University, KSA were analyzed retrospectively. biomarker analysis of ER, PR & HER2 were done using immunohistochemistry (IHC) and Fluorescent in situ hybridization. RESULTS: Ninety-one patients fulfilled the inclusion criteria. HR status changed in 21(23.1%) patients, with a significant difference between patients with stable receptors and those with any receptor conversion; p = 0.000. Five (5.5%) initially HER2 negative tumors became HER2 positive and 10 (11%) initially HER2 positive tumors became HER2 negative after NAC. The difference in HER2 expression level before and after NAC was not statistically significant (p = 0.302). Univariate analysis relating patients' characteristics and 10-years disease-free survival (DFS) showed only significant correlations with the expressions of ER, PR, and any receptor conversion, (ER and/or PR) p< 0.001, p< 0.001, and p = 0.001; respectively. In the univariate analysis, none of the clinicopathological features showed a significant correlation with the OS except for the molecular subtypes P<0.001. CONCLUSIONS: Patients with LABC have significant changes in the ER and PR receptor status following NAC. Post-NAC expressions change of ER and PR (ER and/or PR) are correlated to DFS. Retesting of the hormone receptors should be considered after NAC in Saudi patients with LABC.

Prognostic Significance of HER2 Expression Changes Following Neoadjuvant Chemotherapy in Saudi Patients With Locally Advanced Breast Cancer.

BACKGROUND: Progesterone receptor (PR), estrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2) significantly influence disease prognosis and therapeutic response in patients with breast cancer. Neoadjuvant chemotherapy (NACT) can change the receptor status, affecting the disease characteristics. PATIENTS AND METHODS: A retrospective chart review was carried out at a single tertiary care hospital in Riyadh, Kingdom of Saudi Arabia, from December 2008 to December 2014, where 91 adult female patients diagnosed with locally advanced breast cancer planning to receive NACT were included. Original pathology and surgical histopathology reports were assessed, and patients were followed up to recurrence, death, or until December 2019. An expression for the ER, PR, and HER2 was carried out in pre and post NACT specimens by an experienced pathologist, and all HER2 with 2+ immunohistochemistry was sent for fluorescence in situ hybridization as per American Society of Clinical Oncology guidelines. RESULTS: ER pre- and postoperatively changed from positive to negative in 17.6% of patients and from negative to positive in 1.1% of patients (P < .001). ER status remained stable in 81.3% of patients. PR changed from positive to negative in 13.2% of patients, and from negative to positive in 3.3% of patients (P < .001), whereas it remained stable in 83.5% of patients. HER2 changed from positive to negative in 11% of patients, and from negative to positive in 5.5% of patients (P < .001), and it remained stable in 83.5% of patients. No significant association was found between overall survival and disease-free-survival with HER2 expression change. CONCLUSION: NACT can induce changes in the ER, PR, and HER2 status, which should be evaluated post-NACT to choose the optimal treatment regimens.

Laryngeal epidermal inclusion cyst: report of an unusual case and literature review.

The causes of dysphonia or hoarseness are numerous and can be classified as functional or organic. The report will highlight the clinical presentation, histopathological features and management plan of laryngeal epidermal inclusion cysts (EICs). Laryngeal EICs are rare. The epidermal and dermoid cysts represent only 0.01% of oral cavity cysts. Their clinical presentation varies from a completely asymptomatic presentation to dysphonia for years. This current report represents a case of a 34-year-old female who presented with 2-year history of dysphonia, which was caused by a unilateral laryngeal EIC.

MicroRNA-3148 acts as molecular switch promoting malignant transformation and adipocytic differentiation of immortalized human bone marrow stromal cells via direct targeting of the SMAD2/TGFß pathway.

MicroRNAs (miRs/miRNAs) play a key role in posttranscriptional regulation of gene expression and are implicated in a number of physiological and pathological conditions, including cellular malignant transformation. In the current study, we investigated the role of miR-3148 in regulating human stromal (mesenchymal) stem cell (hMSC) differentiation and transformation. Stable expression of miR-3148 in telomerized hMSC (hMSC-miR-3148) led to significant increase in in vitro adipocytic differentiation and suppression of osteoblastic differentiation. Concordantly, global gene expression profiling revealed significant enrichment in cholesterol biosynthesis pathway, and pathways related to enhanced cell movement and survival, whereas processes related to bone and connective tissue developments, cell death, apoptosis, and necrosis were downregulated. Global proteomic analysis using 2D-DIGE followed by mass spectrometry (MS) revealed significant changes in protein expression in hMSC-miR-3148 and enrichment in protein networks associated with carcinogenesis. Functional studies revealed that hMSC-miR-3148 exhibited enhanced in vitro cell proliferation, colony formation, migration, invasion, sphere formation, doxorubicin resistance, and increased active number of cells in S and G2/M cell cycle phases and formed sarcoma-like tumors with adipocyte infiltration when implanted into immunocompromised mice. SMAD2 was identified as bone fide gene target for miR-3148 using qRT-PCR, Western blotting, and UTR-based reporter assay. In agreement with our data, SMAD2 expression was downregulated in 47% of patients with soft tissue sarcoma. Bioinformatics analysis revealed that elevated miR-3148 expression correlates with poor prognosis in several human cancer types, including sarcoma. Our study identified miR-3148 as factor regulating hMSC differentiation and is involved in promoting malignant transformation of telomerized hMSC.

Sebaceous Gland Carcinoma with Misleading Clinical Appearance: A Case Report of an Eyelid Lesion.

BACKGROUND Sebaceous gland carcinoma (SGC) is a rare malignant lesion that occurs on the eyelids. It is known to mimic other benign or malignant lesions in clinical presentation, such as a chalazion, basal cell carcinoma, and squamous cell carcinoma. The histopathological diagnosis is the mainstay for diagnosis and is often challenging. CASE REPORT We describe a case of SGC in a 53-year-old woman who presented with a cauliflower-appearing lesion with pearly telangiectatic vessels and raised margins at the lower eyelid margin. Clinically, we suspected a diagnosis of basal cell carcinoma. Upon complete resection of the lesion, the final diagnosis was SGC based on the histopathological features and immunohistochemical staining characteristics of the tissue. CONCLUSIONS Due to the possibility of SGC presenting similarly to other lesions, it is essential for ophthalmologists to have a high index of suspicion in its diagnosis. The early and accurate diagnosis of such lesions is important for appropriate management to prevent metastasis or recurrence related to advanced tumors.

MicroRNA Expression Profiling on Paired Primary and Lymph Node Metastatic Breast Cancer Revealed Distinct microRNA Profile Associated With LNM.

Breast cancer (BC) is the foremost cause of cancer-related deaths in women. BC patients are oftentimes presented with lymph node metastasis (LNM), which increases their risk of recurrence. Compelling data have recently implicated microRNAs in promoting BC metastasis. Therefore, the identification of microRNA (miRNA)-based molecular signature associated with LNM could provide an opportunity for a more personalized treatment for BC patients with high risk of LNM. In current study, we performed comprehensive miRNA profiling in matched primary breast and LNM and identified 40 miRNAs, which were differentially expressed in LNM compared to primary tumors. The expression of 14 miRNAs (Up: hsa-miR-155-5p, hsa-miR-150-5p, hsa-miR-146a-5p, hsa-miR-142-5p and down: hsa-miR-200a-3p, hsa-miR-200b-3p, hsa-miR-200c-3p, hsa-miR-205-5p, hsa-miR-210-3p, hsa-miR-214-3p, hsa-miR-141-3p, hsa-miR-127-3p, hsa-miR-125a-5p, and hsa-let-7c-5p) was subsequently validated in a second cohort of 32 breast and 32 matched LNM tumor tissues. Mechanistically, forced expression of hsa-miR-205-5p, or hsa-miR-214-3p epigenetically inhibited MDA-MB-231 cell proliferation, colony formation, and cell migration. Global gene expression profiling on MDA-MB-231 cells overexpressing hsa-miR-205-5p, or hsa-miR-214-3p in combination with in silico target prediction and ingenuity pathway analyses identified multiple bona fide targets for hsa-miR-205-5p, hsa-miR-214-3p affecting cellular proliferation and migration. Interestingly, interrogation of the expression levels of hsa-miR-205 and hsa-miR-214 in the METABRIC breast cancer dataset revealed significantly poor overall survival in patients with downregulated expression of miR-205 [HR = 0.75 (0.61-0.91)], p = 0.003 and hsa-miR-214 [HR = 0.74 (0.59-0.93) p = 0.008]. Our data unraveled the miRNA-transcriptional landscape associated with LNM and provide novel insight on the role of several miRNAs in promoting BC LNM, and suggest their potential utilization in the clinical management of BC patients.

Effects of various doses of glutathione on the proliferation, viability, migration, and ultrastructure of cultured human melanocytes.

Normal human cultured melanocytes were exposed to various glutathione concentrations (0.1, 0.5, 1.0, 5.0, and 10.0 mg/mL) for 72 hours. At the end of the experiment, proliferation, viability, migration, and ultrastructural changes were monitored. Glutathione at the doses of 0.5 to 10.0 mg/mL reduced the viability of melanocytes significantly as compared to the control (P < .05). Glutathione significantly reduced the proliferation of melanocytes at the doses of 0.5 to 10.0 mg/mL as compared to the control (P < .001). Glutathione at 0.5 to 10.0 mg/mL significantly reduced the migration of melanocytes as compared to the control (P < .001). The percentage of mature melanosomes was 53.43% in control and 50.58%, 41.83%, 33.4%, and 8.95% in 0.1, 0.5, 1.0, and 5.0 mg/mL glutathione exposed cells, respectively. This reduction in the number of mature melanosomes was statistically significant as compared to the control. However, no cytotoxic effects were recognized by electron micrographs. These results encourage the potential implementation of glutathione as a skin-lightening agent. However, this study is limited by cell culture and ultrastructural. It should therefore be expanded in the future to include patients with pigmentary disorders.

Safety and efficacy of parenteral glutathione as a promising skin lightening agent: A controlled assessor blinded pharmacohistologic and ultrastructural study in an animal model.

Hyperpigmentation was induced in the skin of experimental animals using UVB at 6 J/cm2 three times a week for three consecutive weeks. Subsequently, glutathione was injected intraperitoneally in the experimental animals at doses of 10, 20, and 40 mg/kg body weight three times a week for three consecutive weeks. At the end of the experiment, blood samples and lung, kidney, liver, and skin tissue specimens were collected from animals for hematological, biochemical, histological, and electron microscopy examination. Glutathione at 40 mg/kg body weight/day reduced skin hyperpigmentation significantly, except at low doses. The skin lightening effect assessed by a chromameter was dose-dependent. There were no statistically significant differences among the mean values of AST, ALT, creatinine, BUN, and CBC counts across the four groups. Lung, kidney, and liver tissue specimens did not show any histological toxic changes. The number of melanin granules was significantly lower in the group treated with the highest dose of glutathione compared to that in the control. Electron microscopy proved that glutathione at 20 and 40 mg/kg body weight/day was able to reduce the number of melanized cells significantly compared to that in the control. Parenteral glutathione was effective as a skin lightening agent and did not provoke any toxic effects in the employed animal model. The limitation of the study was conducted in guinea pigs and was of short-term duration.

Hemophagocytic lymphohistiocytosis associated with Epstein-Barr virus infection: case report and literature review.

Hemophagocytic lymphohistiocytosis (HLH) is rare and life threatening syndrome. There are only a few reported cases of HLH with GI symptoms. We describe the case of an 18 months old boy who presented with a history of fever for 40 days, abdominal distention and hepatosplenomegaly. Abdominal x-ray showed a pneumoperitoneum. Urgent laparotomy was done which revealed an isolated cecal perforation. The histopathological findings in the subsequent resected bowel was HLH with evidence of positive EBV Barr infection.

A Multicenter Study of the Impact of Body Mass Index (BMI) on the incidence of Pathologic Complete Response (pCR) Among Saudi Patients with locally advanced Breast cancer (LABC) post Neoadjuvant Chemotherapy (NAC).

PURPOSE: Obesity was reported to be a poor prognostic factor for breast cancer. There is a growing evidence of increasing prevalence of obesity among Saudi women across all age groups (44%). Since the prognostic significance of obesity was not studied in Saudi patients with breast cancer, the aim of this study was to evaluate the impact of BMI on pCR in LABC patients post NAC. PATIENTS AND METHODS: This is a retrospective study between May 2005 to July 2010; 246 consecutive female patients who were diagnosed of LABC (Stage II & III) and underwent surgery in three tertiary care centers, representative of the Kingdom of Saudi Arabia (King Saud Medical City, Riyadh; King Abdullah Hospital, Mecca and King Fahad Specialist Hospital, Dammam) were included in this study. All included patients have received NAC (Anthracycline/Taxane based combination chemotherapy and ± Herceptin). Patients who were diagnosed to have stage IV breast cancer due to presence of distant metastasis were excluded. Patients were categorized as normal (BMI <25 kg/m2), overweight (BMI of 25 to <30 kg/m2) and obese (BMI >30 kg/m2). pCR was defined as no invasive cancer in the breast or axillary tissue. Univariate and multivariate analysis were used to evaluate the statistical associations between pCR and BMI with respect to the other previously established prognostic factors, namely age, tumor grade, stage, ER/ PR /Her-2neu status, molecular subtypes, and lympho-vascular invasion (LVI). RESULTS: The median age was 50 years (range 24-68). Molecular subtypes were as follows: luminal A; 23.2%, luminal B; 45.1%, triple negative; 16.7% and Her-2 neu positive; 15%. Infiltrating ductal carcinoma represents the majority of our cohort (92.7%). Eighty-six (35%) were stage II and 160 (65%) were stage III. Intermediate and high-grade malignancies were found in 52% and 44.3% of the patients respectively. Positive lymph vascular invasion was detected in 41.5%. Obese patients constitute 55.7% of our cohort. Pathologic complete response was achieved in 62 patients (25.2%). In Univariate analysis LVI and overweight /obesity were negatively correlated with pCR (P= 0.037 and 0.000 respectively) while tumor grade was positively correlated with pCR (P= 0.008). In multivariate analysis, Overweight/ obesity was the only significant independent factor correlating with pCR (P=0.000). No impact of BMI has been demonstrated on both disease-free survival (DFS) and overall survival (OS) (P=0.93, 0.18 respectively). CONCLUSION: In this study, Overweight/Obesity (which represent more than half of the patients =81.3 %) had a negative impact on pCR in Saudi patients with LABC treated with NAC. This poorer outcome in patients with abnormal weight (Overweight/Obesity) necessitates further prospective studies of this risk factor in order to optimize the care of this group of patients.

Neoplastic Transformation of Human Mesenchymal Stromal Cells Mediated via LIN28B.

Bone marrow stromal (Mesenchymal) stem cells (MSCs) are multipotent bone cells capable of differentiating into mesoderm-type cells, such as osteoblasts and adipocytes. Existing evidence suggests that transformation of MSCs gives rise to sarcoma. In order to identify the molecular mechanism leading to spontaneous transformation of human bone marrow MSCs (hBMSCs), we performed comprehensive microRNA (miRNA) and mRNA profiling in the transformed hBMSC-Tum line compared to the parental clone. As a result, we identified multiple dysregulated molecular networks associated with the hBMSC transformed phenotype. LIN28B was upregulated 177.0-fold in hBMSC-Tum, which was associated with marked reduction in LET-7 expression and upregulated expression of its target HMGA2. Targeted depletion of LIN28B or exogenous expression of LET-7b suppressed hBMSC-Tum proliferation, colony formation, and migration. On the other hand, forced expression of LIN28B promoted malignant transformation of parental hBMSC cells as shown by enhanced in vitro colony formation, doxorubicin resistance, and in vivo tumor formation in immunocompromised mice. Analysis of LIN28B and HMGA2 expression levels in cohorts from The Cancer Genome Atlas sarcoma dataset revealed a strong inverse-relationship between elevated expression and overall survival (OS) in 260 patients (p = 0.005) and disease-free survival (DFS) in 231 patients (p = 0.02), suggesting LIN28B and HMGA2 are important regulators of sarcoma biology. Our results highlight an important role for the LIN28B/LET-7 axis in human sarcoma pathogenesis and suggest that the therapeutic targeting of LIN28B may be relevant for patients with sarcoma.

Rutin inhibits carfilzomib-induced oxidative stress and inflammation via the NOS-mediated NF-κB signaling pathway.

BACKGROUND: Carfilzomib (CFZ), a proteasome inhibitor approved by the FDA to treat multiple myeloma, may cause nephrotoxicity. HYPOTHESIS: Rutin is a bioflavonoid with antioxidant properties. We aimed to examine whether rutin protects the kidney from CFZ-induced nephrotoxicity. STUDY DESIGN: This study aimed to demonstrate the effect of rutin on CFZ-induced renal injury via the inhibition of oxidative stress and inflammation. METHODS: Wistar albino rats were divided into six groups (n = 6): Group 1 (normal control; NC) was administered normal saline for 3 weeks; Group 2 (CFZ/toxic group) received CFZ [4 mg/kg, intraperitoneal (i.p.) injection] twice weekly for 3 weeks; Group 3 (standard treatment group) was administered CFZ (4 mg/kg, i.p.) and olmesartan (2 mg/kg, p.o.) for 3 weeks; Group 4 was administered CFZ (4 mg/kg, i.p.) and rutin (10 mg/kg, p.o.) for 3 weeks; Group 5 was administered CFZ (4 mg/kg, i.p.) and rutin (20 mg/kg, p.o.) for 3 weeks; and Group 6 was administered CFZ (4 mg/kg, i.p.) and rutin (40 mg/kg, p.o.) for 3 weeks. We carried out haematological and biochemical analyses, determined oxidative stress, caspase-3 activity, and protein levels, and performed a histopathological evaluation to confirm CFZ-induced nephrotoxicity and its prevention by rutin administration. RESULTS: Exposure to only CFZ significantly (p < 0.05) increased white blood cell (WBC) count, Hb%, and HTC% concentration; however, these features were significantly decreased (p < 0.05) when olmesartan and rutin were administered. CFZ administration significantly decreased (p < 0.0001) the level of antioxidant enzymes; whereas, administration of olmesartan and rutin significantly reversed (p < 0.05) their levels toward the normal range. The levels of caspase-3 enzyme significantly increased (p < 0.001) in the CFZ group and were reduced toward the normal values by olmesartan and rutin administration. Furthermore, the results of NOS-2, NF-κB, IkBa, and IL-17 protein estimation and the histopathological evaluation strengthened our findings that rutin exhibits a protective effect against CFZ-induced nephrotoxicity. CONCLUSION: These findings clearly demonstrate that rutin ameliorates CFZ-induced oxidative stress and inflammation in nephrotoxicity via the NOS-mediated NF-κB signaling pathway.

Gastric xanthelasma associated with hyperplastic polyp and mucosal erosions: report of an unusual case and literature review.

Gastric xanthelasma is a rare benign tumor-like lesion which is usually observed as an incidental finding due to its asymptomatic presentation. Grossly, it is a well-demarcated yellow-white plaque which is microscopically formed by clusters of foamy macrophages in the lamina propria. The pathogenesis and clinical significance are not clear. Gastric hyperplastic polyps are rarely associated with xanthelasma. Mucosal erosions also appear to have an association with the combined lesions of hyperplastic polyp and xanthelasma. Here, we report a rare case of simultaneous occurrence of gastric xanthoma with hyperplastic polyp and mucosal erosions. The lesions are observed in a 78 years old male who presented with a history of chronic anemia. The histological features together with a literature review of other similar reported cases are described and compared.

An Unusual Case of Inflammatory Myofibroblastic Tumor of the Appendix Masquerading as Acute Appendicitis.

Inflammatory myofibroblastic tumor (IMT) is reported virtually in every anatomic location of the body, but most cases are commonly identified in the mesentery and omentum. The etiology of this tumor is unclear with many suggestions of viral, inflammatory, or oncogenic mutational factors that establish it as a clonal neoplasm. Clinical and laboratory workup, including roentgenography, is not usually helpful to reach a pre- or intraoperative diagnosis. Histopathology and immunohistochemistry of the resected specimen provides a definitive answer by the exclusion of a close clinical differential diagnosis of gastrointestinal stromal tumor and many lookalikes. Complete surgical excision with clear margins is the mainstay of treatment. Rare cases have been seen involving the appendix. To the best of our knowledge, only 11 confirmed cases of purely appendiceal IMT have been published in the literature to date.

Orbital T-cell lymphoma in youngest recorded patient - early diagnosis, management, and successful outcome: a case report and review of the literature.

BACKGROUND: Primary orbital peripheral T-cell lymphoma, not otherwise specified is an exceedingly rare disorder with a very poor outcome, and to the best of our knowledge only a few cases have been reported in the English literature. We present the youngest reported case describing the successful outcome after management with a thorough review of the English literature of all the reported cases of primary peripheral T-cell lymphoma, not otherwise specified. CASE PRESENTATION: Our patient is a 3-year-old Syrian boy who presented with gradual progressive orbital swelling. A physical examination showed a left orbital dystopia and a superior medial displacement of the globe. Extraocular motility was limited in upward elevation of his left eye. A computed tomography scan and magnetic resonance imaging of his orbit showed a mass involving the lateral and inferior walls of his left orbit and extending intraconally. A diagnosis of peripheral T-cell lymphoma, not otherwise specified was made by careful histopathological examination and Berlin-Frankfurt-Munster protocol was initiated. A 6-month follow up with orbital magnetic resonance imaging showed no sign of orbital or brain involvement. CONCLUSIONS: Through this report we emphasize two takeaway lessons: (1) always have a high level of suspicion of this entity regardless of the age of the patient; and (2) careful histopathological examination is very important for prompt confirmation of the diagnosis and early commencement of proper treatment.

Primary low-grade endometrial stromal sarcoma arising in the vagina: report of an unusual case and literature review.

Endometrial stromal sarcoma rarely occurs as an extrauterine neoplasm and it is even more unlikely to be found in the vagina. To the best of our knowledge, only six cases of primary vaginal endometrial stromal sarcoma without association with endometriosis have been published to this day. We describe a case of a 58-year-old female with a history of vaginal heaviness caused by a mass lesion. After a biopsy was taken, the histopathological findings and immunohistochemical stains were consistent with low-grade endometrial stromal sarcoma. The patient underwent total hysterectomy and bilateral salpingo-oophorectomy with lymph node dissection followed by hormonal therapy. This line of management was heavily based on the treatment guidelines for endometrial stromal sarcoma.

Vascular sclerosing effects of bleomycin on cutaneous veins: a pharmacopathologic study on experimental animals.

BACKGROUND:: Varicose veins and the complications of venous disease are common disorders in humans. OBJECTIVE:: To study the effects of bleomycin as a potential new sclerosing agent and its adverse events in treating varicose veins. METHODS:: Bleomycin-loaded liposomes 0.1ml was injected in the dorsal ear veins of white New Zealand rabbits. Sodium tetradecyl sulfate was used as a positive control. Normal saline was used as negative control. The blood vessels of the treated ears were photographed before and at one hour and two, eight and 45 days after treatment. Biopsies from the treated areas were obtained for histological examination. Blood samples were collected to determine any possible toxicity. RESULTS:: Bleomycin by itself was ineffective; therefore, liposomes were used as a vector to deliver bleomycin to the vein lumen. Subsequently, bleomycin started showing its sclerosing effects. Toxicity monitoring showed no apparent hematologic, pulmonary, hepatic or renal toxicities. This study revealed that bleomycin induced vasculitis, which led to vascular occlusion, which was observed on day 1 and day 8. No bleomycin-related injury was noted by histopathological examination of lung sections. The calculation of the lung/body weight coefficient indicated that edema was present in the experimental groups compared with the negative and positive controls. STUDY LIMITATIONS:: Relatively small number of experimental animals used. CONCLUSIONS:: This study showed that bleomycin-loaded liposomes were able to induce vasculitis and vascular occlusion without any toxicity or complications. It might be useful, hence, to treat patients suffering from Varicose veins and other ectatic vascular diseases with this agent.

Vascular sclerosing effects of bleomycin on cutaneous veins: a pharmacopathologic study on experimental animals

Abstract: Background: Varicose veins and the complications of venous disease are common disorders in humans. Objective: To study the effects of bleomycin as a potential new sclerosing agent and its adverse events in treating varicose veins. Methods: Bleomycin-loaded liposomes 0.1ml was injected in the dorsal ear veins of white New Zealand rabbits. Sodium tetradecyl sulfate was used as a positive control. Normal saline was used as negative control. The blood vessels of the treated ears were photographed before and at one hour and two, eight and 45 days after treatment. Biopsies from the treated areas were obtained for histological examination. Blood samples were collected to determine any possible toxicity. Results: Bleomycin by itself was ineffective; therefore, liposomes were used as a vector to deliver bleomycin to the vein lumen. Subsequently, bleomycin started showing its sclerosing effects. Toxicity monitoring showed no apparent hematologic, pulmonary, hepatic or renal toxicities. This study revealed that bleomycin induced vasculitis, which led to vascular occlusion, which was observed on day 1 and day 8. No bleomycin-related injury was noted by histopathological examination of lung sections. The calculation of the lung/body weight coefficient indicated that edema was present in the experimental groups compared with the negative and positive controls. Study limitations: Relatively small number of experimental animals used. Conclusions: This study showed that bleomycin-loaded liposomes were able to induce vasculitis and vascular occlusion without any toxicity or complications. It might be useful, hence, to treat patients suffering from Varicose veins and other ectatic vascular diseases with this agent.

Predictive and prognostic significance of CD8+ tumor-infiltrating lymphocytes in patients with luminal B/HER 2 negative breast cancer treated with neoadjuvant chemotherapy.

The immunobiology of breast cancer (BC) subtypes, including luminal cancer, remains unclear. Cluster of differentiation (CD)8+ tumor-infiltrating lymphocytes (TIL) are essential components of tumor-specific cellular adaptive immunity. However, only few studies have addressed the significance of cluster of differentiation 8+(CD8+) TIL in patients with luminal BC. The present study aimed to evaluate the predictive and prognostic significance of CD8+ TIL in patients with luminal B/human epidermal growth factor receptor 2 (HER 2)-negative BC treated with anthracycline-based neoadjuvant chemotherapy (NC). A total of 31 patients who underwent breast-conserving surgery or mastectomy post-NC were enrolled. Immunostaining for CD8+ TIL was performed using rabbit monoclonal antibodies against human CD8+. Intra- and peritumoral CD8+ TIL expression levels were classified into high and low, based on the median value of each. CD8+ TIL expression data were demonstrated to be correlated with disease-free survival (DFS) and overall survival (OS), using Kaplan-Meier and Cox's proportional hazards regression tests. The results revealed that, among all clinicopathological characteristics, only pathological complete response (pCR) was significantly correlated with intratumoral CD8+ TIL expression (P=0.016). A total of 9/16 patients (56%) with high intratumoral CD8+ TIL expression achieved pCR, in contrast with 2 out of 15 patients (13.3%) with low expression (P=0.016). High expression of intratumoral CD8+ TIL was significantly associated with OS (log-rank test, P=0.023). Multivariate Cox regression analysis revealed that intratumoral expression of CD8+ TIL was an independent prognostic factor for OS [hazard ratio (HR)=2.82; 95% confidence interval (CI)=0.911-4.833, P=0.007], but not for DFS (HR=1.11; 95% CI=0.282-2.078; P=0.508). In conclusion, the results of the present study suggested that high intratumoral CD8+ TIL expression was significantly predictive of pCR post-NC, and represented an independent prognostic factor for improved OS. In contrast, low intratumoral CD8+ TIL expression was a strong predictor of lack of pCR to NC, as well as an independent prognostic factor for poor OS. Assessment of the immune response in conjunction with the usual parameters may aid in the further stratification of patients with luminal B/HER 2-negative BC regarding the prediction of pCR post-NC and overall prognosis.