Fernanda Maris Peria

Breast conserving surgery after neoadjuvant therapy for large primary breast cancer

AIM The aim of this study was to evaluate the safety of breast conserving surgery in patients with breast tumours satisfactorily downstaged after neoadjuvant therapy. METHODS A retrospective cohort study was undertaken to analyze the loco-regional recurrence (LRR) after breast conserving surgery. We enrolled 88 patients with breast cancer subjected to neoadjuvant therapy (NAT group) who achieved an objective response due to neoadjuvant treatment and compared them with 191 patients with early breast cancer (EBC group) who were submitted to primary conserving surgery. Lumpectomy or quadrantectomy with axillary lymph node dissection was performed in all patients who received adjuvant radiotherapy. Systemic adjuvant therapy was offered to all patients. The mean periods of observation were 61.3 months in the NAT group and 67.5 months in the EBC group. RESULTS The mean age was 53 years in the NAT group and 56 years in the EBC group (p=0.04). There was no histological type and histological grade difference between groups. In the NAT group, the mean diameter of residual tumour was lower and the mean volume of breast tissue resection was higher than in the EBC group (p=0.01 and p=0.002, respectively). The ipsilateral recurrence rate was 7.9% in the NAT group and 7.8% in the EBC group (p=0.9). The most important predictive factor of recurrence in the NAT group was the age of patient. CONCLUSION Breast conserving therapy is a safe procedure in satisfactorily downstaged breast cancer after neoadjuvant therapy.

Caspase-3 and Bcl-2 expression in glioblastoma: an immunohistochemical study

The unfavorable prognosis of malignant gliomas can also be explained by the incomplete knowledge of their molecular pathways. Studies regarding the regulatory process of apoptosis in glioblastoma (GBM), the most common malignant glioma, are few, and better knowledge of the expression of pro and anti-apoptotic proteins could collaborate with the development of new treatments founded on molecular basis. The objective of this study was to evaluate by immunohistochemistry the expression of caspase-3 and Bcl-2 in 30 samples of GBMs. The expression of caspase-3 (mean 17.67%) was lower than Bcl-2 (mean 30.92%), a statistically significant result (p<0.0001), suggesting low apoptotic activity in these tumors. Other studies of proteins related to the intrinsic and extrinsic pathway of apoptosis are required to provide additional information of this mechanism in GBMs.

ICAM-1 (Lys469Glu) and PECAM-1 (Leu125Val) polymorphisms in diffuse astrocytomas.

Cell adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and platelet-endothelial cell adhesion molecule-1 (PECAM-1) play an important role in glioma invasion and angiogenesis. The aim of this study was to investigate whether specific genetic polymorphisms of ICAM-1 and PECAM-1 could be associated with glioma development and progression. Single-nucleotide polymorphism in codon 469 of ICAM-1 and codon 125 of PECAM-1 were examined in 158 patients with astrocytomas and 162 controls using polymerase chain reaction and restriction enzyme analysis. The distribution of PECAM-1 polymorphic genotypes in astrocytomas did not show any significant difference. However, a specific ICAM-1 genotype (G/G, corresponding to Lys469Glu) exhibited higher frequency in grade II astrocytomas compared to controls, grade III, and grade IV astrocytomas; suggesting that this polymorphism could be involved in the development of grade II astrocytomas.

Pleiotrophin expression in astrocytic and oligodendroglial tumors and it’s correlation with histological diagnosis, microvascular density, cellular proliferation and overall survival

BackgroundPleiotrophin (PTN) is a secreted cytokine with several properties related with tumor development, including differentiation, angiogenesis, invasion, apoptosis and metastasis. There is evidence that PTN has also a relevant role in primary brain neoplasms and its inactivation could be important to treatment response. Astrocytic and oligodendroglial tumors are the most frequent primary brain neoplasms. Astrocytic tumors are classified as pilocytic astrocytoma (PA), diffuse astrocytoma (DA), anaplastic astrocytoma (AA) and glioblastoma (GBM). Oligodendroglial tumors are classified as oligodendroglioma (O) and anaplastic oligodendroglioma (AO). The aim of the present study was to compare PTN expression, in astrocytomas and oligodendrogliomas and its association with the histological diagnosis, microvascular density, proliferate potential and clinical outcome.MethodsSeventy-eight central nervous system tumors were analyzed. The histological diagnosis in accordance with WHO classification was: 13PA, 18DA, 8AA, 15GBM, 16O and 8AO. Immunohistochemistry was realized with these specific antibodies: pleiotrophin, CD31 to microvascular density and Ki-67 to cell proliferation.ResultsPTN expression was significantly higher in GBM and AA when compared to PA and higher in GBM compared to DA. PTN expression did not differ between O and AO. Proliferate index and microvascular density were evaluated only in high grade tumors (AA, GBM and AO) divided in three groups according to PTN expression (low, intermediate and high). These results showed no statistical difference between PTN expression and index of cellular proliferation and neither to PTN expression and microvascular density. Overall survival (OS) analysis (months) showed similar results in high grade gliomas with different levels of PTN expression.ConclusionsOur results suggest that PTN expression is associated with histopathological grade of astrocytomas. Proliferation rate, microvascular density and overall survival do not seem to be associated with PTN expression.

Expression of Hypoxia-inducible factor 1-α and Vascular endothelial growth factor-C in locally advanced breast cancer patients

BACKGROUND: Locally advanced breast cancers are more prevalent in underdeveloped countries. Targeted therapy has been improved to identify hallmarks that are specific to these subtypes of tumors. OBJECTIVES: We aimed to prospectively assess the expression of Hypoxia inducible factor-1 α and vascular endothelial growth factor-C in locally advanced breast cancer patients. METHODS: Thirty women underwent incisional biopsies for the histopathological diagnosis of breast carcinoma and participated in neoadjuvant chemotherapy. The association of Hypoxia inducible factor-1 α and vascular endothelial growth factor-C with age, tumor size, histological grade, clinical staging, hormonal and axillary status, clinical and pathological response after neoadjuvant chemotherapy, expression of estrogen and progesterone receptors, and the presence of c-erbB-2 antigen was studied. RESULTS: Hypoxia inducible factor-1 α expression and Vascular endothelial growth factor-C expression were observed in 66.7% and 63.3% of all patients, respectively, and were marginally associated with each other (p = 0.06). Among the studied variables, only positive axillary status was associated with the presence of HIF-1α (p = 0.02). Complete pathological response was significantly associated (p = 0.04) with the expression of vascular endothelial growth factor-C prior to neoadjuvant chemotherapy. CONCLUSION: We concluded that Hypoxia inducible factor-1 α was associated with a poor prognosis and that vascular endothelial growth factor-C could be used as a predictive factor in locally advanced breast cancer patients with complete pathological response after neoadjuvant chemotherapy.

Serological under expression of microRNA-21, microRNA-34a and microRNA-126 in colorectal cancer

PURPOSE This paper describes the ability of miRNA value predict oncological outcomes in CRC patients and correlates to clinical and pathologic variables. METHODS We prospectively analyzed the serological expression of microRNA-21, microRNA-34a, and microRNA-126 in 37 stage II - IV CRC patients and correlate to seven fit counterparts. Serological microRNAs were extracted using the miRNeasy Mini Kit(r) (Qiagen, Hilden, Germany). Quantification of microRNAs was performed using TaqMan Master Mix(r) reagent (Applied Biosystems, USA). RESULTS We obtained serological underexpression microRNA-21, microRNA-34a, and microRNA-126 in CRC group. However, miRNAs serological values do not impact prognosis. Furthermore, miRNAs was not influenced by CEA values, TNM staging, and histological subtype. CONCLUSION Despite lower expression of miR-21, miR-34a and miR-126 in the CRC group, no association with poor prognosis was found.

Kaurene diterpene induces apoptosis in U87 human malignant glioblastoma cells by suppression of anti-apoptotic signals and activation of cysteine proteases

Gliomas are the most common and malignant primary brain tumors in humans. Studies have shown that classes of kaurene diterpene have anti-tumor activity related to their ability to induce apoptosis. We investigated the response of the human glioblastoma cell line U87 to treatment with ent-kaur-16-en-19-oic acid (kaurenoic acid, KA). We analyzed cell survival and the induction of apoptosis using flow cytometry and annexin V staining. Additionally, the expression of anti-apoptotic (c-FLIP and miR-21) and apoptotic (Fas, caspase-3 and caspase-8) genes was analyzed by relative quantification (real-time PCR) of mRNA levels in U87 cells that were either untreated or treated with KA (30, 50, or 70 µM) for 24, 48, and 72 h. U87 cells treated with KA demonstrated reduced viability, and an increase in annexin V- and annexin V/PI-positive cells was observed. The percentage of apoptotic cells was 9% for control cells, 26% for cells submitted to 48 h of treatment with 50 µM KA, and 31% for cells submitted to 48 h of treatment with 70 µM KA. Similarly, in U87 cells treated with KA for 48 h, we observed an increase in the expression of apoptotic genes (caspase-8, -3) and a decrease in the expression of anti-apoptotic genes (miR-21 and c-FLIP). KA possesses several interesting properties and induces apoptosis through a unique mechanism. Further experiments will be necessary to determine if KA may be used as a lead compound for the development of new chemotherapeutic drugs for the treatment of primary brain tumors.

Apoptosis in Glioma Cells Treated with PDT

BACKGROUND Despite significant advances in neurosurgical techniques, the median survival time of patients with glioblastoma has improved little over the past 50 years and remains less than one year. Photodynamic therapy (PDT) is presently established as a widely accepted modality for the treatment of a variety of solid tumors. OBJECTIVES This study evaluated the effect of PDT-Photogem(®) on five glioma cell lines (U87, U138, U251, U343, and T98G). METHODS The experiments were carried out in 25-cm(3) flasks with different groups of cells seeded at a density of 1 × 10(5) cells per flask. After 3 h, the medium was removed, and the cells were incubated for 4 h with Photogem (5 μg/mL). After the incubation time, the photosensitizer-containing medium was removed and the cells were irradiated with LED (630 nm, 25 mW/cm(2), 25 J/cm(2)) devices for 17 min. For the final steps of the PDT, the cells were returned to the incubator and kept at 37°C with 5% CO(2) for 24 h, the cell viability assay was assessed using the trypan blue method, and the expression of Caspase 3 mRNA levels was assessed by real-time quantitative PCR. RESULTS Upon PDT-Photogem(®) treatment, viable cells, as evaluated by the trypan blue dye-exclusion method, decreased in two cell lines (U87 and U138) but not in the other three. Apoptosis, as assessed by the expression of caspase-3 mRNA levels, was at least partly involved in the death mechanism of the cell lines. CONCLUSIONS Collectively, our results indicated that PDT-Photogem(®) can act in glioma cells, thus encouraging new experiments in this field.

Concurrent Chemoradiotherapy with Weekly Paclitaxel in Malignant Cerebral Glioma Treatment

Background: Anaplastic astrocytomas (AA) and glioblastomas (GB) are the most common malignant gliomas, and despite newly developed drugs and combined treatments, they still have an adverse prognosis. Paclitaxel is a cytotoxic agent with radiosensitizing properties and exerts objective growth inhibition in glioma tumor cells. Patients and Methods: From 1998 to 2002, 61 microneurosurgically treated patients were randomized to group I (18 GB, 14 AA) which received radiotherapy and weekly paclitaxel at dose of 100 mg/m2, and group II (21 GB, 8 AA) which received only radiotherapy as a complementary treatment. Results: Median overall survival was 27.96 months in group I and 23.06 months in group II with no statistical difference. The 12-month survival was 81% in group I and 76% in group II. Kaplan-Meier curves of both groups did not demonstrate any difference. Analysis of each histological subgroup (AA or GB) also showed no statistical difference in the survival curves. All 427 cycles were well tolerated with no treatment-associated deaths. Conclusions: Chemoradiotherapy with weekly paclitaxel is safe and tolerable although there was no increase in the overall survival and 12-month survival of malignant glioma patients. Further investigations modulating the paclitaxel entrance and delivery into the brain should be encouraged.

Elevated serum levels of proinflammatory cytokines potentially correlate with depression and anxiety in colorectal cancer patients in different stages of the antitumor therapy

ABSTRACT Depression and anxiety, the most important psychological disorders in cancer patients, have now been considered as psychoneuroimmunological disorders, in which peripheral immune activation, through the release of proinflammatory cytokines, is implicated in the variety of behavioral, neuroendocrine and neurochemical alterations associated with these disorders. Along with the tumor itself, cancer treatment can also contribute to exacerbate the production of proinflammatory cytokines. This study aimed to investigate whether proinflammatory cytokine levels are related to depression and anxiety in CRC patients in different stages of the antitumor therapy We evaluated 60 patients in three stages of antitumor therapy (Pre‐chemotherapy, Under‐chemotherapy and Post‐chemotherapy, n = 20 in each group) and 20 healthy volunteers by the Hospital Anxiety and Depression Scale (HADS). Serum levels of cytokines were measured by CBA. Depression and/or anxiety were found at clinically relevant levels in CRC patients during all antitumor therapy. Patients in pre‐chemotherapy group exhibited the highest concentrations of pro‐inflammatory cytokines and the lowest levels of IL‐10. In latter stages of treatment, cytokines reached levels similar to the control group. Correlation analysis between HADS score and cytokine serum levels revealed positive associations of anxiety and/or depression with IL‐1&bgr;, IL‐6, IL‐8, and TNF‐&agr;, and a negative correlation with IL‐10, suggesting that cytokines are involved in the pathophysiology of these psychological disorders in CRC patients. A better understanding of the molecular mechanisms involved in these psychological disorders will allow the design of new therapeutic strategies to assist in alleviating such symptoms in cancer patients.