Glycolysis gene expression analysis and selective metabolic advantage in the clinical progression of colorectal cancer.

Production of lactate even in the presence of sufficient levels of oxygen (aerobic glycolysis) seems the prevalent energy metabolism pathway in cancer cells. The analysis of altered expression of effectors causing redirection of glucose metabolism would help to characterize this phenomenon with possible therapeutic implications. We analyzed mRNA expression of the key enzymes involved in aerobic glycolysis in normal mucosa (NM), primary tumor (PT) and liver metastasis (LM) of colorectal cancer (CRC) patients (pts) who underwent primary tumor surgery and liver metastasectomy. Tissues of 48 CRC pts were analyzed by RT-qPCR for mRNA expression of the following genes: hexokinase-1 (HK-1) and 2 (HK-2), embryonic pyruvate kinase (PKM-2), lactate dehydrogenase-A (LDH-A), glucose transporter-1 (GLUT-1), voltage-dependent anion-selective channel protein-1 (VDAC-1). Differences in the expression of the candidate genes between tissues and associations with clinical/pathologic features were studied. GLUT-1, LDH-A, HK-1, PKM-2 and VDAC-1 mRNA expression levels were significantly higher in PT/LM tissues compared with NM. There was a trend for higher expression of these genes in LM compared with PT tissues, but differences were statistically significant for LDH-A expression only. RAS mutation-positive disease was associated with high GLUT-1 mRNA expression levels only. Right-sided colon tumors showed significantly higher GLUT-1, PKM-2 and LDH-A mRNA expression levels. High glycolytic profile was significantly associated with poor prognosis in 20 metastatic, RAS-mutated pts treated with first-line chemotherapy plus Bevacizumab. Altered expression of effectors associated with upregulated glucose uptake and aerobic glycolysis occurs in CRC tissues. Additional analyses are warranted for addressing the role of these changes in anti-angiogenic resistance and for developing novel therapeutics.

Clinical impact of the HGF/MET pathway activation in patients with advanced gastric cancer treated with palliative chemotherapy.

In gastric cancer, available clinical studies focusing on the activated hepatocyte growth factor (HGF)/MET pathway are limited to surgical and often heterogeneous series. MET copy number gain (CNG) and an activating truncation in the HGF promoter (deoxyadenosine tract element, DATE+) were studied in tumors of 95 patients with advanced gastric cancer treated with palliative chemotherapy. Associations with overall survival (OS) and the pattern of metastatic disease were studied. Median OS was 9.7 months in 80 MET CNG <5 copies cases (MET-), and 6.4 months in 15 MET CNG was ⩾5 copies cases (MET+) (P=0.001). MET+ status confirmed the adverse prognostic effect in the multivariate model. A significantly different distribution of MET+/DATE+ and MET-/DATE- cases was observed between patients with and without peritoneal carcinomatosis (PC). MET+ status confirms its adverse prognostic role in advanced gastric cancer patients. The activated MET/HGF axis seems to be associated with PC. These findings are relevant to the development of anti-MET/HGF compounds.

Loss of hMLH1 expression correlates with improved survival in stage III-IV ovarian cancer patients.

Pre-clinical data suggest a relationship between DNA MisMatch Repair (MMR) system failure, particularly the inactivation of genes hMLH1 and hMSH2, and resistance to drugs like cisplatin and carboplatin. We studied the correlation between loss of hMLH1 expression in tumour cells and clinical outcome in 38 patients with ovarian cancer, who underwent cisplatin-based chemotherapy. 19 patients (56%) showed loss of hMLH1 expression (Group A) while 15 patients (44%) showed normal hMLH1 expression (Group B). 4 patients were not evaluable for hMLH1 expression. The 2 groups of patients were similar for clinical characteristics, response to chemotherapy and time to progression. Group A patients showed a median survival of 55 months whereas Group B patients had a median survival of 12 months (P=0.014). Loss of hMLH1 expression was the only independent predictor of survival in the multivariate analysis. Our observations suggest a relationship between loss of hMLH1 and improved survival in advanced ovarian cancer.

Elastofibrolipoma of the mediastinum. A previously undescribed benign tumor containing abnormal elastic fibers.

We report the case of a 57-year-old woman who was found to have a mass in the anterior mediastinum. Surgical excision of the mass revealed a well-delimited lesion 10 cm in largest diameter. Histologically, the mass was composed of mature fat alternating with sclerotic connective tissue, which also contained extensive eosinophilic deposits, similar to the abnormal elastic fibers seen in elastofibroma dorsi. The elastic nature of these deposits was confirmed by elastic staining and electron microscopy. We consider this lesion, which we named elastofibrolipoma, a true benign neoplasm that is characterized by tumoral elastogenesis.

Epithelioid haemangioma of the heart.

The authors report a case of epithelioid haemangioma (EH) of the right atrium, the first description of this tumour originating in the heart. The lesion was found incidentally during a cardiac echocardiogram and diagnosed pre-operatively as cardiac myxoma. The tumour must be differentiated from the exceptionally rare epithelioid haemangioendothelioma (EHE) of the heart and from a cardiac myxoma. A correct pathological diagnosis is clinically important since EH is a benign tumour, whereas EHE and cardiac myxoma can recur and metastasize. The uneventful follow-up of this patient confirms the benign nature of EH.

Eosinophilic fasciitis: a mast cell disorder?

The rarity of eosinophilic fasciitis has so far prevented systematic investigations. Its etiology is still unknown and its nosographical position to be defined. We report here a further case whose distinctive features were: a gradual onset simultaneous with allergic bronchial asthma; the absence of eosinophils and presence of a high number of degranulating mast cells and Sezary-like cells in the inflamed fascia. The follow-up and a second biopsy suggested that early steroid treatment is advisable in these patients.

p53 immunostaining and HPV DNA detection by PCR in cervical intraepithelial neoplasia: clinical implications of a combinated evaluation.

We analyzed p53 immunoreactivity and clinical outcome in a series of cervical intraepithelial neoplasias (CIN), with respect to HPV DNA positivity. Cervical biopsy samples were obtained from 86 women who attended our Colposcopic Service from January 1993 to June 1994 due to abnormal pap-smear suspicious for CIN and/or human papillomavirus infection. Forty-one women with histologically confirmed CIN were included in the study. p53 positivity was immunohistochemically detected by monoclonal antibody anti-human p53 (pAb D0-7, Dako Denmark; dilution 1:50), and expressed as the percentage of positive cells. p53 positivity was observed in 78% of CIN lesions. In particular, all the HPV DNA-negative dysplasias expressed p53 protein while only 12 out of 21 (57%) HPV DNA-positive were p53 immunoreactive; (P = .003) the p53 immunostaining was also significantly higher in HPV DNA-negative than in positive CIN (P = .049). By analyzing p53 positivity with respect to clinical-pathologic evolution of the disease, among HPV DNA-negative cases, progressive dysplasia had significantly higher values of p53 immunostaining when compared to persistent and/or regressive lesions (P = .002). These findings imply that p53 immunostaining, when analyzed with respect to HPV DNA status, may help to understand the behavior of dysplastic lesions and define their therapeutic approach. Extensive p53 staining in HPV DNA-negative CIN is probably correlated with a high risk of progression.

Extraskeletal osteosarcoma of the mediastinum associated with long-term patient survival. A case report.

The authors report a case of mediastinal extraskeletal osteosarcoma showing immunohistochemical and ultrastructural features of epithelial differentiation and associated with a long-term patient survival. The possible role of flow cytometric DNA analysis in defining the prognosis of this tumor is discussed.

Proliferating cell nuclear antigen (PCNA) in prostatic invasive adenocarcinoma. Is the proliferation state in the marginal zone of the tumour higher than in the central part?

Expression and location of Proliferating Cell Nuclear Antigen in epithelial nuclei were assessed in invasive adenocarcinoma of the prostate gland. The PCNA-positive nuclei showed homogeneous or granular types of immunostaining or a mixture of both, and a gradation in the intensity of staining. Nuclei with homogeneous pattern appeared darker brown than the lighter granular and mixed patterns. Darker nuclei were quite frequently noted, mainly among the epithelial cells adjacent to the stroma. For the marginal zone of invasive adenocarcinoma, the mean proportion of PCNA-stained nuclei in the small acinar pattern was somewhat similar to that in the large acinar pattern, i.e., 8.66% and 9.06%, respectively. In contrast, the mean values in the cribriform pattern were greater than in the small and large acinar patterns, and decreased from the nuclei in the basal position, or adjacent to the stroma, toward the lumen: 14.40% in the basal position, 11.84% in the intermediate and 9.26% in the lumenal. In the solid/trabecular pattern, the proportions of PCNA-positive nuclei were higher than in all the other patterns: 17.60% in the cell layer adjacent to the stroma and 13.88% in the other layers. The trend of value changes in the central zone of the tumour was similar to that obtained in the marginal zone. However, the proportions were lower and the differences statistically significant. This might indicate that the proliferation state is higher in the marginal zone and that the tumour grows eccentrically rather than centrally.

Frequency and location of mitoses in prostatic intraepithelial neoplasia (PIN).

The aim of our study was to assess the frequency and location of mitoses in routine haematoxylin- and eosin-stained sections of prostatic intraepithelial neoplasia (PIN) and then to compare the patterns with those in benign prostatic hyperplasia (BPH) and prostatic invasive adenocarcinoma (PAC). The frequency of mitoses in the epithelial cell layers increased from BPH through PIN up to PAC. The proportions of mitoses in PIN lesions of low grade (PINlow) and high grade (PINhigh) were greater than in BPH (mean 0.001%; standard error, SE, 0.001%), the values decreasing from the basal layer towards the lumenal. In PINlow, the mean category values were 0.087% (SE 0.04%) in the basal, 0.046% (SE 0.033%) in the intermediate and 0.024% (SE 0.024%) in the lumenal position. In PINhigh, the mean category values were 0.194% (SE 0.178%) in the basal position, 0.075% (SE 0.06%) in the intermediate and 0.049% (SE 0.033%) in the lumenal position. The proportions of mitoses in adenocarcinoma with cribriform pattern decreased from the basal towards the lumenal layer, as for PIN: 0.154% (SE 0.096%) in the basal position, 0.072% (SE 0.044%) in the intermediate and 0.064% (SE 0.04%) in the lumenal position. In the solid/trabecular adenocarcinomas, the mean category value in the cell layer adjacent to the stroma was 0.22% (SE 0.111%), whereas in the other cell layers it was 0.074% (SE 0.045). In small and large acinar adenocarcinomas, the proportions of mitoses were 0.058% (SE 0.024%) and 0.068% (SE 0.019%), respectively. In conclusion, the evaluation of mitotic frequency and location in haematoxylin- and eosin-stained sections gives accurate information on how the mitotic activity in PIN compares with BPH and PAC.

Comparison of computerized analysis of nuclear DNA changes in uterine cervix dysplasia and in urothelial non-invasive papillary carcinoma.

The nuclear DNA content was measured in preneoplastic lesions of the uterine cervix and in papillary carcinomas of the bladder. Three groups of features were calculated from the raw data: basic DNA, DNA deviation and DNA distribution. The basic DNA features, concerning both the cervix and the bladder, showed a progressive increase in the mean DNA content, a decrease in the percentage of diploid nuclei and steadily increasing values of polyploid and aneuploid nuclei. Among the DNA deviation features, the malignancy grade value was zero in the normal cervical epithelium and in the normal urothelium. An increase in this value was evident in moderate dysplasia and in urothelial papillary carcinoma of grade 2, the highest value being in CIS and in grade 3. Concerning the DNA distribution features, the values of the 15th and 95th percentiles and their difference were progressively higher both in the cervix and in the bladder, expressing a continuous shift and spread of the DNA content measurements in the different diagnostic categories, with respect to normal epithelium and urothelium. The statistical analysis showed that the strongest correlation is between 2c D.I. and % of polyploid nuclei in the cervix and between M.I. and % of aneuploid nuclei greater than 4c in the bladder. In the cervix the most discriminating feature is the Malignancy Grade, whereas in the bladder it is the percentage of diploid nuclei. The comparison between the results of the three groups of features showed that: 1) Mild dysplasia of the cervix and urothelial papillary carcinoma of grade 1 showed similar changes in DNA features. Both were basically characterized by increased proliferative activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Cisplatin, epirubicin and cyclophosphamide (PEC) in the treatment of advanced ovarian cancer.

We report the long-term results of a series of patients affected by advanced epithelial ovarian cancer treated with the PEC combination (cisplatin 60 mg/m2, epirubicin 60 mg/m2 and cyclophosphamide 750 mg/m2, all at day 1, every 21 days). Response was evaluated after three cycles, and treatment continued in responsive patients. A total of 80 patients with a median follow-up of 55 months were studied. Fifty-eight patients with stage III ovarian cancer and 22 patients with stage IV received PEC as primary treatment (41 patients), or for residual disease after surgery (37 patients), or for relapsed disease after primary surgery (2 patients). The overall response rate was 67.5% (20.0% complete response, 47.5% partial response), with 22.5% stable disease and 3.7% progressive disease. Median progression free survival was 13.0 months, and median survival was 25 months. Grade III-IV toxicity was moderate: leukopenia 20.0% of patients, thrombocytopenia 5.0%, anemia 16.2%. No cardiac toxicity was observed. In conclusion, the PEC combination, an anthracycline-containing platinum-based regimen, proved to be effective in advanced ovarian cancer, in terms of response rate and overall survival. The regimen was devoid of significant toxicity and in particular of cardiac toxicity.

Modulation of expression of p53 and cell proliferation in locally advanced cervical carcinoma after neoadjuvant combination chemotherapy.

OBJECTIVE: In the present study, we investigated changes of p53 expression and the cell proliferation index detected with MIB 1 in tumors before and after neoadjuvant combination chemotherapy with respect to the outcome of the disease. Our aim was to define more appropriately the significance of chemotherapy in locally advanced cervical carcinoma. MATERIALS AND METHODS: Our study included 17 women with locally advanced squamous cervical carcinoma who had been admitted to the Institute of Gynecology and Obstetrics Ancona University, between January 1990 and December 1994. The patients received neoadjuvant combination chemotherapy consisting of three cycles of cisplatin (80 mg/m2) and bleomycin (30 mg/m2). After chemotherapy, radical surgery was performed. Bioptic specimens were obtained from cervical tumors before and after chemotherapy and processed for immunohistochemical staining with a monoclonal antibody against p53 and with the monoclonal antibody MIB 1. RESULTS: Thirteen patients (76.5%) showed a clinical response (4 complete and 9 partial), while of the remaining 4 cases (23.5%) 3 had no change and 1 showed progression after neoadjuvant combination chemotherapy. A significant relationship was observed between the overexpression of p53 and the sensitivity to chemotherapy; responder patients showed a higher frequency of p53 positive cells than non-responders (P = 0.03). No significant relationship with MIB 1 index was observed. Both expression of p53 protein (P < 0.001) and reaction with MIB 1 (P = 0.003) significantly decreased after chemotherapy. The decrease in expression of p53 protein and staining with antibody MIB 1 was particularly evident in patients who responded to chemotherapy. DISCUSSION: In tumors, p53 protein and index of proliferating cells as determined with MIB 1 showed a significant modulation after treatment, suggesting an association with sensitivity to chemotherapy. However, the limited number of our series of patients does not permit a statement on the clinical implication of expression of p53 and cell proliferation in patients undergoing neoadjuvant combination chemotherapy for locally advanced cervical carcinoma.

Combined malignant hemangiopericytoma and deep venous thrombosis. A case report.

Malignancies, antiproliferative drug treatment, cancer-related conditions like immobilization, perioperative status and radiotherapy are risk factors for hypercoagulability. Setting aside mass or invasion-related venous thrombosis, the differential diagnosis regarding the etiopathogenesis (paraneoplastic syndrome or antiproliferative treatment) is usually problematic. The authors report a case of combined malignant hemangiopericytoma and recurrent deep venous thrombosis in the right inferior limb. Through a literature review, the following issues are discussed: 1) the criteria for cyto-histopathologic assessment; 2) the involvement of pericytes both in coagulation and platelet aggregation; 3) the importance of discriminating true paraneoplastic syndromes from other tumor-related clinical manifestations; 4) the response to external radiotherapy of malignant hemangiopericytoma as limited disease; 5) the poor results of doxorubicin-ifosfamide polychemotherapy and dacarbazine monochemotherapy in metastatic disease. Although doxorubicin-ifosfamide treatment was in progress in the reported case, the authors conclude that the recurrent deep venous thrombosis is likely to be paraneoplastic, even if such a diagnosis has not been previously reported in the literature.

Endometrioid carcinoma of the ovary. Retrospective study.

From 1985 to 1991, 9 patients with endometrioid carcinoma of the ovary were treated and followed at the University of Ancona, Department of Gynecology and Obstetrics. Four patients (44.4%) had Stage I disease, 1 (11.1%) Stage II, 1 (11.1%) Stage III and 3 (33.3%) Stage IV. Six patients (66.6%) had grade 2 of the disease and 3 (33.3%) grade 3. Two of the patients (22.2%) had synchronous endometrial carcinoma while 3 had histologic evidence of endometriosis at the time of presentation. All the patients received treatment of combination of surgery, polychemotherapy, hormone and/or immunotherapy. The overall survival rate after a median follow up of 26.6 months was 66.6%. A high survival (100%) was observed for patients with associated endometriosis.

[Angiomatoid malignant fibrous histiocytoma. Clinico-pathologic and immunohistochemical study of a case]. / Istiocitoma fibroso maligno angiomatoide. Studio clinico-patologico ed immunoistochimico di un caso.

The results of a clinico-pathologic and immunohistochemical study of an angiomatoid malignant fibrous histiocytoma are reported. This lesion is an uncommon tumor of the superficial soft tissue, of low-grade malignancy, typical of adolescence and early adult life. The patient, a 10-year-old female, presented with a mass of the left popliteal fossa, treated with surgical excision of the tumor and the surrounding cutaneous and subcutaneous tissue. The tumor was a well-circumscribed, firm nodule measuring 2.5 x 1.0 cm. Histologically, it showed aggregates of spindled and rounded cells often lining cystic cavities filled with blood. The immunohistochemical analysis revealed a cytoplasmatic immunoreactivity for KP1 (CD68), which was taken as indicating that the tumoral mesenchymal cells had acquired phagocytic capacities. The patient is well without signs of local recurrence or metastatic disease 4 years after the surgical treatment. The case reported confirms that appropriate local surgery is the elective therapy for this type of soft tissue tumor.

Breast cancer and primary systemic therapy. Results of the Consensus Meeting on the recommendations for pathological examination and histological report of breast cancer specimens in the Marche Region.

Primary systemic therapy (PST) adds some practical problems to the pathologic examination of neoplastic breast tissue obtained from patients before and after chemotherapy. Pathologists, oncologists, breast surgeons, radiotherapists and radiologists in the Marche Region held a Consensus Meeting in Ancona on May 13, 2010, in which 15 statements dealing with neoadjuvant chemotherapy were approved by all participants. The first two statements are related to the pre-PST phase and concern the technical procedures and the histological report of the core biopsy. The other statements deal with similar issues of the post-PST surgical specimen.