Pathological classification of DCIS and planning of therapeutic management.

BACKGROUND: Ductal intraepitelial neoplasia (DIN) represents a spectrum of disease that may progress from usual hyperplasia to ductal carcinoma in situ (DCIS) grade 3. The aim of the study was to asses the correlation between the DIN classification and the surgical treatment including sentinel lymph node biopsy (SLNB). PATIENTS AND METHODS: In this retrospective study, 229 patients with DIN had undergone conservative or radical surgical treatment and SLNB in cases of DIN1C-DIN3. RESULTS: Breast conservative surgery was the definitive treatment in 80% of the cases. The H&E evaluation of excised sentinel nodes was negative for metastatic disease; nevertheless the immunohistochemical (IHC) evaluation revealed the presence of metastatic cells in 6 patients (3.7%). CONCLUSION: In cases of DIN lesions SLNB is not indicated. The only reason SLNB should be considered is when there is an evidence of invasive foci at definitive histology or when radical mastectomy is proposed.

Phenotypic and genotypic alterations characterize patients bearing plasma cell dyscrasias with a high M-component.

As at present only a long-term follow-up can fully determine whether monoclonal gammapathies of undetermined significance (MGUS) will evolve into multiple myeloma (MM), this study attempted to identify other variables connected with the amount of monoclonal component (MC), generally considered as the most reliable marker of malignant evolution. Thirty-four MGUS subjects showing a high MC (> or = 15.0 g/l) but without clinical evidence of MM (MGUS group b), were characterized for their phenotypic and genotypic profile by comparing them either with 40 MM patients or with 24 subjects affected by a benign form of monoclonal gammapathy (MGUS group a) according to the standard criteria. In addition to the usual laboratory markers, the levels of expression of a panel of CD membrane subsets were measured on B and T lymphocytes. Also, the serum level of the p53 mutant protein and the structural alterations of the c-myc oncogene were evaluated. The results show that for MGUS group b patients, an increased M-protein was accompanied by significantly increased levels of peripheral blood CD3+ T cells and oncogenetic aberrations in c-myc. Since a high serum MC level seems to indicate a greater likelihood of malignant transformation for MGUS patients, these findings suggest that this relationship may be a result of the concomitant alterations observed at a phenotypic and genotypic level. Such alterations may be potentially useful as surrogate markers for the transition of benign to malignant (MM) plasma cell dyscrasia.

Correlation between tumor necrosis factor-alpha and D-dimer levels in non-small cell lung cancer patients.

The present study was designed to investigate whether a correlation exists between IL-6, TNF-alpha and coagulation (Thrombin-antithrombin, TATc) or fibrinolysis (D-dimer) activation in non-small cell lung cancer (NSCLC) patients. One hundred thirty patients with NSCLC (n=65, 53 males, mean age 65 +/- 8, adenocarcinoma n=32, squamous cancer n=33) or chronic obstructive pulmonary disease (COPD) (n=65, 51 males, mean age 67 +/- 9) were studied. As control group 65 healthy donors (51 males, mean age 61 +/- 14) were also evaluated. The results obtained showed that median D-dimer levels were higher in NSCLC patients (3.0 microg/ml) compared either to COPD patients (1.1 microg/ml, P<0.05) or controls (0.3 microg/ml, P<0.0001). Positive TNF-alpha levels (>10 pg/ml) were found in 26% of NSCLC compared to 3% of COPD (P<0.002) and 5% of controls (P<0.0005). On the other hand, positive (>8.5 pg/ml) IL-6 levels were found in 53% of NSCLC and 21% of COPD patients, compared to 5% of control subjects (P<0.001). Median TATc levels were elevated in either NSCLC (6.9 microg/l) or COPD (5.7 microg/l) patients compared to controls (1.8 microg/l, P<0.0001). Elevated D-dimer levels were significantly associated to positive TNF-alpha levels in patients without distant metastasis (F=4.3, P<0.05). Moreover, TNF-alpha levels (P<0.01) were independently related to the presence of positive D-dimer levels in patients with non-metastatic NSCLC. These results suggest that increased levels of TNF-alpha might be responsible for an activation of fibrinolysis in patients with NSCLC.

Role of P53 and BCL-2 in high-risk breast cancer patients treated with adjuvant anthracycline-based chemotherapy.

PURPOSE: Adjuvant therapy has become an integral component of the managment of primary high-risk breast cancer patients. However, a considerable fraction of women receive no benefit from this treatment. This study investigates whether a number of biopathological factors can influence the outcome of patients submitted to adjuvant chemotherapy involving the use of high-dose epirubicin and cyclophosphamide. METHODS: One hundred and fifty-seven primary breast cancer patients, considered at high risk according to the St. Gallen Meeting Consensus Conference, were evaluated immunohistochemically for estrogen, progesterone receptors, p53, bcl-2, HER-2/neu, and Ki-67, of which the results were correlated with patient outcome. RESULTS: Results obtained demonstrated that p53 is a significant predictor of disease-free survival (DFS P < 0.0001) and overall survival (OS P = 0.0002) both in ductal and lobular carcinomas, whereas bcl-2 expression seems to be of prognostic value only in lobular carcinomas (DFS P = 0.01; OS P = 0.02). CONCLUSIONS: This data indicates that in high-risk breast cancer patients the immunohistochemical evaluation of p53 and bcl-2 may be of clinical value in distinguishing different responses to adjuvant anthracycline-based chemotherapy.

Potential usefulness of serum p53 for laboratory management of plasma cell dyscrasias.

We measured the serum levels of p53 mutant protein (p53M-ELISA) in 65 patients with plasma cell dyscrasia (PCD) and compared them with some conventional laboratory variables. Our aim was to assess, for the first time, the potential of this parameter as a new marker for laboratory management of PCD. Twenthy-tree out of 65 patients had monoclonal gammapathy of undetermined significance (MGUS) and 42 suffered from multiple myeloma (MM). MM patients, with no prior chemotherapy consecutively entered this study. They were treated with standard regimens of Melphalan and Prednisone (MP) and were analyzed for serum p53M level from the time of diagnosis to response to therapy or death. A subgroup of nine patients was regularly monitored for changes occurring in p53M levels during MP therapy. Serum levels of p53M were elevated in MM patients compared with MGUS and healthy controls (p = 0.002). Significantly higher p53M levels were shown by MM patients refractory to chemotherapy than by responding patients (0.38 ng/ml vs 0.22 ng/ml, p = 0.05). The measurement of serum p53M in the nine patients during the course of chemotherapy correlated with disease progression or response to therapy. If confirmed on a larger series of patients, these results suggest a potential role of serum p53 mutant levels in laboratory management of PCD patients.

[Treatment of malignant pleural effusion by pleurodesis with talc]. / Trattamento del versamento pleurico maligno mediante pleurodesi con talco.

In some types of cancer (breast, lung) a malignant pleural effusion may be present during the evolution of the neoplastic disease in more than 50% of cases. The main therapeutic option for palliative purposes in these cases is chemical pleurodesis with talc. The aims of this study were to report on our experience with the use of pleurodesis with talc in the treatment of patients affected by malignant pleural effusions and to analyse the results in the short and mean term. Over the period from January 1998 to December 1999, 16 patients were included in the study. The causes of the pleural effusion were a pleural mesothelioma in 1 patient and pleural metastases in 15 patients (from lung and breast cancers in 62%). We treated 14 of these patients with talc poudrage and 2 patients with talc slurry. The talc was applied under video-assisted thorascopic management in 15 patients, while in 1 patient the talc was injected via the thoracic drainage tube. Two patients died within the first month as a result of progression of the neoplastic disease and one patient was withdrawn from the study owing to failure to collaborate. Of the other 13 patients, 11 (84%) had a total or partial response to the pleurodesis; in 9 of these patients (69.2%) the response remained stable until death, while in 2 patients the pleural effusion reappeared after 3 and 5 months, respectively. Failure of the pleurodesis occurred in 2/13 patients owing to reappearance of the pleural effusion within the first month.

[IL-6, p53 and proto-oncogene c-myc play different roles as biological markers of plasma cell dyscrasias]. / IL-6, p53 e il proto-oncogene c-myc esercitano ruoli diversi come marcatori biologici di discrasie plasmacellulari.

PURPOSE: To determine the role of serum levels of IL-6 and p53 mutant protein as well as of c-myc proto-oncogene alterations: a) in discriminating between benign (MGUS) and malignant Plasma cell dyscrasias (Multiple and Microsecreting Myeloma, Plasmocytoma); b) in monitoring the clinical course of malignant forms of this disease. PATIENTS AND METHODS: Eighty-eight patients affected by Plasma cell dyscrasias (58 MGUS, 24 MM and 6 PLC) entered this study. Using commercially available ELISA kits, serum levels of IL-6 and p53 have been determined in all the patients. In addition, a selected group of patients (n = 30) was also analyzed for structural c-myc gene alterations by Southern blot technique. RESULTS: The results show that, conversely from p53 protein, IL-6 and c-myc gene may represent useful diagnostic markers for discriminating benign from malignant forms of Plasma cell dyscrasia. On the contrary, preliminary findings of the same work indicate a potential role for the mutant p53 protein in monitoring the response to chemotherapy of patients affected by MM or PLM. CONCLUSIONS: Overall, these data suggest that the combined use of IL-6, p53 and c-myc may provide a new approach for a more rational management of Plasma cell dyscrasia patients.

[Chemotherapy of advanced stage melanoma using cisplatin, epirubicin and alpha-interferon]. / Chemioimmunoterapia con cisplatino, epirubicina ed alfa-interferone nel melanoma in fase avanzata.

PURPOSE: To evaluate the activity and toxicity of cisplatin (DDP), epirubicin (EPI) and interferon alfa-2a (a-IFN) in patients (pts) with metastatic melanoma. PATIENTS AND METHODS: Thirty-seven pts with histologically-proven metastatic melanoma were treated with DDP 75 mg/m2 e.v. and EPI 90 mg/m2 e.v. on day 1 + alpha-IFN 9 MUI/die s.c. on days 4 to 8 and 18 to 22. Cycles were repeated every 4 weeks. RESULTS: Characteristics of the patients were the following: median age 55 years (range, 24-75), median WHO performance status 1 (range, 0-2), prior chemotherapy 9, prior immunotherapy 16 (adjuvant/advanced 11/5), sites of disease: soft tissue only 10, lung 22, liver 11, bone 1, brain 3. In 35 evaluable patients we have obtained 3 complete and 10 partial responses, for an overall response rate of 37%. Dose-limiting toxicity was myelosuppression with grade (G) 4 neutropenia in 59.5% of patients and G4 thrombocytopenia in 11% of patients. Other toxicities were generally mild to moderate with nausea and vomiting in 67.5% of patients, flu-like syndrome in 78.5% and fatigue in 48.5% of the patients. Median time to response, median time to progression and survival were 3 (range, 2-6), 7 (range, 2-45+) and 10 months (range, 4-45+), respectively. CONCLUSION: This combination is active and well tolerated in metastatic melanoma. Toxicity was manageable and has enabled us to conduct this trial on an outpatient basis.

[Gemcitabine in advanced stage soft tissue sarcoma: a phase II study]. / Gemcitabina nei sarcomi dei tessuti molli in fase avanzata: studio di fase II.

PURPOSE: To assess the activity and toxicity of gemcitabine in locally advanced or metastatic soft tissue sarcoma patients (pts). PATIENTS AND METHODS: Gemcitabine was administered on days 1, 8, 15 every 4 weeks at a dose of 1.000/1.250 mg/m2, respectively, in pretreated or not pretreated pts. RESULTS: Eighteen pts entered this phase II trial; sixteen had been previously treated with anthracyclines and ifosfamide. A partial response was observed in a woman with fibrous malignant istocytoma, whereas in 7 pts the disease remained stable. Median time to progression was 4 months. The treatment was well tolerated. Grade 4 toxicity was not observed. CONCLUSIONS: These results do not suggest that gemcitabine, in the dose and schedule used in this trial, may be of value in the treatment of soft tissue sarcomas.

Single-agent ifosfamide in the treatment of anthracycline-refractory adult sarcomas.

OBJECTIVE: The objective of this trial was to assess the therapeutic activity and toxicity of ifosfamide (IFO) with mesna uroprotection as salvage therapy in patients (pts) with soft tissue sarcomas (STS) who had failed high-dose epirubicin treatment. PATIENTS AND METHODS: IFO was administered at a dose of 2.0 g/m2 daily for 5 consecutive days by a 2-h i.v. infusion every 3 weeks. RESULTS: Partial responses were observed in 5/31 (16%) evaluable patients, whereas in other 5 pts the disease remained stable. The median duration of response was 8 months. The median overall survival was 6.5 months. The most common toxicity was hematologic with grade 3 or 4 neutropenia occurring in 47% of the pts. Neurologic toxicity was infrequent, but in 1 patient treatment discontinuation was needed because of severe mental confusion and disorientation. CONCLUSIONS: Although IFO can be of value in a minority of pts with anthracycline-refractory STS, more active agents and new salvage cytotoxic regimens should be investigated in this disease.

Determinants of homocysteine levels in colorectal and breast cancer patients.

BACKGROUND: Homocysteinemia has been associated with oncogenic risk. This study was designed to investigate the homocysteine (Hcy) genotype/phenotype interactions together with the inflammatory and nutritional status of cancer patients. PATIENTS AND METHODS: The Hcy levels were analyzed in 47 cancer patients in association with methylenetetrahydrofolate reductase (MTHFR) polymorphisms, folate and inflammatory markers. RESULTS: The MTHFR C677T and A1298C genotype distributions did not differ from those predicted by the Hardy-Weinberg distribution. Conversely, the Hcy levels were higher in the cancer patients (p=0.04), who were also characterized by low-grade inflammation. The Hcy levels correlated with the interleukin-6 (IL-6) (p=0.001), tumor necrosis factor-alpha (TNF-alpha) (p=0.042) and folate (p<0.0001) levels of the patients. Multivariate analysis showed that TNF-alpha (p=0.014) and folate (p=0.019) were independent predictors of elevated Hcy levels in the cancer patients. CONCLUSION: The MTHFR polymorphisms do not significantly contribute to tHcy (total Hcy) levels in cancer patients, and cancer-related inflammation may be associated with elevated tHcy levels, possibly involving a TNF-alpha mediated pathway.

Anatomical basis and rationale of total mesorectal excision.

The concept of TME for cancer of the mid rectum has been introduced by Heald in 1982. Since then the evidence in favor of routinely applying TME in all operable cases of mid and low rectal cancer has kept growing. TME has been shown to reduce the number of R1 resections and increase the number of R0 resections, resulting in a significantly reduced recurrence rate compared to traditional surgical technique. The authors have produced a video which illustrates the anatomical basis and technical details of TME. TME is the resection of the rectum together with the fatty and lymphatic tissue contained within the visceral sheet of the pelvic fascia. This paper details the anatomical basis of TME, describing the fascial structures and fibrous spaces along which the dissection must proceed.

[Epididymo-testicular abscess]. / Abscesos epidídimo-testiculares.

We reviewed the records of 34 patients with epididymal and/or testicular abscess that were treated at our institution. The mean age of the patients was 48.6 years. The most common clinical manifestation was scrotal pain. The diagnosis was made on the clinical and/or scrotal ultrasound findings. E. coli was isolated in 84.6% of the cases. Chronic and acute orchitis with abscess formation were the most common histological findings. Twenty-nine cases required antibiotic therapy plus surgery and five cases required antibiotics alone.