A new nested primer pair improves the specificity of CK-19 mRNA detection by RT-PCR in occult breast cancer cells.

Reverse transcription polymerase chain reaction (RT-PCR) of cytokeratin-19 (CK-19) has been widely used to detect small numbers of circulating malignant epithelial cells in the bone marrow or the peripheral blood of patients with breast cancer. However, a high percentage of false positive results has been recorded and conflicting reports question the clinical relevance of this technical approach. We demonstrate that the use of a new nested primer pair for CK-19 RT-PCR avoids false positive results without affecting the sensitivity of the assay. Our experiments were carried out using MCF-7 cells alone or mixed with peripheral blood mononuclear cells (PBMNC) of healthy donors. The results were also validated in a large series of healthy donors and in a preliminary study on a limited number of patients with breast cancer, thus suggesting that our assay is feasible for application in the clinical evaluation of occult malignant epithelial cells.

The impact of a psychological intervention on quality of life in non-metastatic breast cancer.

The aim of this study was to determine whether psychological intervention had a beneficial effect on the quality of life and behaviour of women diagnosed with breast cancer. 36 consecutive patients with non-metastatic breast cancer assigned to surgery and systemic chemotherapy were randomised to receive either psychological intervention (weekly cognitive individual psychotherapy and bimonthly family counselling) or standard follow-up. Personality (16-PF and IIQ), quality of life (FLIC), and depression (BDI) scores were the endpoints for this study, and the questionnaires were completed by the patients at diagnosis, and up to 9 months after diagnosis. Cognitive psychotherapy and family counselling improved both depression and quality of life indexes compared with the control group. Better emotional coping behaviours were also revealed by some changes in personality traits in the intervention group.

Tissue polypeptide antigen in breast cancer cytosol: a new effective prognostic indicator.

Since 1982 we have been evaluating oestrogen and progesterone receptors (PgR), cathepsin D and the cytosolic levels of the tumour marker, tissue polypeptide antigen (TPA), in 257 patients radically resected for breast cancer (follow-up 24-81 months). TPA was measured by an immunoradiometric assay previously validated for cytosol. No significant associations were found between cytosolic TPA and age, tumour size, lymph-node status, receptor status and cathepsin D. TPA+ cases showed a significantly longer disease-free survival (DFS) and overall survival (OS) than TPA-patients (log-rank P < 0.0001). The prognostic value of cytosolic TPA was also demonstrated after stratification by nodal status, PgR and cathepsin D. The prognostic value of TPA was independent of the other prognostic indicators, being the most powerful among the evaluated indices (Cox multivariate analysis: chi 2 15.5 for DFS, 11.4 for OS). We conclude that cytosolic TPA is a powerful additional prognostic factor in primary breast cancer. Its prognostic role should therefore be extensively evaluated.

Epirubicin, methotrexate and bleomycin in the management of recurrent squamous cell head and neck cancer. A GSTTC randomised phase II study.

53 patients with squamous cell carcinoma of the head and neck recurrent after initial treatment were entered into a phase II trial of the epirubicin, methotrexate and bleomycin (EMB) combination. The primary objective of the study was to evaluate the activity of this combination. Compliance to EMB and the possible non-cross-resistance to previous cisplatin-containing chemotherapy were secondary objectives. In order to avoid patient selection bias, the study involved randomisation between EMB and a cisplatin-methotrexate-bleomycin (DMB) combination (with EMB: DMB = 2:1). 23 out of 53 (43% +/- 13) EMB patients showed an objective response, lasting a median of 12 (range 4-39) weeks; interestingly, 5 out of 14 (36% +/- 25) patients pretreated with cisplatin plus 5-fluorouracil responded to EMB. The treatment compliance was good and a median of three courses was delivered. No patient refused the treatment after the initial cycle. Leukopenia (47%) and oral mucositis (42%) were the main side effects. DMB produced a response rate of 33% +/- 18 with a median duration of 5 (4-13) weeks. None of the patients previously treated with cisplatin plus 5-fluorouracil responded. 5 patients refused the treatment after the first cycle and a median of two cycles (0-5) was delivered. In conclusion, EMB produced results similar to cisplatin-containing regimens, with a mild to moderate toxicity and a good compliance; the possible non cross-resistance with cisplatin plus 5-fluorouracil deserves further evaluation.

Biochemical parameters for prognostic evaluation in patients with breast cancer.

We evaluated the prognostic value of tissue polypeptide antigen (TPA), cathepsin D and pS2 in 267 patients operated for primary breast cancer. Cathepsin D, pS2 and cytosol TPA were independent of each other and of N, T, estrogen (ER) and progesterone (PgR) receptors. Cathepsin D was the best prognostic indicator for disease-free survival and pS2 for overall survival. The simultaneous evaluation of the three parameters was an effective discriminator between high and low risk patients in both N- and N+. Considering that cathepsin D, pS2 and cytosol TPA can be easily measured with reliable methods in small amounts of tissue, we conclude that they are a promising panel of biochemical parameters suitable for the assessment of the risk of relapse in patients with breast cancer.

ErbB2 assay in breast cancer: possibly improved clinical information using a quantitative method.

ErbB2/neu protein (p185) expression was evaluated by ELISA in 115 breast cancer specimens. Distribution was subdivided in quartiles and showed a distinct behaviour in comparison with both clinico-biological parameters and clinical outcome. In particular, intermediate concentration groups showed a significantly better disease-free survival than the low and high concentration groups (p = 0.02). We classified the patients as "low risk" (64 samples with p185 concentrations between 2150 and 30000 U/mg of proteins) and "high risk" on the basis of the results of the multivariate analysis. The p185 grouped as described showed a significant relationship with the disease free survival in multivariate analysis. Although the data must be considered as preliminary, they suggest the possibility of identifying more appropriately the high risk patients through the biochemical determination of p185.

Response and toxicity of cisplatin and 120-h 5-fluorouracil infusion in pretreated and untreated patients with advanced epidermoid cancer of the head and neck.

Eighty-two patients with advanced or recurrent squamous cell carcinoma of the head and neck were treated with bolus cisplatin and 120-h infusion of 5-fluorouracil. Among 49 pretreated patients, there were 9 complete and 12 partial responses, for an overall response rate of 43% and a median estimated survival of 8 months. Hematologic toxicity in this group was relevant, with 4 early deaths and 30% of cases with moderate to severe leukopenia; mucosal and renal toxicities were also important. Among 33 patients with no prior therapy, there were 8 complete and 17 partial responses, for an overall response rate of 76%. Fifteen of the 25 responding patients received subsequent locoregional treatment. The median estimated survival in this group was 29 months. Hematologic, mucosal, and renal toxicities were only mild to moderate. Episodes of possible 5-fluorouracil-related cardiotoxicity were recorded in both pretreated and untreated patients. Twelve of 41 partial responses observed after the second cycle of therapy were converted to complete responses with a third (8 cases) and also a fourth (4 cases) course. This study confirmed that cisplatin plus 5-fluorouracil is a first-choice combination in previously untreated patients. Definitive evidence that chemotherapy can favorable influence survival awaits confirmation by randomized trials, using a control arm with conventional locoregional treatment. In previously treated patients with recurrent disease, less intensive regimens not requiring hospitalization seem more useful for the quality of life.

Femoral nerve palsy secondary to anticoagulant induced iliacus hematoma. A case report.

A case of femoral neuropathy from iliac muscle hematoma occurring in a patient treated with urokinase, subcutaneous heparin and aspirin for myocardial infarction is reported. Diagnosis of this complication was suspected on the basis of clinical signs and on the fact that the patient had received anticoagulants. Computed tomography allowed direct and clear visualization of the hematoma. Anticoagulant suspension followed by an early surgical decompression seems to be the ideal treatment for this neuropathy; however, our patient died for a reinfarction after stopping heparinic administration. This may indicate that, in some patients "at risk", it is better to reduce rather than stop anticoagulant therapy.

Vindesine in the treatment of squamous cell carcinoma (WHO I), adenocarcinoma (WHO III), and large cell carcinoma (WHO IV) of the lung.

The antineoplastic activity of vindesine was evaluated in 57 patients with non-small-cell carcinoma of the lung, 53 patients were fully evaluable for response and toxicity. Twenty-seven patients had squamous cell carcinoma (WHO I), 14 had adenocarcinoma (WHO III), and 12 had large cell carcinoma (WHO IV). Forty percent of patients were previously treated. Vindesine was administered at a weekly i.v. dose of 3 mg/m2. Partial remissions were observed in 2 of 12 patients with large cell carcinoma and in 1 of 27 patients with squamous cell carcinoma. Among 14 patients with adenocarcinoma, 3 minor responses were observed. Drug-related toxic effects (mainly leukopenia with manageable and reversible neurotoxicity) required modification of dose in 41% of patients: this finding and previous treatment may have adversely affected the response rate. It is concluded that vindesine as a single agent has some activity in large cell carcinoma. Activity in the other histologic types was minimal but not totally absent and deserves further evaluation, possibly in non-pretreated patients.

Serum copper level in non-Hodgkin's lymphomas.

Serum copper level (SCL) was studied by the atomic absorption technique in 103 patients with non-Hodgkin's lymphoma. SCL was increased in 61% of patients at diagnosis or during active disease; values within normal range were found in 88% of patients in complete remission. The difference between mean SCL during active disease and in remission was highly significant, independently of stage and histologic type, so that: a) Within the same clinical stage high SCL at diagnosis was associated with poorer response to therapy in stage II and stage III (respectively P = 0.033 and P = 0.049), but not in stage IV, where the complete remissions were only 8 out of 42. A shorter 5-year survival was also shown in stages III and IV with high SCL at diagnosis (respectively P less than 0.025 and P less than 0.05), but not in stage II where the deaths were only 3 out of 24. b) Within histologic types, SCL is a useful prognostic index of response to therapy and survival, although a statistically significant difference was only reached for poorly differentiated lymphocytic lymphoma. We conclude that SCL may be a good parameter of disease activity and a useful index of response to therapy and survival in non-Hodgkin's lymphoma.

Phase II evaluation of vindesine in mycosis fungoides, extraosseous plasmacytoma and other hematologic malignancies.

We conducted a phase II trial of Vindesine in 24 patients, mostly pretreated (23/24 fully evaluable for therapeutic response) with advanced hematologic malignancies. The drug was administered at weekly bolus doses of 3 mg/m2 i.v. Overall, objective tumor regressions were seen in 9 of 23 patients. The drug appeared effective in extraosseous plasmacytoma (1 complete response, 1 partial response and 1 minor response in 6 patients). Further phase II trials in these 2 diseases are justified. In addition, 3 partial responses in 7 patients with advanced lymphoma were also obtained. Previous vinca-alkaloid exposure did not adversely affect the response rate: 8 of 9 responsive patients had previously received vincristine and/or vinblastine. Drug-related toxic effects were mainly represented by manageable and reversible neurotoxicity and by moderate leukopenia with apparent lack of thrombocytopenia. In heavily pretreated patients, leukopenia may be occasionally severe: in these conditions a starting dose of 2 mg/m2 seems more appropriate.

Cisplatin plus vindesine versus cisplatin plus VP16 versus doxorubicin plus cytoxan in non-small-cell carcinoma of the lung. A randomized study.

From March 1981 to January 1984, 116 patients with advanced non-small-cell carcinoma of the lung (NSCCL) were randomly assigned to 3 combinations as follows: CDDP + DVA, CDDP + VP16 and DXR + CTX. 94 patients were evaluable for response, 106 for toxicity and survival. Of 31 patients, 15 (48%; 3 CRs and 12 PRs) responded to CDDP + DVA; of 33 patients, 12 (36%, 2 CRs and 10 PRs) responded to CDDP + VP16; of 30 patients, 3 (10%) obtained a PR with DXR + CTX (CDDP + DVA vs DXR + CTX, P less than 0.005; CDDP + VP16 vs DXR + CTX, P less than 0.05; CDDP + DVA vs CDDP + VP16, P = NS). The median duration of response was 22 weeks in the CDDP-DVA group, 17 weeks in the CDDP-VP16 group, and 16 weeks in the DXR + CTX group. No significant difference in survival was observed among the 3 groups (median: 43, 47, 41 weeks, respectively). Hematologic and neurologic toxicities were significantly higher in the DVA-containing regimen. Despite the lack of improvement of overall survival with the CDDP-containing combinations over the DXR + CTX control group, the good response rate makes them suitable to be used in combined therapeutic strategies.

Cis-dichlorodiammineplatinum (II), VP 16-213, and prednisone (DVP regimen) in the treatment of pretreated advanced malignant lymphomas.

Eighteen evaluable patients with advanced malignant lymphoma were treated with a combination of cis-dichlorodiammineplatinum (II) (50 mg/m2 i.v. on day 1), VP 16-213 (100 mg/m2 i.v. on days 1, 3, 5), and prednisone (50 mg/m2 per os on days 1-5), recycling every 2 weeks. All patients were previously pretreated. There were 3 complete remissions (patients with Hodgkin's disease), and 4 partial remission (2 patients with Hodgkin's and 2 with non-Hodgkin's lymphoma), for a median duration of 8 weeks. In addition, 2 minor responses (patients with Hodgkin's disease) were observed. Vomiting and myelosuppression were the most prominent toxic effects. In most heavily pretreated patients, myelosuppression was moderate to severe: in these patients and in patients with bone marrow involvement, a schedule interval of 3 weeks should be more appropriate. Nephrotoxicity was minimal. This combination chemotherapy showed some activity in the management of advanced malignant lymphomas; further studies in this area are justified.

Phase II evaluation of 4'epi-doxorubicin in patients with metastatic colorectal carcinoma.

Thirty-four evaluable patients with metastatic colorectal carcinoma (13 rectal primary and 21 colonic primary, 4 pretreated and 30 untreated) received 4'epi-doxorubicin at the dose of 75 mg/m2 i.v. once every 21 days, for a minimum of 2 courses. Symptomatic toxicity (mainly confined to gastrointestinal complaints) was short-lived and easily managed. Hematologic toxicity was mild. Transient electrocardiographic abnormalities were found in 50% of patients, without signs of significant cumulative cardiotoxicity. Three previously untreated patients achieved a partial response (lasting 16, 12 and 12 weeks, respectively) with a response rate of 9% (3%-23%, 95% confidence interval). More interestingly, all responsive patients had rectal cancer: further studies of 4'epi-doxorubicin confined to the rectal localization seem warranted.

[A rare case of recurrent meningitis: intranasal encephalocele]. / Una rara causa di meningiti recidivanti: l'encefalocele intranasale.

Intranasal meningoencephalocele is a rare malformation characterized by a protrusion of brain tissue and meninges out of the cranial cavity into the nose, through a discontinuity of the ethmoidal cribriform plate. It is a congenital anomaly but it may be also due to trauma or to chronic intracranial hypertension. It is clinically apparent as a small mass that may be confused with nasal polyp. A cerebrospinal fluid leakage may be present. In a few cases it gives no symptoms until adulthood, but usually recurrent meningitis may occur. A case of young woman with intranasal encephalomeningocele who suffered from 18 episodes of meningitis is reported. Nevertheless she is at present without neurological consequences.

[Superficial bladder neoplasia unresponsive to endocavitary treatment: when should the treatment approach be changed?]. / Neoplasie vescicali superficiali non responsive al trattamento endocavitario: quando cambiare approccio terapeutico?

PURPOSE: The appropriate treatment of superficial bladder neoplasm is still debated. The urologist must weigh the risk of tumor recurrence and progression against the possible side effects of conservative treatment (transurethral resection, intravesical therapy). Furthermore it is difficult to decide exactly when to abandon the conservative therapy and proceed with radical cystectomy and urinary diversion in order to prevent the potentially lethal sequelae of invasive bladder cancer. There are no certain scientific data on the appropriate therapeutic approach of recurrences of superficial bladder cancer after intravesical therapy and often the urologist takes a decision based on his personal experience ("art rather than science"). Based on these considerations, our aim was to evaluate applicable criteria to predict the risks of tumor recurrence and progression and so decide the best treatment for each patient. METHODS: 148 patients with multifocal, multirecurrent or persistent superficial bladder cancer (stage Ta-T1-Tis, G1-3) were treated with transurethral resection and/or two or more administration of intravesical chemo- (Mitomycin C, Doxorubicin, Epirubicin, Mitoxantron) or immuno-therapy (BCG) using common treatment schedule. Our first end point was the disease-free survival (DFS) evaluated by three different criteria: 1) "dynamic" stage (stage T1 diagnosed at the beginning, or during the follow-up or never); 2) "dynamic" grade (G3 tumor diagnosed at the beginning or during the follow-up or never); 3) "number of positive cystoscopies at the 3-year follow-up". Data were evaluated by a univariate statistical analysis (log-rank test) and a multivariate ones (MPLR stepwise procedure and L-ratio Cox's test). RESULTS: "Dynamic" stage: patients who never developed a T1 stage tumor have a better DFS than patients who developed a T1 stage tumor and even more than patients in which T1 was diagnosed from the beginning (p < 0.0001). "Dynamic" grade: patients who never developed a G3 tumor have a better DFS than patients who developed a G3 tumor and patients in which G3 tumor was diagnosed from the beginning (p < 0.0017). "Number of positive cystoscopies at the 3-year follow-up": patients with less than 3 positive cystoscopies have a better prognosis than patients with 3 or more positive cystoscopies at the three-year follow-up (p < 0.0380). DISCUSSION: We have found three independent predictive prognostic factors: "dynamic" stage, "dynamic" grade and number of positive cystoscopies at the 3-year follow-up. The statistical univariate and multivariate analyses allow us to define three risk categories for tumor progression (> or = T2): low, moderate, high.

A prospective observational study to evaluate G-CSF usage in patients with solid tumors receiving myelosuppressive chemotherapy in Italian clinical oncology practice.

Febrile neutropenia (FN) is a severe dose-limiting side effect of myelosuppressive chemotherapy in patients with solid tumors. Clinical practice guidelines recommend primary prophylaxis with G-CSF in patients with an overall ≥ 20 % risk of FN. AIOM Italian guidelines recommend starting G-CSF within 24-72 h after chemotherapy; for daily G-CSF, administration should continue until the absolute neutrophil count (ANC) is 1 × 10(9)/L post-nadir and should not be terminated after ANC increase in the early days of administration. The aim of this study was to assess guideline adherence in oncology practice in Italy. In this multicenter, prospective, observational study, patients were enrolled at the first G-CSF use in any cycle and were followed for two subsequent cycles (or until the end of chemotherapy if less than two additional cycles). Primary objective was to explore G-CSF use in Italian clinical practice; therefore, data were collected on the G-CSF type, timing of administration, and number of doses. 512 eligible patients were enrolled (median age, 62). The most common tumor types were breast (36 %), lung (18 %), and colorectal (13 %). A total of 1,164 G-CSF cycles (daily G-CSF, 718; pegfilgrastim, 446) were observed. Daily G-CSF was administered later than 72 h after chemotherapy in 42 % of cycles, and the median [range] number of doses was four [1, 10]. Pegfilgrastim was administered later than 72 h in 8 % of cycles. G-CSF prophylaxis in Italy is frequently administered in a manner which is not supported by evidence-based guidelines. As this practice may lead to poor outcomes, educational initiatives are recommended.

Activity of endovesical gemcitabine in BCG-refractory bladder cancer patients: a translational study.

Intravesical gemcitabine (Gem) has shown promising activity against transitional cell carcinomas (TCC) of the bladder, with moderate urinary toxicity and low systemic absorption. The present phase II study evaluated the activity of biweekly intravesical treatment with Gem using a scheme directly derived from in vitro preclinical studies. Patients with Bacille Calmette-Guérin (BCG) -refractory Ta G3, T1 G1-3 TCC underwent transurethral bladder resection and then intravesical instillation with 2000 mg Gem diluted in 50 ml saline solution on days 1 and 3 for 6 consecutive weeks. Thirty-eight (95%) of the 40 patients showed persistent negative post-treatment cystoscopy and cytology 6 months after Gem treatment, while the remaining 2 patients relapsed at 5 and 6 months. At a median follow-up of 28 months, recurrences had occurred in 14 patients. Among these, four had downstaged (T) disease, three had a lower grade (G) lesion and three had a reduction in both T and G. Urinary and systemic toxicity was very low, with no alterations in biochemical profiles. In conclusion, biweekly instillation of Gem proved active in BCG-refractory Ta G3, T1 G1-3 TCC. Our results highlight the importance of preclinical studies using in vitro systems that adequately reproduce the conditions of intravesical clinical treatment to define the best therapeutic schedule.

Phase II study of sequential hormonal therapy with anastrozole/exemestane in advanced and metastatic breast cancer.

Hormonal therapy is the preferred systemic treatment for recurrent or metastatic, post-menopausal hormone-receptor-positive breast cancer. Previous studies have shown that there is no cross-resistance between exemestane and reversible aromatase inhibitors. Exposure to hormonal therapy does not hamper later response to chemotherapy. Patients with locally advanced or metastatic, hormonal receptor positive or unknown, breast cancer were treated with oral anastrozole, until disease progression, followed by oral exemestane until new evidence of disease progression. The primary end point of the study was clinical benefit, defined as the sum of complete responses (CR), partial responses (PR) and > 24 weeks stable disease (SD). In all, 100 patients were enrolled in the study. Anastrozole produced eight CR and 19 PR for an overall response rate of 27% (95% CI: 18.6-36.8%). An additional 46 patients had long-term (> 24 weeks) SD for an overall clinical benefit of 73% (95% CI: 63.2-81.4). Median time to progression (TTP) was 11 months (95% CI: 10-12). A total of 50 patients were evaluated for the second-line treatment: exemestane produced one CR and three PR; 25 patients had SD which lasted > or = 6 months in 18 patients. Median TTP was 5 months. Toxicity of treatment was low. Our study confirms that treatment with sequential hormonal agents can extend the period of time during which endocrine therapy can be used, thereby deferring the decision to use chemotherapy.

Retroperitoneal, mediastinal and subcutaneous emphysema as a complication of routine upper gastrointestinal endoscopy.

Diagnostic endoscopy of the upper gastrointestinal tract is a safe procedure, which, however, is not without complications. We report the rare occurrence of retroperitoneal, mediastinal and subcutaneous emphysema following routine endoscopy, with no obvious evidence of a site of perforation. Possible etiological aspects are discussed. This complication appeared to be a benign clinical condition that was resolved with conservative, nonsurgical treatment.