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.

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.

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.

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.

Serum lactate dehydrogenase (LDH) as a prognostic index for non-Hodgkin's lymphoma.

According to pretreatment values of serum lactate dehydrogenase (LDH), 113 consecutive patients with non-Hodgkin's lymphoma were divided into three levels: level 1 (within normal range) with LDH less than 250 U/l; level 2 (moderately increased) with LDH between 250 and 500 U/l; level 3 (highly increased) with LDH more than 500 U/l. LDH was elevated in 46 of 113 patients (41%). Normal values of LDH were associated with a better response to therapy and a longer survival, independent of histological type and clinical stage, with one exception; in stage IV patients conclusions could not be drawn concerning the response to therapy (complete remission occurred only in 8 of 44). Even though level 2 patients behaved slightly better than level 3 patients, no statistical difference has been observed between the two levels. Accordingly, serum LDH can be considered a useful predictor of response to therapy and of survival in non-Hodgkin's lymphoma.

The combination of mitomycin, vinblastine and cisplatin is active in the palliation of stage IIIB-IV non-small-cell lung cancer.

Twenty-eight patients with stage IIIB-IV non-small-cell lung cancer were treated with mitomycin C, vinblastine and cisplatin (MVP) in a phase II--minimax 2-stage design--randomized trial (with cisplatin plus etoposide as control arm). As indicated by the study design, the accrual was stopped after the 11th responder, and the combination was considered as active at the 40% level. Forty-six percent of patients had an improvement of their initial Karnofsky performance score, lasting a median of 24 weeks, and about 38% had a complete relief of symptoms. Hematologic toxicity was moderate to severe in about 50% of patients, and neurologic toxicity in about 18%; no grade 4 toxicity was observed. The estimated median progression-free survival was of 25 weeks. The observed activity and manageability, together with the positive effect on patient quality of life, account for a positive evaluation of MVP as a palliative treatment in advanced non-small-cell lung cancer.

Is stage pT4a (D1) reliable in assessing transitional cell carcinoma involvement of the prostate in patients with a concurrent bladder cancer? A necessary distinction for contiguous or noncontiguous involvement.

PURPOSE: A series of patients with concurrent transitional cell carcinoma involvement of the prostate and bladder is reviewed to define the impact of prostate involvement pathways and the degree of prostate invasion on survival rate. MATERIALS AND METHODS: A total of 72 patients who underwent radical cystectomy for pathological stage pT4a (D1) cancer was divided into contiguous--stage pT4a, transitional cell carcinoma of the bladder extended into the prostate through the bladder wall and noncontiguous--stage pT4a simultaneous transitional cell carcinoma of the prostate and bladder carcinoma that did not directly infiltrate into the prostate through the bladder wall. In the latter group the degree of prostate invasion was classified as urethral mucosal involvement, ductal/acinar involvement, stromal invasion and extracapsular extension. The survival rate was estimated by the Kaplan-Meier and Cox proportional hazards methods. Comparisons between curves were performed by univariate log rank and multivariate L-ratio tests. RESULTS: The overall 5-year survival rate for stage pT4a was 21.5% (median followup 64 months). Furthermore, 46% and 7% of patients in noncontiguous and contiguous pT4a groups, respectively, were estimated to be alive (p < 0.000). Those with positive nodes experienced a poor outcome in both groups. Of patients with noncontiguous pT4a stage 100% with urethral mucosal involvement, 50% with ductal/acinar involvement and 40% with stromal invasion were estimated to be alive. The major prognostic factors were bladder tumor stage, nodal involvement and degree of prostate invasion. CONCLUSIONS: The invasion pathways of the prostate in patients with transitional cell bladder carcinoma have a statistically significant prognostic role. Contiguous and noncontiguous involvements are 2 distinct clinicopathological features and they should not be included in the same stage. In the noncontiguous stage pT4a group bladder and prostate transitional cell carcinoma should be separately staged, and prostate involvement also should be staged according to invasion degree.

Late relapses in Hodgkin's disease: outcome of patients relapsing more than twelve months after primary chemotherapy.

BACKGROUND: Patients with Hodgkin's disease whose initial complete remissions (CR) after primary chemotherapy were longer than 1 year are thought to have better prognoses than patients whose initial remissions were shorter than 1 year. However, only a few studies have analyzed the long-term survival in addition to the results of retreatment in patients relapsing after CR lasting more than 1 year. PATIENTS AND METHODS: We analyzed the data of 40 patients with Hodgkin's disease who were treated in a single institution and whose CR were > 1 year after primary chemotherapy. Therapy at relapse was not standardized: of 36 patients evaluable for response, 29 received second-line chemotherapy and 7 received radiotherapy alone. RESULTS: Sixty-five percent of the patients obtained CR (median duration: 21 months). Sixty-eight percent of the complete responders relapsed again; however, long-lasting third and fourth remissions were observed. All of the 7 patients whose retreatment consisted of radiotherapy alone obtained CR, but only 1 is in continuous CR. The presence of nodular sclerosing histologic subtype, the absence of extranodal involvement and the use of hybrid MOPP/ABVD or ABVD alone as salvage treatment are independently associated with a higher CR rate and a higher probability of 5-year survival. The 5-year survival for all 40 patients is 49%. For the patients obtaining CR, the 5-year survival and the 5-year relapse-free survival are 76% and 25%, respectively. However, the survival curve continues to fall in the succeeding years because of third and fourth relapses and the occurrence of secondary acute leukemia and non-Hodgkin's lymphoma. CONCLUSIONS: A high percentage of patients relapsing more than 12 months after primary chemotherapy can obtain second CR. Even if most of our patients eventually relapse, third and fourth CRs are not uncommon. However, the long-term survival is low and it is further diminished by secondary leukemia and non-Hodgkin's lymphoma.

Hypnosis in the treatment of anticipatory nausea and vomiting in patients receiving cancer chemotherapy.

AIMS AND BACKGROUND: In addition to nausea and vomiting following chemotherapy treatment, cancer patients can experience these side effects prior to a treatment session, the so-called anticipatory nausea and vomiting. As various psychological and neurophysiological aspects have been claimed to be implied in its etiopathogenesis, the present paper aims to shortly review the etiological, epidemiological and therapeutical assumptions on the topic, in particular the psychological-behavioral therapies. PATIENTS AND METHODS: The present study was carried out on 16 consecutive adult cancer patients affected by chemotherapy-induced anticipatory nausea and vomiting who had received at least four treatment cycles. All of them were submitted to induction of relaxation followed by hypnosis. RESULTS: In all subjects anticipatory nausea and vomiting disappeared, and major responses to chemotherapy-induced emesis control were recorded in almost all patients. CONCLUSIONS: The experience highlights the potential value of hypnosis in the management of anticipatory nausea and vomiting; furthermore, the susceptibility to anticipatory nausea and vomiting is discussed under the psychoanalytic point of view.

PS2 in breast cancer--alternative or complementary tool to steroid receptor status? Evaluation of 446 cases.

The oestrogen induced pS2 protein was measured in the cytosol of 446 breast cancer samples by an immunoradiometric assay. The relationships between pS2 and several clinical and biological parameters were evaluated. pS2 was not correlated to age, pT and nodal status, while it was higher in pre- than in peri- and post-menopausal women. A statistically significant positive association was found between pS2 and ER, PgR and cathepsin D. However, the frequency of pS2 negative values in ER+ (25.6%), PgR+ (21.7%) and cathepsin D-(19.0%) cases suggests that pS2 provides information independent of the above parameters in a fairly high percentage of patients. The prognostic role of pS2 was evaluated in 267 cases (follow up time 24-102 months). pS2+ showed longer RFS (P = 0.016) and OS (P = 0.004) than pS2-. pS2+ cases were significantly associated with a better prognosis in N+ but not in N- cases. Multivariate analysis showed that pS2 is an independent prognostic factor being the second most effective indicator for OS after nodal status and the third for RFS after nodal status and cathepsin D. From the present findings, we conclude that pS2 probably provides additional biological information to steroid receptor status and cathepsin D in patients with primary breast cancer.

Peptichemio in pretreated patients with plasmacell neoplasms.

Twenty-one patients with alkylator-resistant plasmacell neoplasms were treated with Peptichemio (PTC) at a dose of 40 mg/m2 for 3 days every 3 weeks or, in the case of persistent leukopenia and/or thrombocytopenia, at the single dose of 70 mg/m2 every 2-3 weeks according to haematological recovery. Seventeen patients, 10 with multiple myeloma and seven with extramedullary plasmacytoma (EMP), were fully evaluable. Six of 17 patients (35%) responded: three of seven EMP patients had a complete remission and 3 of 10 multiple myeloma patients had an objective response greater than 50%. The median duration of response was 8.5 months. An EMP patient obtained a complete response lasting for 16 months. The most frequent toxic effect were phlebosclerosis, occurring in all the patients, and myelosuppression, which was severe in only one case. PTC appears to be an active drug in patients with plasmacell neoplasms even if resistant to alkylating agents.