Hematopoietic progenitor cells (HPCs) in node-negative invasive breast carcinomas: Immunohistochemical analysis and clinico-pathological correlations.

Using immunohistochemistry, we investigated 603 negative lymph nodes from 51 patients affected by invasive breast cancer (BC) to recognize bone marrow-derived hematopoietic progenitor cells (HPCs). HPC aggregates, revealed by CD34, CD133, VEGFR1, and CD117 antisera, were determined by an intensity-distribution score (ID). Cases with an ID-score >3 at least for one marker were considered to strongly express HPCs. Twenty-five of 51 (49%) high expressor patients were identified by CD34 antiserum, while 24/51 (47.1%), 17/51 (33.3%), and 15/51 (29.4%) were identified by CD117, CD133, and VEGFR1, respectively. No significant relationships were found between HPCs status and histotype, tumor grade, stage, and hormone receptors, as determined at the moment of the first diagnosis. A significant correlation was recorded for Ki-67 values, as well as for death from invasive BC. No statistical significance was achieved regarding HER2 status, although a tendency toward a statistically significant P value was obtained. A significant relationship (P<0.001) was found between high expressors of HPC and progression of disease, documented by the development of distant metastases. An equivalent P value was ascertained for osseous localizations, with a lesser value in other metastatic sites. Regarding the appearance of distant metastases, the greatest efficiency value was obtained by CD133 (85.7%). Overall survival (OS) and distant metastases-free survival (DMFS) revealed a high statistical significance for HPC expression, Ki-67 values, and HER2 status. By multivariate analysis, HPC expression and Ki-67 values emerged as the higher independent prognostic variables in the analysis of DMFS and OS, respectively.

Oral vinorelbine as first line chemotherapy in unfit elderly patients with hormone-refractory prostate cancer.

Hormone-refractory prostate cancer (HRPC) is a rapidly progressive disease which produces considerable morbidity and involves mostly men over 70, often comorbid and with poor tolerance to chemotherapy. Low-toxicity chemotherapy is a reasonable option in this setting. Vinorelbine and a corticosteroid show activity and clinical benefit responses in HRPC. An oral regimen is preferable for elderly patients. This study aimed to evaluate safety, prostate-specific antigen (PSA) response, clinical benefit and progression-free survival in chemonaive elderly HRPC patients. 33 men, median age 78.2, were treated with oral vinorelbine 60 mg/m2 days 1 and 8 every 3 weeks, escalable to 80 mg/m2 after the first cycle, and prednisone 5 mg b.i.d. The main toxicity was hematopoietic (mild at 60 mg/m2 and moderate at 80 mg/m2). Of 27 evaluable patients, 9 (33%) had PSA responses and 9 had clinical benefit, PSA-correlated in 5 cases (56%). Median progression-free survival was 13.4 weeks, median overall survival 45 weeks. Oral vinorelbine plus prednisone is safe and has moderate activity, with biochemical and clinical responses in about one-third of patients and could be an option in unfit elderly HRPC patients.

Protective effect of leuprolide on ovarian function in young women treated with adjuvant chemotherapy for early breast cancer: a multicenter phase II study.

The aim of this study was to evaluate the protective effect of concomitant leuprolide treatment on ovarian function in young women undergoing adjuvant chemotherapy for early breast cancer. 19 women, median age 36.5 years (range 26-40 years), with operable breast cancer and negative hormonal receptors, received six cycles of FEC 100 regimen as adjuvant chemotherapy and co-treatment with leuprolide. Menstrual resumption was gained in all patients in a median time of 5 months (range 3-8). Follicle-stimulating hormone and estradiol assessment was performed in all patients. The return to pre-menopausal values was achieved within 6 months of the last leuprolide administration. At a median follow-up of 3 years (range 1-5 years), no patient relapsed and four full-term pregnancies were recorded in four women, each of whom delivered a healthy infant. Our data are in agreement with similar experiences and confirm the activity of GnRH therapy in preventing ovarian failure.

Overview and new strategies in metastatic breast cancer (MBC) for treatment of tamoxifen-resistant patients.

The treatment with aromatase inhibitors (AIs) and fulvestrant has been demonstrated to be active in a proportion of tamoxifen-resistant breast cancer patients, obtaining, in some cases, a long-term control of tumor growth. Results from clinical trials indicate that treatment with fulvestrant might either precede or follow AIs. However, the AIs are now replacing tamoxifen as first-line advanced and adjuvant therapies, and thus, other options following tamoxifen failure are required. Fulvestrant may be effective in this setting, even if there is also evidence of a lack of cross-resistance between nonsteroidal and steroidal AIs, resulting in the potential use of steroidal AIs following nonsteroidal AI failure and vice versa. Resistance mechanisms to these therapies appear to be related to a cross talk between estrogen receptor (ER) and growth factor-signaling cascades. Novel therapeutic approaches for ER+ patients, which combine hormonal agents and signal transduction inhibitors, have been developed to overcoming resistance. Several trials are now investigating signal transduction inhibitors combined with endocrine agents. This approach might provide efficient treatments and delay the onset of antihormone resistance, thereby significantly improving patient's survival.

A modified weekly docetaxel schedule as first-line chemotherapy in elderly metastatic breast cancer: a safety study.

Standard dose docetaxel is burdened by severe toxicity. Weekly schedules have been shown to be active as standard scheme with reduced side effects. In 20-30% of elderly patients (pts) the classic 6-week schedule induces grade 3/4 fatigue and other cumulative toxicities. We carried out this safety study in order to evaluate whether a modified weekly docetaxel schedule would improve the toxicity profile. Twenty-one untreated elderly (> or = 70 years) pts suffering from metastatic breast cancer were enrolled in the study. Pts were treated with a weekly dose of 35 mg/m2 docetaxel for 6 weeks, followed by a 2-week rest. Further cycles were performed with this modified schedule: docetaxel days 1, 8 and 15 every 29 days. All pts received at least the first cycle (6 weeks). A total of 261 doses were delivered. No toxic deaths occurred. The toxicity was mild: we recorded 1 episode of grade 3 neutropenia and severe asthenia in only 2 pts (10%). We recorded an overall response rate of 33% (1 CR, 6 PR). Our data showed a reduced incidence of severe asthenia (2/21), obtained with a light modification of a weekly docetaxel schedule.

Venous damage prevention by defibrotide in vinorelbine-treated patients.

GOALS: The aim of our study was to evaluate the incidence of venous toxicity induced by vinorelbine administration in patients who received a preventive therapy with defibrotide. PATIENTS AND METHODS: From July 1996 to July 2002 we treated 203 patients with vinorelbine, 51 with vinorelbine alone and 152 with vinorelbine in combination with other drugs via peripheral vein infusion. Of the 203 patients, 123 were male and 80 female with a median age of 67 years (range 18 to 82 years), and 118 were chemotherapy-naive. Defibrotide was delivered i.v. at a dose of 400 mg in 250 ml normal saline. After infusion of 125 ml over about 15 min, vinorelbine mixed with 10 ml normal saline was delivered as quick brief repeated pulses over 5 min through the plastic tube, followed by infusion of the remaining defibrotide. The specific Rittenberg scale was used to assess venous irritation episodes. RESULTS: Among a total of 1336 vinorelbine infusions, with a median of five infusions per patient, the incidence of venous irritation episodes graded according to Rittenberg scale was 1.1% (15), of which 0.6% (8) were grade 2 and 0.5% (7) grade 1. Globally, 15 patients (7.3%) developed venous toxicity after a median of 3 infusions (range 1-14), but no patient had more than one event. CONCLUSION: Our findings support the use of defibrotide as an effective, safe and low-cost means for preventing vinorelbine-related venous damage.

Influence of 5-fluorouracil and folinic acid on interleukin-18 production in colorectal cancer patients.

AIMS AND BACKGROUND: This study was carried out to evaluate the IL-18 blood concentrations of operated colorectal cancer patients and their possible variation in response to combination chemotherapy with 5-fluorouracil (5-FU) and folinic acid. METHODS: IL-18 levels were assayed in sera of 18 healthy donors and 18 surgical colorectal cancer patients before and after adjuvant chemotherapy with 5-fluorouracil and folinic acid. An ELISA kit for human IL-18 was used for the assay. RESULTS: Colorectal cancer patients showed significantly higher baseline levels of IL-18 than healthy donors (p<0.005). Furthermore, serum IL-18 levels increased significantly with respect to baseline in patients receiving adjuvant chemotherapy (p<0.005). CONCLUSIONS: This study suggests that treatment with 5-fluorouracil and folinic acid may provoke an increase in IL-18 serum levels in colorectal cancer patients. This increase may help to explain the efficacy of adjuvant chemotherapy with 5-FU in colorectal cancer.

Ipsilateral supraclavicular lymph nodes metastases from breast cancer as only site of disseminated disease. Chemotherapy alone vs. induction chemotherapy to radical radiation therapy.

BACKGROUND: To define the role of radiotherapy (RT) in the treatment of ipsilateral supraclavicular lymph-nodes metastases (ISLM) from breast cancer as only site of disseminated disease, we started a prospective non-randomized clinical trial in 1989. Here we report the final results with a median follow-up of 8.75 years. PATIENTS AND METHODS: Thirty-seven patients (pts), with ISLM from breast cancer, were consecutively enrolled into two arms. Arm A (18 pts): chemotherapy (CT) for six courses. Arm B (19 pts): CT for three courses followed by RT to the site of ISLM at 'radical' dose of 50-60 Gy. RESULTS: In arm A, a median Time to Progression (TtP) of 7 months with a median Overall Survival (OS) of 28 months was recorded. In comparison, patients in arm B had a longer median TtP with 20 months as well as a better median OS with 41 months, respectively. An actuarial five-year disease-free survival of 5.5% was obtained in arm A vs. 21% in arm B. A statistically significant difference in TtP was demonstrated between the two groups (P = 0.01). CONCLUSIONS: These data demonstrate that a better event-free survival could be achieved in patients with ISLM submitted to induction CT and radical irradiation. This also translated into a longer survival although this did not achieve statistical significance. We want to stress the importance of local control by RT since it does imply that not all of these patients have micrometastases at the time of relapse in the supraclavicular fossa.

Cisapride and dexamethasone in the prevention of delayed emesis after cisplatin administration.

Management of delayed emesis (DE) remains unsatisfactory, and only 50% of the patients achieve complete protection. Cisapride is a strong prokinetic gastrointestinal drug that could have a role in the prevention of DE. We enrolled 31 adult naive outpatients who were scheduled to receive cisplatin chemotherapy at doses of > or = 75 mg/m2. All patients received the same prophylactic treatment for acute emesis (20 mg dexamethasone and 8 mg ondansetron i.v.) and, as preventive therapy for DE, oral cisapride, 10 mg every 8 h on days 2-4, combined with dexamethasone i.m., 8 mg twice daily on days 2 and 3, and 4 mg twice daily on day 4. All patients were evaluable for activity. Complete protection from acute vomiting was 80.7%, from nausea 71% and from nausea/vomiting 64.5%. The overall protection from DE (days 2-4) was 74.1% for vomiting, 64.5% for nausea and 58% for nausea/vomiting. In our study the combination of cisapride and dexamethasone was effective, giving 58% of complete protection from DE, and it is therefore worthy of further studies.

Oxaliplatin and raltitrexed in the treatment of inoperable malignant pleural mesothelioma: results of a pilot study.

AIMS AND BACKGROUND: The treatment of inoperable malignant pleural mesothelioma is a challenge for the oncologist. Available chemotherapy regimens achieve poor results, therefore new agents or combinations are needed. In a phase I study, the combination of oxaliplatin and raltitrexed was shown to be active against malignant pleural mesothelioma. We herein report the results of a pilot study about the treatment of this disease. METHODS: From April 1999 to June 2000, we enrolled 11 chemotherapy-naïve patients with inoperable malignant pleural mesothelioma suitable to receive the following combination chemotherapy: raltitrexed, 3 mg/m2 iv, and oxaliplatin, 130 mg/m2, as a 2-hr infusion every 3 weeks. RESULTS: Four partial responses, 1 regression of disease (objective response rate, 45%; 95% CI, 15.6-74.4%), 4 stable diseases and 2 progressions of disease were observed. An improvement in disease-related symptoms was recorded in all responders and in 2 patients with stable disease. Toxicity was mild, with no toxic-related death and only 1 episode of grade 4 neurotoxicity. CONCLUSIONS: We consider the combination promising and worthy of further studies.

[Malignant lymphoma. Epidemiologic review of 150 cases]. / Linfomi maligni. Revisione epidemiologica di 150 casi.

In the present paper the incidence of lymphomatous disease in Messina and its province, with growing urbanization and rural limiting areas, is discussed: by analysing 150 cases of malignant lymphoma observed at our Institute from 1990 to 1995. The method proposed, based on data obtained from the medical files of these patients, took into consideration various parameters such as age, sex, residence, profession, clinical and bioptic diagnosis, LDH and disease presentation. The final results showed an increase of the risk for NHL in the rural province where the main profession is agriculture or handicraft (ceramics, forged iron, glasswork, refinery), in subjects above 60 years of age; for the HL instead, over the years, a minor incidence of risk has been observed. The data obtained were partially similar to those reported in the international literature. The most present form in NHL was the lymphocytic and the centrocytic follicular form, while for HL it was the mixed cells form. The relationship between the two sexes was higher in males with HL and almost equal in NHL. The age range mostly affected by HL was between 25 and 65 years of age.

Bleomycin, epirubicin, carboplatin (BECA) in the treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck.

The aim of this study was to evaluate three active agents, bleomycin (BLM), epirubicin and carboplatin in a new combination (BECA) in terms of feasibility, activity and toxicity in patients with recurrent and metastatic squamous cell carcinoma of the head and neck. From April 1992 to February 1993 15 pts (12M/3F), median age 53 years, all pretreated (6 surgery + radiotherapy; 3 radiotherapy + chemotherapy; 6 radiotherapy), were treated with BLM 15 mg/m2 days 1-14; epirubicin 30 mg/m2 days 1-14 and carboplatin 300 mg/m2 day 1 every 28 days. In the 14 evaluable pts we observed 1 complete response, CR (7.1%), 4 partial responses, PR (28.6%), 5 stable disease, SD and 4 disease progression, PD with an overall response of 35.7%. The treatment was globally well tolerated, 1 pt with grade 3 leukopenia and 1 pt with grade 3 thrombocytopenia, 1 pt with grade 3 emesis and 1 pt with grade 3 mucositis. At the last follow-up the duration of CR was 34 months, the duration of PRs were respectively 22-10-10-7 months, but the SD ranged from 4 to 6 months. The overall median survival was 8 months (3-36), 14 for responders and 4 for non-responders. This final report seems to confirm the activity and efficacy of the BECA regimen, suitable for outpatient administration with an overall response equal to other more aggressive combinations.

Ondansetron plus dexamethasone in the control of high dose cisplatin-induced emesis.

Twenty-two patients who underwent chemotherapy with cisplatin (CDDP) at doses > 100 mg/m2 also received antiemetic treatment comprised of the combination of ondansetron plus dexamethasone. The results obtained have shown a good activity from this combination with these high doses of CDDP, with a response of 81.8% (complete+major protection). There were also three therapeutic failures in patients with a few negative prognostic characteristics. It is our intention to use a benzodiazepine and adequate psychological support in an attempt to increase the response percentages in these kinds of patients.

[Clodronate and radiotherapy for the treatment of osteolysis caused by metastasis of breast carcinoma and non-small cell lung carcinoma. A retrospective study]. / Clodronato più radioterapia nel trattamento delle osteolisi metastatiche da carcinoma mammario e polmonare non microcitoma. Studio retrospettivo.

We have retrospectively examined 94 evaluable patients with metastatic osteolysis from breast cancer (BC) and non-small cell lung (NSCLC) cancer, who received RT from Nov. 88 to Nov. 89.27 (15 BC and 12 NSCLC) were in treatment with Clodronate for at least 3 days from the beginning of RT; of the remaining 67 treated with RT alone, 31 had NSCLC and 36 BC. We have evaluated: increase in pain (IP) occurring on the first days of RT, percentages of complete pain relief (CPR) at the end of RT and 4-6 weeks after. A decreased occurrence of IP was observed more in NSCLC patients receiving RT + Clodronate compared to those treated with RT alone (33.3% vs 41.9%). Both at the end of RT and 4-6 weeks after, we registered a significant difference in the percentages of CPR in the RT + Clodronate group (40.7 vs 20.9 and 70.3% vs 53.7%). We believe the points of interest focused in this paper-greater precision in centering and defining the target volume, decreased occurrence of IP during the first days of RT, increase in percentage of CPR--need a prospective confirmation.

Treatment of advanced and/or metastatic epidermoid carcinoma of the head and neck: an effective combination chemotherapy with bleomycin, methotrexate and ftorafur.

29 evaluable patients with advanced and/or metastatic epidermoid carcinomas of the head and neck were treated with a combination of bleomycin, methotrexate and ftorafur. 3 complete remission, 12 partial remission (objective response 51.7%), 10 stable disease and 4 progressed disease were obtained, with the best responses in the oral cavity and skin carcinomas. The grade of performance status and the pretreatments affected the response, with a very high response rate in nonpretreated patients, where objective results were obtained in all cases. The toxicity was very mild. We believe that this combination can be recommended for epidermoid carcinomas of the skin and oral cavity, considering its high response rate, feasibility and low toxicity.

VP16, epirubicin and procarbazine in the treatment of advanced non-small-cell lung cancer.

We report the results obtained in the treatment of 52 advanced non-small-cell lung cancer patients with the combination chemotherapy VP16 (120 mg/m2 i.v., days 1-2-3), epirubicin (50 mg/m2 i.v., day 1) and procarbazine (100 mg/m2 p.o., days 1 through 8). The courses were repeated every 21 days. No patient had been pretreated. A median of 5 courses was administered. Partial response was obtained in 33% and no change in 21% of patients. Median remission time was 6.5 months, and median survival of responders was 10 months. The best response rate and median survival were obtained in the lowest grade performance status patients and in locally advanced disease patients. Major chemotherapy related toxicities were grade 1-2 leukopenia and grade 2-3 alopecia.

[Behavior of serum sialic acid levels at various stages of neoplastic disease]. / Comportamento del livello sierico dell'acido sialico in momenti diversi della malattia neoplastica.

Serum sialic acid levels were measured at two different stages of neoplasia (active and non-active phases). CEA levels were also assayed at the same time. 98 patients suffering from different neoplastic diseases and a group of healthy controls were studied. Serum sialic acid levels were always significantly higher in the neoplastic patients. When neoplastic disease were divided into active and non-active groups, it was observed that the level of this glycoprotein was specific in the non-active (NA) phase only for breast tumours and lymphomas. Correlation with CEA levels was also significant in these cases. It is concluded that serum sialic acid assay may be useful only for melanomas, breast tumours and lymphomas where the level of this membrane protein undergoes significant changes according to the stage of the tumour.

The treatment of recurrent and metastatic cervical carcinoma. Evaluation of an antiblastic combination of methotrexate-adriamycin-bleomycin (MAB).

Thirty patients with local recurrent and/or distant metastatic cervical carcinoma were treated by combined chemotherapy with methotrexate, adriamycin and bleomycin (MAB). Among the 25 evaluable patients 1 CR (4%), 5 PR (20%), 9 SD (36%) and 10 PD (40%) were obtained. A high incidence of cardiotoxicity (20%) and alopecia (32%) was observed. Both phenomena are linked to the anthracyclinic component of the regimen. As the results are not better than those reported by using only methotrexate and bleomycin, the authors did not find it useful to insert adriamycin in this regimen.