Convergent total synthesis of (±) myricanol, a cyclic natural diarylheptanoid.

Myricanol 1, a constituent of Myrica species, has been reported to lower the levels of the microtubule-associated protein tau (MAPT), whose accumulation plays an important role in some neurodegenerative diseases, such as Alzheimer's disease (AD). Herein we described a new synthetic route to prepare myricanol in 9 steps and 4.9% overall yield starting from commercially available 2,3-dimethoxyphenol and methyl 3-(4-benzyloxyphenyl)propanoate. The key steps are a cross-metathesis to obtain a linear diarylheptanoid intermediate and a Suzuki-Miyaura domino reaction to generate the challenging macrocycle.

Gemcitabine in advanced angiosarcoma: a retrospective case series analysis from the Italian Rare Cancer Network.

BACKGROUND: Angiosarcoma is a highly aggressive soft tissue sarcoma. Responses to anthracyclines plus/minus ifosfamide, and taxanes alone or in combination with gemcitabine are well documented. Very few data are available on gemcitabine as a single agent. PATIENTS AND METHODS: We retrospectively reviewed all cases of advanced progressive angiosarcoma treated with gemcitabine as a single agent (1000 mg/m(2) i.v. every week for 3 weeks every 4 weeks), at Istituto Nazionale Tumori and within the Italian Rare Cancers Network from January 2008 to November 2010. RESULTS: Twenty-five patients [mean age: 52 years; radiation therapy (RT)-related: 8] received gemcitabine. Best tumor response by RECIST was as follows: complete response = 2, partial response = 14, stable disease = 2, progressive disease = 7 cases, for an overall response rate (PR + CR) of 68%. Six of eight post-RT angiosarcomas responded to treatment. Median overall survival (OS) was 17 months. Median progression-free survival (PFS) was 7 months (range 1-40 months). One patient with a locally advanced thyroid angiosarcoma became resectable after 5 months of gemcitabine, with <10% residual viable tumor cells seen on surgical specimen. Overall, gemcitabine was well tolerated. CONCLUSIONS: Gemcitabine is active in both RT- and non-RT-related angiosarcoma, with dimensional and possibly long-lasting responses. A formal phase II study on gemcitabine as a single agent is warranted.

Phase II study of panitumumab, oxaliplatin, 5-fluorouracil, and concurrent radiotherapy as preoperative treatment in high-risk locally advanced rectal cancer patients (StarPan/STAR-02 Study).

BACKGROUND: The aim of this phase II study was to assess the activity of panitumumab in combination with oxaliplatin, 5-fluorouracil, and external radiotherapy (RT) as preoperative treatment in locally advanced rectal cancer patients. PATIENTS AND METHODS: Patients had rectal adenocarcinoma, cT3N+ or cT4N-/+ stage, located <12 cm from the anal margin. Panitumumab was administered before the start of chemo-RT, and every 2 weeks in combination with 5-fluorouracil-oxaliplatin with concurrent RT. Rectal surgery was carried out 7-8 weeks after the end of neoadjuvant treatment. The primary end point was a pathological complete response rate of 25%. RESULTS: Sixty patients were enrolled from February 2007 to October 2009. Fifty-five (91.7%) patients underwent surgery. Rate of pathological complete response was 21.1% (95% confidence interval 10.4% to 31.6%). Pathological downstaging occurred in 33 of 57 (57.9%) patients. Grade 3-4 toxicity during neoadjuvant treatment was diarrhea (38.9%), cutaneous reactions (18.6%), nausea (5.1%), asthenia (3.4%), anorexia (3.4%), and neutropenia (1.7%). One toxic death was observed for diarrhea. CONCLUSIONS: In our study, the primary end point is not reached and panitumumab combination treatment was associated with high incidence of grade 3-4 diarrhea. The higher pathological complete response rate in comparison with the results of previous neoadjuvant rectal cancer trials with anti-epidermal growth factor receptor monoclonal antibodies supports further studies necessary to understand the possibility of optimal regimens and sequences with chemo-RT.

Should we continue to study high-dose chemotherapy in metastatic breast cancer patients? A critical review of the published data.

Data from eight randomised trials on high-dose chemotherapy (HDC) for metastatic breast cancer (MBC) have been published, but only seven studies are evaluable after the Bezwoda trial was discredited. Moreover, overall survival (OS) has been evaluated in only four out of seven studies since three had a crossover design. OS was similar for the HDC and standard-dose chemotherapy (SDC) group in the four evaluable trials, while disease-free survival (DFS) was improved in the HDC group in six of the seven trials. The delay in relapse for patients with metastatic disease represents an important clinical outcome; furthermore, since none of the reported studies randomised more than 220 patients, their statistical power may have been too limited to detect meaningful survival differences. Finally, preliminary experiences have shown that HDC seems to be the ideal platform upon which to build novel therapies. In conclusion, HDC remains an important field of clinical research for breast cancer patients with stage IV disease and, from the studies reported in this article, there is some evidence for offering this therapeutic modality to selected patients who are interested in a medically aggressive approach.

Changes in leaf hexokinase activity and metabolite levels in response to drying in the desiccation-tolerant species Sporobolus stapfianus and Xerophyta viscosa.

The phosphorylation of glucose and fructose is an important step in regulating the supply of hexose sugars for biosynthesis and metabolism. Changes in leaf hexokinase (EC 2.7.1.1) activity and in vivo metabolite levels were examined during drying in desiccation-tolerant Sporobolus stapfianus and Xerophyta viscosa. Leaf hexokinase activity was significantly induced from 85% to 29% relative water content (RWC) in S. stapfianus and from 89% to 55% RWC in X. viscosa. The increase in hexokinase corresponded to the region of sucrose accumulation in both species, with the highest activity levels coinciding with region of net glucose and fructose removal. The decline of hexose sugars and accumulation of sucrose in both plant species was not associated with a decline in acid and neutral invertase. The increase in hexokinase activity may be important to ensure that the phosphorylation and incorporation of glucose and fructose into metabolism exceeded production from potential hydrolytic activity. Total cellular glucose-6-phosphate (Glc-6-P) and fructose-6-phosphate (Fru-6-P) levels were held constant throughout dehydration. In contrast to hexokinase, fructokinase activity was unchanged during dehydration. Hexokinase activity was not fully induced in leaves of S. stapfianus dried detached from the plant, suggesting that the increase in hexokinase may be associated with the acquisition of desiccation-tolerance.

Long-term infusional systems: complications in cancer patients.

Long-term central vein catheters have found clinical application in different fields of medicine and particularly in oncology. In fact, the continuous infusion of some drugs has become the standard treatment in a wide variety of cancers, but central vein catheters are not without risks. The authors report their experience with central vein catheters. From January 1,1998, to December 31, 1999, 98 central vein catheters were placed in neoplastic patients. Seventy-seven (78.6%) Groshong and 16 (16.3%) Port-a-cath catheters were used. The central vein catheters were placed under local anesthesia. Before placement of the central vein catheters, the patients were checked by chest X-ray and neck ultrasonography. The procedure was performed under fluoroscopic control. The central vein catheters were flushed periodically with normal saline solution and sodium heparin. Sterile transparent adhesive dressings were used to occlude the operative site. The median follow-up of patients was 9 catheter months (range, 1-24 months). There were a few early and late clinically evident complications. The early complications were dislodgement in 5 cases (5.1%). The late complications were: fibrin sleeve in 1 case (1.1%), thrombosis in 2 cases (2.1%) and skin infection in 4 cases (4.1%). The low prevalence of major complications related to implants and management of these supports an increased use in oncology.

FEP regimen (epidoxorubicin, etoposide and cisplatin) in advanced gastric cancer, with or without low-dose GM-CSF: an Italian Trial in Medical Oncology (ITMO) study.

The new regimens developed over the last few years have led to an improvement in the treatment of advanced gastric cancer, and our previous experience confirmed the fact that the combination of etoposide, doxorubicin and cisplatin (EAP regimen) is an active treatment that leads to interesting complete remission rates. The primary end point of the present multicentre, randomized, parallel-group phase II study was to determine the activity of the simplified 2-day EAP schedule in patients with locally advanced or metastatic gastric cancer, and to verify whether the addition of low doses of granulocyte-macrophage colony-stimulating factor (GM-CSF) made it possible to increase dose intensity. Of the 62 enrolled patients, 30 were randomized to receive epirubicin 35 mg m(-2), etoposide 120 mg m(-2) and cisplatin 45 mg m(-2) (FEP) on days 1 and 2 every 28 days and 32 to receive the same schedule plus subcutaneous GM-CSF (molgramostin) 150 microg day(-1) on days 5-14 every 21 days. The patients were stratified by age and the number of disease sites. The characteristics of the patients were well balanced between the two groups. The objective response rate of the patients as a whole was 34% (21 out of 62; 95% confidence interval 22-46), with only one complete remission. The median response duration was 4.5 months (range 1-24 months). The median time to treatment failure was 5 months (range 1-14 months), without any difference between the two groups. The median survival of the patients as a whole was 9 months. Full doses were administered in 92% and 94% of the cycles in the control and GM-CSF arms respectively. The average dose intensity calculated for all drugs was 0.96% in the control and 1.27% in the GM-CSF group. CTC-NCI grade 3-4 neutropenia was reported in 39% vs 45% of patients, thrombocytopenia in 11% vs 35% (P = 0.020) and anaemia in 7% vs 35% (P = 0.014). The FEP combination is as active (OR: 34%) in the treatment of patients with advanced gastric cancer as the EAP regimen, although it leads to fewer complete remissions. The patients randomized to receive low-dose GM-CSF achieved a significantly higher dose intensity than controls (P = 0.0001).

Fourier transform infrared microspectroscopy detects changes in protein secondary structure associated with desiccation tolerance in developing maize embryos

Isolated immature maize (Zea mays L.) embryos have been shown to acquire tolerance to rapid drying between 22 and 25 d after pollination (DAP) and to slow drying from 18 DAP onward. To investigate adaptations in protein profile in association with the acquisition of desiccation tolerance in isolated, immature maize embryos, we applied in situ Fourier transform infrared microspectroscopy. In fresh, viable, 20- and 25-DAP embryo axes, the shapes of the different amide-I bands were identical, and this was maintained after flash drying. On rapid drying, the 20-DAP axes had a reduced relative proportion of alpha-helical protein structure and lost viability. Rapidly dried 25-DAP embryos germinated (74%) and had a protein profile similar to the fresh control axes. On slow drying, the alpha-helical contribution in both the 20- and 25-DAP embryo axes increased compared with that in the fresh control axes, and survival of desiccation was high. The protein profile in dry, mature axes resembled that after slow drying of the immature axes. Rapid drying resulted in an almost complete loss of membrane integrity in the 20-DAP embryo axes and much less so in the 25-DAP axes. After slow drying, low plasma membrane permeability ensued in both the 20- and 25-DAP axes. We conclude that slow drying of excised, immature embryos leads to an increased proportion of alpha-helical protein structures in their axes, which coincides with additional tolerance of desiccation stress.

Epirubicin plus medroxyprogesterone as second-line treatment of advanced prostatic cancer. A study by the Italian Trials in Medical Oncology Group.

The evaluation of drug efficacy in patients with advanced prostatic cancer who have progressed to hormonal therapy is difficult, although palliation of the pain related to bone involvement still represents an important endpoint. In this study, epirubicin (EpiADM) plus medroxyprogesterone acetate (MPA) were given to advanced prostatic cancer patients with symptomatic bone involvement who had progressed to hormonal therapy. EpiADM was administered at a dose of 30 mg/m2 i.v. weekly and MPA at a daily dose of 1,000 mg p.o. for the first month and 500 mg thereafter. Fifty-four patients entered the trial, all of whom were evaluable. Amelioration of pain and a > or = 50% reduction in analgesic intake were observed in 52% of cases, with a mean duration of 4 months. Of the 28 responsive patients, 26 had already received two lines of hormonal therapy or were resistant to first-line therapy. Of the 23 patients with measurable lesions, 6 obtained a > or = 50% tumor shrinkage at these sites. The treatment was well tolerated, and no cardiac toxicity was observed up to a total cumulative EpiADM dose of 660 mg/m2. In conclusion, this regimen seems to have a palliative effect in patients with advanced prostatic cancer who have progressed to hormonal therapy, and it is feasible in an outpatient setting.

Phase II study of the etoposide, leucovorin and fluorouracil combination for patients with advanced gastric cancer unsuitable for aggressive chemotherapy.

Many patients with advanced gastric cancer cannot be treated with intensive chemotherapy. In an attempt to provide a feasible regimen for such patients, the combination of etoposide, leucovorin and fluorouracil (ELF) has been developed with promising results. The present study involved 42 patients with advanced gastric cancer who where unsuitable for cisplatin- or anthracycline-containing regimens because of their age (24 patients over 65 years), poor performance status (12) or the presence of concomitant illness (6). The treatment consisted of etoposide 120 mg/m2 i.v., 1-leucovorin 150 mg/m2 i.v. and fluorouracil 500 mg/m2 i.v. for 3 consecutive days every 3 weeks. Among the 41 evaluable patients, there was a 32% objective response rate (95% confidence interval 19-48%), with 7% of complete remissions. The median response duration was 4 months, the median time to progression in all patients was 5 months and the median overall survival was 10 months. No drug-related deaths or WHO grade 4 side effects were observed. On the basis of these results, we concluded that the ELF regimen is feasible and that its activity warrants randomized studies comparing the ELF combination with fluorouracil plus folinic acid.

A phase II trial of dacarbazine, fluorouracil and epirubicin in patients with neuroendocrine tumours. A study by the Italian Trials in Medical Oncology (I.T.M.O.) Group.

BACKGROUND: Previous experiences in the treatment of neuroendocrine tumours have demonstrated some activity of single agents such as adriamycin, fluorouracil (FU), streptozotocin and dacarbazine (DTIC). Opinions concerning the usefulness of polychemotherapy in carcinoid tumours are discordant, whereas better results have been achieved in other endocrine pancreatic neoplasms. Based on this background, we used multidrug chemotherapy with DTIC, FU and epirubicin in the treatment of different neuroendocrine tumours. METHODS: The study involved 38 pts with progressive and measurable disease. The treatment schedule was FU 250 mg/m2 i.v., epirubicin 25 mg/m2 i.v., and DTIC 200 mg/m2 i.v. on days 1, 2 and 3 every 3 weeks. RESULTS: The responses achieved by histologic types were carcinoids 2/20, medullary thyroid carcinoma 1/7, neuroendocrine tumours 1/6; and Merkel cell carcinoma 3/5. The median duration of response was 5 months (range 2-11). Stable disease was observed in 13 cases (34%). Out of the 18 cases in progression, 17 had not responded to previous medical treatment. No symptom control was observed in 4 pts with carcinoid syndrome. Treatment toxicity was moderate and included nausea and vomiting, alopecia, leukopenia and mucositis. CONCLUSIONS: Our results document the moderate efficacy of the regimen in all of the histologic types. The major difference in comparison with previous studies was the lower response rate observed in patients with neuroendocrine tumours.

[Sideropenic anemia and celiac disease]. / Anemia sideropenica e malattia celiaca.

Since the beginning of the use of Antigliadin Antibodies (AGA) in the screening of coeliac disease (CD) we have observed an increasing in the total number of cases diagnosed, in particular of the cases with monosymptomatic and atypical forms. Iron deficiency anemia is one of the more frequent findings that we can find in CD, either in association with other typical coeliac signs, or as an isolated expression of the disease. The first aim of our study was to determine the incidence of iron deficiency anemia in our patients affected by CD at the moment of diagnosis. The second aim was to determine the incidence of CD in a group of 96 patients attending our Pediatric Hematology department for iron deficiency anemia of unknown etiology and refractory to iron therapy. 103 patients out of our 212 coeliacs (48.5%) showed hypochromic and microcytic anemia. In the second sample we found 6 (6.2%) patients, positive in AGA and Antiendomysium Antibodies (AEA), that showed a typical coeliac picture at the jejunal biopsy. Our study confirms the high incidence of iron deficiency anemia in patients affected by coeliac disease. However the most important conclusion of our study is that a certain percentage of patients affected by hypochromic anemia of unknown etiology may be affected by coeliac disease. It is only by performing the specific screening tests (AGA and AEA) in the patients affected by iron deficiency anemia of unknown etiology, that we can diagnose this monosymptomatic expression of CD.

[Celiac disease in children with Down's syndrome]. / Malattia celiaca in bambini con sindrome di Down.

The coexistence of Down's syndrome (DS) and coeliac disease (CD) has been occasionally reported and both diseases are often related to autoimmune disorders. The pathogenetic factor that links CD and DS may be an altered immune system and/or the presence of a common genetic factor. Some epidemiological investigations, performed in patients with CD, showed an increased incidence of DS compared to the natural incidence of this abnormality in the general population. We studied the prevalence of CD in 83 individuals with DS compared to a group of 200 patients with other gastroenterologic disorders and a random scholastic sample of 500 non symptomatic children. IgG and IgA antigliadin antibodies (AGA) were determined in all patients. Antiendomysium antibodies (EmA) were investigated in all the patients of the first group, while in the other two groups, 27 and 108 cases respectively, selected by AGA positivity, were investigated for EmA. The percentage of AGA IgA positivity in the first group was 31.3% (26/83), in gastroenterologic controls 10% (20/200), in scholastic sample 2.8% (14/500), that shows a significant statistical difference. On the contrary EmA were positive in quite a similar percentage in the three groups. Duodenal [correction of Jejunal] biopsies, were performed in 11 DS patients and in 9 of the other two groups. EmA were positive only in the case with subtotal atrophy in all the groups: 5/11 in the first, 2/4 in the second, 2/5 in the third. On the contrary AGA IgA were often positive also in patients with non coeliac histologic findings.(ABSTRACT TRUNCATED AT 250 WORDS)

[Discordance in the onset of celiac disease in monozygotic twins]. / Discordanza nell'esordio di malattia celiaca in gemelli monozigoti.

Coeliac disease (CD) is a gluten intolerance caused by a combination of genetic and environmental factors such as nutrition and infections. Monozygotic twins appear to have a concordance for CD up to 71%. This paper reports a third case of late onset of CD in monozygotic twin girls. The twins were defined as monozygotic based upon paired clinical and laboratory examinations. Clinical examinations included genotypic, phenotypic and dermatoglyphic analysis, while laboratory examinations included HLA typing and blood groups. Following European Society of Pediatric Gastroenterology and Nutrition criteria, CD was diagnosed in both girls, though 4 years and 8/12 months apart. The twins achieved clinical, laboratory and histological remissions within 1 year, after the institution of a gluten-free diet. Genetic markers are undoubtedly the main precondition for CD development. Environmental factors, however, may play a more significant role in triggering the onset of disease.

Etoposide, doxorubicin and cisplatin (EAP) treatment in advanced gastric carcinoma: a multicentre study of the Italian Trials in Medical Oncology (I.T.M.O.) Group.

Various reports have documented the efficacy of the combination of etoposide, doxorubicin and cisplatin (EAP) in the treatment of advanced gastric cancer, although other studies have not confirmed such results. This multicentre phase II study was designed to try to define the efficacy and tolerability of the original EAP regimen. From January 1990 to May 1992, 96 patients with locally advanced or metastatic gastric cancer were treated every 3 weeks with etoposide (120 mg/m2) on days 4, 5 and 6, doxorubicin (20 mg/m2) on days 1 and 7, and cisplatin (40 mg/m2) on days 2 and 8. All of the patients had measurable lesions, and were to receive a maximum of six cycles. A total of 416 courses was given (median four/patient), 27% with a delay of > or = 2 weeks. Objective responses were achieved in 34 of the 91 evaluable patients (37%: confidence interval 27-47%), with complete response (CR) in 11 (12%) and partial response (PR) in 23 (25%). The median duration of response was 6 months (range 1-19), and the median survival of the 96 eligible patients was 9 months. Side-effects (WHO grade 3-4) were leucopenia (30%), thrombocytopenia (9%) and mucositis (10%). We conclude that the EAP regimen is active in inducing major objective responses (12% of CR), and that treatment is feasible in patients with good performance status.

A phase II study of mitoxantrone combined with beta-interferon in unresectable hepatocellular carcinoma.

BACKGROUND: Chemoimmunotherapy is being evaluated in the most common gastrointestinal tumors, but little data are available on hepatocellular carcinoma (HCC). Considering the encouraging objective response rates and the absence of important side effects obtained with mitoxantrone in HCC, we tested the activity and feasibility of a schedule combining beta-interferon (beta-IFN) and mitoxantrone. METHODS: Forty patients (ECOG Performance Status 0-1) with unresectable HCC received mitoxantrone (12 mg/m2 intravenously every 3 weeks) plus beta-IFN (3 x 10(6) U on days 1, 2, and 3; 6 x 10(6) from day 4 to day 60; and then 6 x 10(6) U three times a week for 10 months). RESULTS: Thirty-eight patients were evaluable for response and toxicity with a median of four administered cycles (range, 2-10 cycles). Nine patients achieved a partial response (23%) (95% confidence interval, 11-40%) with a median duration of response of 4 months. In 15 cases, the disease was stable for at least 2 months; 14 patients had disease progression. The median survival time of the group as a whole was 8 months. Patients who were alpha-fetoprotein positive had a median survival time of 7 months; those who were alpha-fetoprotein negative had a median survival time of 9 months. The most common side effects were hematologic (World Health Organization Grade 3, 15 patients; Grade 4, 3 patients). Mild or moderate flu-like syndrome was present in 50% of treated patients, whereas 10 patients experienced mild or moderate nausea. CONCLUSIONS: The schedule was active on advanced tumors with high alpha-fetoprotein values, and side effects were manageable. However, the addition of beta-IFN did not seem to improve significantly the response rate in HCC.

Medical treatment of neuroendocrine tumors.

BACKGROUND: Tumors of the neuroendocrine system are characterized by amine precursor uptake and decarboxylation, and they represent a heterogeneous group of carcinomas including carcinoids, islet cell carcinomas of the pancreas, medullary thyroid carcinomas and Merkel cell carcinomas. Their similar cytochemical and ultrastructural properties sustain the hypothesis of a common embryologic origin within the neural crest. Many of these tumors grow slowly, and reducing tumor burden represents the treatment of choice. However, when surgery is not feasible, medical treatment has to be considered. Therapeutic approaches in metastatic disease often do not consider the different biologic behaviors of these neoplasms. Moreover, efficacy of the treatment is associated with lack of a clear definition of the type of response: objective, symptomatic or biochemical. METHODS: In this review we have analyzed the different medical approaches used in the treatment of neuroendocrine tumors in an attempt to define their precise role in the different neoplasms. RESULTS: In carcinoid tumors, immunotherapy and the somatostatin analogue can be efficaciously used for the control of carcinoid syndrome. For inhibition of tumor growth, chemotherapy should be used only in patients with rapidly progressive disease, and the results are still unsatisfactory. CONCLUSIONS: Although all these tumors appear to have similar cytochemical properties, the responsiveness of the various neoplasms is very different. In the future, a specific treatment modality and a clear definition of the type of response (objective, symptomatic or biochemical) need to be defined for each type of neuroendocrine tumor.

Treatment of metastatic carcinoids and other neuroendocrine tumors with recombinant interferon-alpha-2a. A study by the Italian Trials in Medical Oncology Group.

BACKGROUND: Using a wide range of interferon (IFN) doses and schedules, a number of authors have found them to be active against neuroendocrine tumors. METHODS: To verify the clinical activity of IFN, 49 evaluable patients with advanced stage low- and intermediate-grade neuroendocrine tumors were treated with recombinant IFN-alpha-2a at a daily dose of 6 x 10(6) IU intramuscularly for 8 weeks, and 3 times weekly thereafter. The predominant histotype was carcinoid, although a few cases had malignant islet cell tumors, medullary thyroid carcinoma, Merkel cell carcinoma, or other neuroendocrine tumors. All of the patients had measurable lesions and most had multiple sites. Carcinoid syndrome was present in 14 cases. RESULTS: After a median treatment duration of 6 months, complete regression was achieved in 1 of the 7 cases of medullary thyroid carcinoma, and partial response was observed in 4 of 34 carcinoids. Response duration ranged from 1-11 months. Control of the syndrome was obtained in nine patients and a greater than or equal to 50% reduction of 5-hydroxyindoleacetic acid in eight patients. The treatment was well-tolerated. The most frequently observed side effects were fever, flu-like syndrome, and leukopenia. After 12 months of recombinant IFN-alpha-2a, 15 cases in progression and 4 with stable disease or partial response received another treatment (either radiometabolic therapy with I131 metaiodobenzylguanidine or polychemotherapy with streptozotocin plus epirubicin). CONCLUSIONS: The use of recombinant IFN-alpha-2a at these doses is well-tolerated and effective in controlling carcinoid syndrome (complete remission plus partial remission, 64%), although it has limited activity on tumor growth inhibition. No definitive data can be given for the other protocol treatments.

Disodium pamidronate in the treatment of bone metastases from breast cancer.

AIMS AND BACKGROUND: Symptomatic relief of bone metastases with biphosphonates has been previously reported, but limited data are available on the possibility of the induction of sclerosis in osteolytic lesions. METHODS: We therefore initiated an open study with disodium pamidronate (45 mg infused over 1 h and repeated every 21 days) in patients with bone metastases from breast cancer pretreated with chemotherapy and/or hormonetherapy. Fourteen patients with measurable lytic or mixed bone disease entereted the study. No other systemic therapy for breast cancer was allowed after their inclusion in the study. RESULTS: No radiologic evidence of bone sclerosis of lytic disease was seen. After 2 months of therapy, 9 patients had progressed and 5 had stable disease. The median time to progression of bone disease was 1.6 months (range, 1-9). No significant improvement in terms of symptomatic status or analgesic consumption was recorded. The treatment was well tolerated, and no significant local or systemic toxicity was observed. CONCLUSIONS: Disodium pamidronate at a dose of 45 mg every 3 weeks is not capable of inducing sclerosis of lytic lesions from pretreated breast cancer. Further trials concentrating on higher dosages of disodium pamidronate are warranted.

Prognostic factors in patients affected by hepatocellular carcinoma treated with systemic chemotherapy: the experience of the National Cancer Institute of Milan.

BACKGROUND: Survival times and overall response rates are generally poor in patients with unresectable hepatocellular carcinoma submitted to systemic chemotherapy. Limited data are reported in the literature concerning the factors influencing survival among this subset of patients but the distribution of these variables may affect the results of clinical trials. PATIENTS AND METHODS: The data on 103 patients undergoing systemic chemotherapy at the Istituto Nazionale Tumori from January 1988 through July 1991 have been analyzed using univariate and Cox multivariate analysis. Forty-eight patients were treated with mitoxantrone alone, 40 with mitoxantrone plus beta-interferon, 11 with fluorouracil plus folinic acid and the remaining four with adriamycin. RESULTS: Median survival time, and 6-month and 12-month survival rates, were 7.1, 55% and 29%, respectively. Lactate dehydrogenase value (P = 0.0009), TNM stage (P = 0.001), vascular invasion (P = 0.001), bilirubin (P = 0.008), Child status (P = 0.01), aspartate amino-transferase (P = 0.02), extent of liver involvement (P = 0.02) and performance status (P = 0.03) were the most significant factors influencing survival in univariate analysis. In the multivariate analysis, aspartate amino-transferase (P = 0.02) and, particularly, TNM stage (p = 0.0009) were confirmed as independent variables correlating with survival. A prognostic index was calculated on the basis of these factors and high- and low-risk groups were identified. Median survival time and 12-month survival were 11.1 months and 43% for the low-risk group, and 4.0 months and 9% for the high-risk group (p = 0.0005). CONCLUSION: The results of this analysis may provide guidance for the design of future therapeutic trials in unresectable hepatocellular carcinoma. In particular, patient stratification should be considered for further clinical trials.