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La disabilità non è mai, di per sé, causa di accertamento dello stato di abbandono, salvo che si rifletta in una incapacità genitoriale non emendabile e non vi siano risorse parentali vicarianti. In ambito minorile non esitino "categorie" e neppure "automatismi", ma valutazioni caso per caso, che permettano di cogliere le pecu-liarità della singola situazione, al fine di realizzare l'interesse del minore, alla pro-pria famiglia o ad una famiglia adottiva, come un "vestito ritagliato su misura". Vi sono diverse disabilità e quelle psichiche sono più critiche perché solitamente si ac-compagnano alla negazione della patologia ed al rifiuto degli aiuti, vissuti come atti persecutori, oltre che ad altri fattori di rischio ambientali-familiari

Currently there are no reliable biomarkers to predict outcome of exemestane treatment. We designed a prospective study to investigate whether constitutive genetic background might affect response to therapy. In a population of 302 advanced breast cancer patients treated with exemestane we showed that a 5-polymorphism-based genetic score could be used to identify patients with different risks of progression and death.Introduction: Approximately 50% of locally advanced or metastatic breast cancer (MBC) patients treated with first-line exemestane do not show objective response and currently there are no reliable biomarkers to predict the outcome of patients using this therapy. The constitutive genetic background might be responsible for differences in the outcome of exemestane-treated patients. We designed a prospective study to investigate the role of germ line polymorphisms as biomarkers of survival. Patients and Methods: Three hundred two locally advanced or MBC patients treated with first-line exemestane were genotyped for 74 germ line polymorphisms in 39 candidate genes involved in drug activity, hormone balance, DNA replication and repair, and cell signaling pathways. Associations with progression-free survival (PFS) and overall survival (OS) were tested with multivariate Cox regression. Bootstrap resampling was used as an internal assessment of results reproducibility. Results: Cytochrome P450 19A1-rs10046TC/CC, solute carrier organic anion transporter 1B1-rs4149056TT, adenosine triphosphate binding cassette subfamily G member 2-rs2046134GG, fibroblast growth factor receptor-4-rs351855TT, and X-ray repair cross complementing 3-rs861539TT were significantly associated with PFS and then combined into a risk score (0-1, 2, 3, or 4-6 risk points). Patients with the highest risk score (4-6 risk points) compared with ones with the lowest score (0-1 risk points) had a median PFS of 10 months versus 26.3 months (adjusted hazard ratio [AdjHR], 3.12 [95% confidence interval (CI), 2.18-4.48]; P < .001) and a median OS of 38.9 months versus 63.0 months (AdjHR, 2.41 [95% CI, 1.22-4.79], P = .012), respectively. Conclusion: In this study we defined a score including 5 polymorphisms to stratify patients for PFS and OS. This score, if validated, might be translated to personalize locally advanced or MBC patient treatment and management.

The combination of docetaxel, cisplatin, and 5-fluorouracil (5-FU) has demonstrated a survival advantage over cisplatin and 5-FU, but with substantial hematological toxicity. We aimed to evaluate the efficacy and toxicity of a sequential regimen with cisplatin, leucovorin, and 5-FU (PLF) followed by docetaxel in metastatic gastric cancer patients.Treatment consisted of 4 cycles of biweekly PLF (cisplatin 50 mg/m(2) as a 30-min infusion on day 1, leucovorin 200 mg/m(2) in a 2-h infusion, and 5-FU 2,800 mg/m(2) in a 48-h continuous infusion starting on day 1) followed, in cases of response or stable disease, by 3 cycles of docetaxel (75 mg/m(2), every 3 weeks).Thirty-four patients were enrolled, with an average age of 64 years (range 34-69). The main cumulative grade 3-4 toxicities were: neutropenia (38.2%), febrile neutropenia (11.8%), and fatigue (14.7%). After the planned 7 cycles of treatment, the overall response rate was 38.2% (95% confidence interval [CI] 21.9-54.6), with 3 complete and 10 partial responses. Median progression-free survival and overall survival were 4.8 and 10.6 months, respectively.For patients with metastatic gastric cancer, the sequential administration of cisplatin, leucovorin, 5-FU, and docetaxel may be an effective palliative option and offers a far more favorable toxicity profile than the simultaneous use of docetaxel, cisplatin, and 5-FU.

Background Previous studies investigating the prognostic role of mucinous histology of colorectal cancer produced conflicting results. This retrospective analysis was carried out in order to explore whether mucinous adenocarcinoma (MC) is associated with a comparatively worse prognosis than that of nonmucinous adenocarcinoma (NMC) for patients undergoing curative resection for stage II and III colon cancer. Patients and methods: This study involved 1025 unselected patients who underwent curative surgery for sporadic colon cancer and follow-up procedures at six different oncology departments. Results MCs accounted for 17.4% (n = 178) of tumours. Patients with MC had 5- and 8-year overall survival rates of 78.6% and 68.8%, respectively, compared with 72.3% and 63.8%, respectively, for patients with nonmucinous tumours. Multivariate analysis using the Cox proportional hazards model showed that the clinically significant prognostic factors were stage of disease and adjuvant chemotherapy. No statistically significant interaction between mucinous histology and adjuvant chemotherapy was found. Conclusions For patients with stage II and III colon cancer who underwent curative surgery, mucinous histology has no significant correlation with prognosis compared with NMC. This retrospective analysis suggests a comparable benefit from adjuvant chemotherapy for MC compared with NMC.

Catalano V, Mellone P, d’Avino A, Shridhar V, Staccioli M P, Graziano F, Giordani P, Rossi D, Baldelli A M, Alessandroni P, Santini D, Lorenzon L, Testa E, D’Emidio S, De Nictolis M, Muretto P, Fedeli S L & Baldi A (2011) Histopathology58, 669–678 HtrA1, a potential predictor of response to cisplatin-based combination chemotherapy in gastric cancer Aims: HtrA1 is a member of the HtrA (high-temperature requirement factor A) family of serine proteases. HtrA1 plays a protective role in various malignancies due to its tumour suppressive properties. The aim of this study was to determine HtrA1 expression as a predictor of chemoresponse in patients with advanced gastric cancer. Methods and results: HtrA1 expression was determined by immunohistochemistry on specimens of primary gastric cancer from 80 patients treated consecutively with cisplatin-based combination chemotherapy. Response to chemotherapy was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Our population consisted of males/females [51/29; median age 64 years (range 32–82)]. A complete or partial response was observed in 71.4% [95% confidence interval (CI) 54.7–88.2], 66.7% (95% CI 47.8–85.5) and 28.6% (95 CI 11.8–45.3) of tumours showing high, medium and low HtrA1 expression, respectively. A statistically significant association between HtrA1 expression and the clinical response was observed (P = 0.002). The median overall survival for patients with high/medium expression was 17 months compared to 9.5 months for patients with low HtrA1 expression (P = 0.037). Conclusions: Identification of HtrA1 in gastric cancer prior to chemotherapy indicates that levels of HtrA1 could be used to predict response to platinum-based combination therapies. Further assessment of HtrA1 expression is highly warranted in large, prospective studies.

Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Efficacy of this drug was documented in the BR.21 trial showing that adenocarcinoma, female gender, Asian ethnicity and never-smoker status are predictive of clinical response to erlotinib. Retrospective studies documented the same benefits for elderly patients as young patients in terms of response, progression-free survival, and overall survival. The primary aim of our trial was to confirm these findings in a prospective way; the secondary aim was to identify if the aforementioned clinical characteristics may be predictive of response even in elderly patients. The trial included 31 patients with pretreated stage IIIB (2) and IV (29) non-small cell lung cancer (NSCLC). Median age was 75 years (range: 65-85). Twenty-seven patients were current/former-smokers and four never-smokers. Twenty-three patients are evaluable for response. Objective response rates were reported in five patients (16%). Five patients had stable disease (16%) and 13 progressive disease (43%). Seven patients had a "clinical benefit" from erlotinib (22.5%; 95% C.I.: 7.9-37.2%). Grade 3 skin rash was recorded in three patients (10%). Median survival was 9 months (range 1-30). Median time to progression was 3 months (range: 1-24 months). Our study confirmed erlotinib activity and safety as second- and third-line treatment in elderly patients with advanced NSCLC, especially in terms of median survival. Even though this trial does not allow us to draw a definitive conclusion about the role of a particular clinical characteristic predictive of response, the "clinical benefit" was documented especially in females, in patients with adenocarcinoma histology and skin rash, confirming previous retrospective data.

The objective of this study was to investigate the efficacy of first-line chemotherapy containing irinotecan and/or oxaliplatin in patients with advanced mucinous colorectal cancer. Prognostic factors associated with response rate and survival were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. The population included 255 patients, of whom 49 (19%) had mucinous and 206 (81%) had non-mucinous colorectal cancer. The overall response rates for mucinous and non-mucinous tumours were 18.4 (95% CI, 7.5-29.2%) and 49% (95% CI, 42.2-55.8%), respectively (P=0.0002). After a median follow-up of 45 months, median overall survival for the mucinous patients was 14.0 months compared with 23.4 months for the non-mucinous group (hazard ratio (HR), 1.74; CI 95%, 1.27-3.31; P=0.0034). After adjustment for significant features by multivariate Cox regression analysis, mucinous histology was associated with poor overall survival (HR, 1.593, 95% CI, 1.05-2.40; P=0.0267), together with performance status ECOG 2, number of metastatic sitesor =2, and peritoneal metastases. This retrospective analysis shows that patients with mucinous colorectal cancer have poor responsiveness to oxaliplatin/irinotecan-based first-line combination chemotherapy and an unfavourable prognosis compared with non-mucinous colorectal cancer patients.

Background: It is known that 15 % of patients with breast cancer presents with locally advanced disease (LABC) without distant metastases. We carried out a phase II trial to investigate the activity of epirubicin and mitoxantrone combination as induction intra-arterial chemotherapy (IAC) in LABC.

PURPOSE: Intravenous vinorelbine has demonstrated its efficacy and tolerability in advanced non–small-cell lung cancer (NSCLC). An oral formulation of vinorelbine has been developed, and a number of phase II studies have shown its activity in chemotherapy-naive NSCLC, even in elderly patients, but no study has been performed to test activity and toxicity of oral vinorelbine in pretreated patients. The aims of our study were to investigate the activity and toxicity of oral vinorelbine in patients with NSCLC as salvage treatment. PATIENTS AND METHODS: Twenty pretreated patients with locally advanced (n = 6) and metastatic (n = 14) NSCLC entered the study. The schedule was oral vinorelbine 60 mg/m2 once a week until progression or development of unacceptable toxicity. Median age was 70 years (range, 49-84 years). RESULTS: Seventeen patients were evaluable for response and all for toxicity. A median of 9 cycles were administered (range, 2-21 cycles). No objective responses were reported, 5 patients experienced stable disease, and 12 patients had progressive disease. Median time to progression was 2 months (range, 1-6 months), and median survival was 4 months (range, 1-13 months). Treatment was well tolerated, with grade 4 neutropenia in 1 patient (heavily pretreated); grade 2 diarrhea in 2 patients; asthenia in 2 patients; and abdominal pain in 1 patient. CONCLUSION: Oral vinorelbine 60 mg/m2 once a week is a very safe schedule in heavily pretreated locally advanced and metastatic NSCLC; however, at this dose, the drug is inactive. Other phase II studies with oral vinorelbine 80 mg/m2 weekly are warranted.

The aim of our analysis was to assess retrospectively the effect on local relapse, overall survival (OS) and disease-free survival (DFS) of a limited or an extended lymphadenectomy in radically resected gastric cancer patients. This study was performed in order to identify a subgroup of patients possibly not benefiting from a therapeutic approach such as chemoradiation therapy. We divided our patients into two groups according to lymphadenectomy type: group A for limited ( 25 resected lymph nodes) lymph nodes resection. A total of 418 patients were analysed: tumour stage at diagnosis was pT2–3 pN1–3 M0 in 339 patients and pT3 N0 M0 in 79 patients. Median age at diagnosis was 68 years (range 30–92 years). A total of 306 patients (73.2%) were in group A and 112 (26.8%) in group B. The median survival time (OS) for patients in groups A and B was 58.8 and 84.8 months, respectively (P=0.0371); median DFS was 28.8 months in group A and 59.9 months in group B (P=0.0027). At multivariate analysis, extension within the gastric wall, nodal involvement and the number of resected lymph nodes appeared to affect both OS and DFS. An inadequate lymph nodes resection can affect survival and result in a higher incidence of local relapse, making the latter group of patients optimal candidates for adjuvant chemoradiation.

Background: To evaluate the safety and efficacy of the novel raltitrexed/oxaliplatin combination (TOMOX) as first-line chemotherapy for patients with advanced colorectal cancer. Materials and methods: Previously untreated patients with metastatic colorectal cancer received raltitrexed 3 mg/m 2 plus oxaliplatin 100 mg/m 2 , both intravenously, on day 1 every 3 weeks. Patients were re-evaluated after every third cycle and chemotherapy was continued up to tolerance or disease progression. Results: Fifty-eight patients from 13 Italian Group for the Study of Gastrointestinal Tract Carcinomas (GISCAD) centers were accrued from September 1999 to November 2000. According to the intentionto-treat analysis from 58 patients, the overall response rate was 50% [95% confidence interval (CI) 38% to 62%], with three complete responses and 26 partial responses. The median overall survival (44 patients currently alive) was >9 months and the median time to disease progression was 6.5 months (range 1–15 months). The main hematological toxicity was grade III/IV neutropenia, which occurred in 17% of patients, while anemia and thrombocytopenia were uncommon. Grade III/IV non-hematological toxicities were transient transaminitis (17% of patients); asthenia (16% of patients); neurotoxicity (10% of patients) and diarrhea (7% of patients). No toxic death was observed, one patient with grade IV asthenia after the first cycle refused chemotherapy. Conclusions: The results of this study suggest that the TOMOX combination is an effective and well tolerated regimen for the treatment of advanced colorectal cancer. Its ease of administration and patient tolerance warrant further investigation as an alternative to fluoropyrimidine-based regimens with

Recently, we reported a highly active regimen in advanced gastric cancer including a weekly administration of cisplatin, epidoxorubicin, leucovorin, 5-fluorouracil with the support of filgrastim. In order to simplify the administration and to decrease the toxicity of these drugs, mainly epidoxorubicin-induced alopecia, we designed a regimen including an infusional 5-fluorouracil schedule according to the de Gramont regimen, cisplatin and mitomycin C replacing epidoxorubicin. Forty-five patients with advanced or metastatic gastric cancer were treated with cisplatin 50 mg m−2 i.v. on day 1, every 2 weeks, 6S-stereoisomer-leucovorin 100 mg m−2 i.v. followed by 5-fluorouracil 400 mg m−2 i.v. bolus and 600 mg m−2 i.v. in a 22-h infusion, on days 1 and 2, every 2 weeks, and mitomycin C 7 mg m−2 i.v. bolus on day 2, every 6 weeks. Grades 3–4 toxicities (National Cancer Institute-Common Toxicity Criteria) consisted mainly of neutropenia and thrombocytopenia. Five patients had a complete response and 16 had a partial response for an overall response rate of 46.7% (95% confidence interval, 32.1–61.2%). The median survival was 11 months. The combination of cisplatin, 5-fluorouracil and leucovorin according to de Gramont, and mitomycin C seems to be an active and safe regimen in the treatment of advanced gastric cancer. Because of its low cost it may be suggested for patients not enrolled into clinical trials. British Journal of Cancer (2002) 86, 213–217. DOI: 10.1038/sj/bjc/6600046 www.bjcancer.com © 2002 The Cancer Research Campaign

Gastrointestinal cancers account for a large amount of human tumors. Surgery is the standard treatment for localized gastrointestinal cancer, but in a large number of patients, tumors are unresectable at time of diagnosis and even when resectable, survival is often poor. Current attempts to improve these results include the use of chemotherapy in the adjuvant setting, in the advanced disease, or as neoadjuvant treatment. However, less than half the patients respond to chemotherapeutic treatments, mostly reporting important side-effects. The identification of molecular markers, such as p53, thymidylate synthase, K-ras, and others, may provide an important tool for medical oncologists in defining subsets of patients with gastrointestinal cancers more suitable to benefit from chemotherapy or from experimental therapies. The relationship between the clinical outcome to anticancer drugs and molecular markers in gastrointestinal tumors has been reviewed. Available data are promising, but most of them arise from retrospective and small studies. Well designed, prospective trials are warranted to change the target approach from a general to an individual treatment strategy.

In advanced gastric cancer, we investigated feasibility and activity of sequential chemotherapy with docetaxel after an intensive weekly regimen consisting of cisplatin, epidoxorubicin, fluorouracil, leucovorin (PELF) plus filgrastim. Chemotherapy-naive patients with relapsed or metastatic gastric cancer received 8 weekly administrations of chemotherapy with cisplatin 40 mg/m2, fluorouracil 500 mg/m2,epi-doxorubicin 35 mg/m2, 6S-steroisomer of leucovorin 250 mg/m2and glutathione 1.5 g/m2. On the other days filgrastim 5 μg kg–1was administered by subcutanous injection. Subsequently, patients with partial response or stable disease received 3 cycles of docetaxel 100 mg/m2every 3 weeks. 40 patients have been enrolled and they are evaluable for response and toxicity. After the PELF regimen, 3 patients achieved complete response, 13 patients showed partial response, 21 patients had stable disease and 3 patients progressed (40% response rate; 95% CI 25% to 55%). After docetaxel, 9 out 34 patients improved the outcome (26.5%); 7 patients with stable disease achieved partial response and 2 patients with partial response achieved complete response. The overall response rate in the 40 patients was 57.5% (95% CI, 42.5% to 72.5%). The PELF regimen did not cause any grade IV toxicity, the most frequent grade III acute side-effects were thrombocytopenia and vomiting which occurred in the 10% of 320 PELF cycles. Docetaxel caused grade III–IV neutropenia and thrombocytopenia in the 10% and the 19% of cycles respectively. Fatigue was a frequent side-effect during both PELF and docetaxel chemotherapy. The sequential application of docetaxel after PELF chemotherapy gained major objective responses with manageable toxicity. This strategy is worth of further investigation in the setting of palliative or neoadjuvant chemotherapy. © 2001 Cancer Research Campaign http://www.bjcancer.com

Aims and background The phase II trial was designed to evaluate the activity of combined oxaliplatin (L-OHP), continuous infusion (CI) ± bolus 5-fluorouracil (5FU) and levo-folinic acid (IFA) in patients with metastatic colorectal cancer progressing after one or more lines of 5FU-based chemotherapy. Patients and methods We designed two contemporary studies: in the former we enrolled patients previously treated with 1 line of chemotherapy, and in the latter, patients previously treated with 2, 3 and 4 lines. Seventy-six consecutive patients were enrolled: 45 received L-OHP (85 mg/m2 iv 2 h on day 1) + I-FA (100 mg/m2 iv 2 h on days 1 and 2) + 5FU iv bolus (400 mg/m2 days 1 and 2) + 5FU (600 mg/m2 CI 22 h days 1 and 2 (FOLFOX 4); 31 received L-OHP (100 mg/m2 iv 2 h on day 1) + I-FA (250 mg/m2 iv 2 h on days 1 and 2), followed by 5FU (1500 mg/m2 CI 24 h days 1 and 2 (FOLFOX 2). The treatment was recycled every 2 weeks and continued until progression and/or unacceptable toxicity or patient preference. The primary end point was activity (tumor growth control [TGC]: partial response [PR] + stable disease [SD]); the secondary end points were time to progression (TTP), overall survival (OS) and toxicity. Results Forty-five patients in 2nd line (22 FOLFOX 4, 23 FOLFOX 2), 23 (17 FOLFOX 4, 6 FOLFOX 2) in 3rd, 4 in 4th and 1 in 5th line were assessable; 3 were lost to follow-up. In 15 patients (11 FOLFOX 4, 4 FOLFOX 2), disease involved the liver only. A total of 533 courses were administered with a range of 1-14 in FOLFOX4 and 1-12 in FOLFOX2; dose intensity was 92.85%, and the total dose of the administered L-OHP was 98.29%. As a 2nd line treatment, FOLFOX 4 achieved TGC in 72.8% of the patients (PR, 18.2%; SD, 54.6%), with a median TTP of 6 months and a median OS of 7 months, whereas in the FOLFOX 2 group these figures were 78.3% (PR 21.8%, SD 56.5%), and 5 and 9 months. As a 3rd line treatment, FOLFOX 4 produced TGC in 41.1% of patients (PR 23.5%, SD 17.6%), with a median TTP of 5 months and median OS of 7+ months, whereas FOLFOX 2 obtained respective values of 50% (PR 16.7%, SD 33.3%), 7 and 9 months. As a 4th line of treatment, TGC was achieved in 2 patients (1 PR, 1 SD); the patient in 5th line therapy obtained a SD. With “de Gramont” as the first-line regimen, patients assessable were 24 in FOLFOX 4 and 18 in FOLFOX 2. In the former population, TGC was 70.8% (PR 37.5%, SD 33.3%), with a TTP of 6 months and OS of 10 months, whereas with FOLFOX2 these values were 61.1% (PR 5.6%, SD 55.5), 5 and 7 months. In patients with liver involvement only, FOLFOX 4 obtained TGC in 63.6% of cases (with a TTP of 7 months and OS of 6+ months), FOLFOX 2 in 100% (with a TTP of 9.5 months and OS of 13.5+ months). Both schedules exhibited an acceptable toxicity: neurologic, hematologic and hepatic grade 3 side effects occurred in a limited number of patients, with a higher frequency in the FOLFOX 2 group. Conclusions Treatment with L-OHP, CI ± bolus 5FU and I-FA was well tolerated. The activity in terms of TGC was interesting and comparable with results reported in the literature for the standard treatment for 2nd line, i.e. irinotecan alone. Treatment was effective in 2nd line and in patients previously treated with more than two chemotherapy lines; in particular, treatment was active in patients with hepatic disease only. Although the two schedules seemed to achieve the same benefit with the same tolerance, we could not define from the study the better regime.

The vascular endothelial growth factor (VEGF) plays a central role in promoting angiogenesis, and it is the target of innovative anti-cancer therapies. In colorectal carcinomas, differences in the VEGF expression have been found between the primary tumor and its metastases. We postulated that differences in the VEGF expression may also exist between liver and abdominal metastases from colon cancer. Consecutive colon cancer patients with liver or abdominal metastases were considered eligible for the study. Biopsies had to be performed before chemotherapy and the VEGF analysis were conducted through immunohistochemistry. The staining results were correlated to the metastatic pattern. The study population consisted of 41 patients with a metastatic site in the liver in 19 patients and the abdomen in 22 patients. A positive VEGF staining was found in 19 of the 41 metastatic samples (46%). Cases with positive VEGF expression were found more frequently in abdominal (15 out of 22 patients; 68%) than in liver metastases (4 out of 19 patients; 21%). Also, the degree of VEGF immunoreactivity was significantly higher in abdominal than in liver metastases. Evidence is supported that the VEGF expression may be different between colon cancer metastatic sites. The efficacy of anti-VEGF treatments may depend on the VEGF expression status, and this finding deserves further investigation.

Brustkrebs ist heute die zweithaufigste Krebstodesursache bei Frauen (nach Lungenkrebs) und die am weitesten verbreitete Krebsart bei Frauen, mit Ausnahme nicht melanozytarer Hautkrebsarten (weiser Hautkrebs). Laut der American Cancer Society wird Brustkrebs jahrlich bei 1,3 Millionen Frauen weltweit diagnostiziert, und ca. 465.000 sterben an der Krankheit.

Elderly patients are generally underrepresented in the study populations of combination chemotherapy trials. This study evaluates the efficacy and safety of a modified FOLFOX regimen in elderly patients with metastatic gastric cancer and presenting associated disease(s). A total of 43 patients aged ≥70 years received oxaliplatin 85 mg/m2 together with 6S-leucovorin 200 mg/m2 on day 1, followed by a 46-h infusion of 5-fluorouracil 2,400 mg/m2, every 2 weeks. Assessment of response was performed every four cycles according to RECIST criteria. Median patient age was 74 years (range, 70–83 years). Overall response rate was 34.9 % [95 % confidence interval (CI), 20.6–49.1, with 3 complete responses and 12 partial responses. Grade 3 neutropenia occurred in 4 patients (9.3 %), fatigue in 3 patients (7.0 %), and vomiting in 2 patients (4.6 %). Grade 2 and 3 peripheral neuropathy was observed in 5 patients (11.6 %) and 1 patient (2.3 %), respectively. No treatment-related death was observed. Median progression-free and overall survival were 6.8 and 10.5 months, respectively. This modified FOLFOX regimen is an active and well-tolerated treatment for elderly patients with metastatic gastric cancer and also represents a good therapeutic option in patients with associated disease(s).

In this case report we describe the case of a patient with multiple bone metastases of NSCLC, adenocarcinoma with exon 21 point-mutation of EGFR, treated with gefitinib. After only 3 months, FDG-PET / CT scan showed a complete response of bone metastases and right hylar adenopathy. Implications for need of early use of FDG-PET/CT scan after gefitinib treatment are discussed. doi:10.4021/wjon441w

HtrA1 is a member of the HtrA (high-temperature requirement factor A) family of serine proteases. HtrA1 plays a protective role in various malignancies due to its tumour suppressive properties. The aim of this study was to determine HtrA1 expression as a predictor of chemoresponse in patients with advanced gastric cancer.HtrA1 expression was determined by immunohistochemistry on specimens of primary gastric cancer from 80 patients treated consecutively with cisplatin-based combination chemotherapy. Response to chemotherapy was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Our population consisted of males/females [51/29; median age 64 years (range 32-82)]. A complete or partial response was observed in 71.4% [95% confidence interval (CI) 54.7-88.2], 66.7% (95% CI 47.8-85.5) and 28.6% (95 CI 11.8-45.3) of tumours showing high, medium and low HtrA1 expression, respectively. A statistically significant association between HtrA1 expression and the clinical response was observed (P = 0.002). The median overall survival for patients with high/medium expression was 17 months compared to 9.5 months for patients with low HtrA1 expression (P = 0.037).Identification of HtrA1 in gastric cancer prior to chemotherapy indicates that levels of HtrA1 could be used to predict response to platinum-based combination therapies. Further assessment of HtrA1 expression is highly warranted in large, prospective studies.

Summary Purpose: This multicenter phase II study was designed to assess the efficacy of the alternating schedule of tomudex with methotrexate (MTX)/5-fluorouracil (5-FU)/leucovorin (LV) in first-line chemotherapy for metastatic colorectal cancer. Patients and methods: Patients with histologically proven metastatic colorectal cancer and at least one bidimensionally measurable lesion, aged 18-70, with performance status =S 2, normal baseline biological values, and no prior chemotherapy, were selected. Treatment was tomudex 3 mg/m 2 and, after two weeks, MTX, 200 mg/m 2 by 30' infusion after hydration with 1500 ml saline solution, followed on day 2 by 5-FU, 600 mg/m 2 and leucovorin, orally, 15 mg for six times every 6 hours, beginning 24 hours after MTX. Cycles were repeated every four weeks. Tumor response assessment was performed after three cycles. Results: Thirty-four patients were enrolled in this study, of whom twenty-four had liver metastases, nine local relapse, five lymph node involvement, four lung metastases, and three peritoneal carcinomatosis. Four patients achieved objective responses (one complete and three partial), for an overall response rate of 12% (95% CI: 0%-22%). Twelve patients had stable disease and 18 progressed on therapy. Median survival for all patients was 13 months. Two patients experienced grade 3 WHO neutropenia while hepatotoxicity was reported in 13 patients (6 grade 1, 3 grade 2, 3 grade 3, 1 grade 4), suggesting that this combination could increase hepatic toxicity in comparison to tomudex or MTX/5-FU alone. Conclusions: Our results suggest that this regimen does not warrant further investigation in advanced colorectal cancer patients, at least not with this schedule and doses.

Purpose: Paclitaxel and platinum-based chemotherapy is considered to be a standard approach for locally advanced and metastatic non–small-cell lung cancer (NSCLC). In recent years, weekly paclitaxel has been widely used for its safety profile, especially in breast and ovarian cancer. Otherwise, only a few studies are available in NSCLC. The aim of our study was to investigate the activity and safety of weekly paclitaxel in elderly patients with locally advanced (stage IIIB) and metastatic (stage IV) NSCLC. Patients and Methods: Twenty-seven patients entered the study; 10 had stage IIIB disease (5 “wet” and 5 “dry”), and 17 had stage IV disease. Median age was 73 years (range, 70-83 years). Sixteen patients (59%) presented with comorbidities. The schedule was weekly paclitaxel 80 mg/m2 for 6 weeks with 2 weeks of rest (1 cycle). Results: All patients were evaluable for response and toxicity; a median of 1 cycle was administered (range, 1-5 cycles). Partial responses were recorded in 9 patients (37.5%; 33.3%, according to intentionto-treat analysis; 95% CI, 15.5%-51.1%); 7 had stable disease (29%), and 8 had progressive disease (33.5%). Median time to progression was 5 months (range, 1-23 months), and median survival was 12 months (range, 1-36 months). Grade 2/3 asthenia was the main toxicity in 7 patients (29%); a hypersensitivity reaction presented in 1 patient. No other episode of grade 3/4 toxicity was recorded. Conclusion: Our study confirmed that paclitaxel 80 mg/m2 weekly is active in patients with locally advanced and metastatic NSCLC with a good safety profile; this schedule might be considered an alternative choice to gemcitabine or vinorelbine as first-line treatment in elderly patients, particularly patients with comorbidities. Phase III studies that compare these third-generation drugs are warranted to draw definitive conclusion about the best approach in these patients.

Purpose: Capecitabine is an orally administered precursor of 5'-deoxy-5-fluorouridine that was rationally designed to generate 5-fluorouracil (5-FU) preferentially in tumor tissue. The drug enables chronic dosing that mimics continous infusion of 5-FU. Phase II trials of capecitabine at 1250 mg/m² twice daily for 14 days followed by 7 days of rest, is active in anthracycline- and taxane-pretreated patients; the main toxicity is palmarplantar erythrodysesthesia, diarrhea, and nausea. To overcome these side effects, the dose has been reduced to 1000 mg/m² twice daily with a better therapeutic profile and encouraging efficacy. The aim of our study was to confirm safety and activity of capecitabine at lower doses in patients with metastatic breast cancer (MBC). Patients and Methods: Thirty-seven patients with advanced breast cancer entered the study. The first 7 patients were treated with capecitabine 1250 mg/m² twice daily (for 14 days followed by 7 days of rest) and the next 30 patients with capecitabine 1000 mg/m². The median age was 62 years (range, 38-87 years). Thirteen patients were chemotherapy naive and 24 were pretreated with chemotherapy (9 patients, 1 line; 15 patients, ≥ 2 lines). Anthracyclines and/or taxane schedules were administered in 22 patients. Soft tissue metastases were documented in 36 patients; visceral metastases in 24 patients; visceral and soft tissue metastases in 23 patients. Results: Thirty patients were evaluable for response (5 at “higher” dose and 25 at “lower” dose) and all for toxicity. Overall objective response rate was 57% (5 complete responses and 12 partial responses); 95% CI, 39%-74%; stable disease 20% and progressive disease 23%. Eight of 13 chemotherapy-naive patients (61.5%) and 9 of 24 pretreated patients (37.5%) responded to capecitabine, according to the intent-to-treat principle (6 of 9 responses were obtained at a lower dose). Three responses at the “higher” dose and 14 at the “lower” dose were reported. Median time to progression was 7 months (range, 1-38 months) and median overall survival was 19 months (range, 2-47 months). Toxicity was as follows: grade 2/3 palmar-plantar erythrodysesthesia in 9 patients (24%), grade 2/3 asthenia in 7 patients (19%), grade 2 vomiting in 4 patients (11%), grade 2 renal toxicity in 1 patient, grade 2 skin reaction in 1 patient, and suspected cardiac toxicity in 1 patient. Conclusion: Our study confirmed that a lower dose of capecitabine has a good toxicity profile and is active in patients with MBC.

No established second-line chemotherapy is available for patients with advanced gastric cancer failing to respond or progressing to first-line chemotherapy. However, 20-40% of these patients commonly receive second-line chemotherapy. We evaluated the influence of clinico-pathologic factors on the survival of 175 advanced gastric cancer patients, who received second-line chemotherapy at three oncology departments. Univariate and multivariate analyses found five factors which were independently associated with poor overall survival: performance status 2 (hazard ratio (HR), 1.79; 95% CI, 1.16-2.77; P=0.008), haemoglobin/=11.5 g l(-1) (HR, 1.48; 95% CI, 1.06-2.05; P=0.019), CEA level50 ng ml(-1) (HR, 1.86; 95% CI, 1.21-2.88; P=0.004), the presence of greater than or equal to three metastatic sites of disease (HR, 1.72; 95% CI, 1.16-2.53; P=0.006), and time-to-progression under first-line chemotherapy/=6 months (HR, 1.97; 95% CI, 1.39-2.80; P0.0001). A prognostic index was constructed dividing patients into low- (no risk factor), intermediate- (one to two risk factors), or high- (three to five risk factors) risk groups, and median survival times for each group were 12.7 months, 7.1 months, and 3.3 months, respectively (P0.001). In the absence of data deriving from randomised trials, this analysis suggests that some easily available clinical factors may help to select patients with advanced gastric cancer who could derive more benefit from second-line chemotherapy.

Background Elderly patients have been often excluded from or underrepresented in the study populations of combination chemotherapy trials. The primary end point of this study was to determine the response rate and the toxicity of the weekly oxaliplatin, 5-fluorouracil and folinic acid (OXALF) regimen in elderly patients with advanced gastric cancer. The secondary objective was to measure the time to disease progression and the survival time. Methods Chemotherapy-naive patients with advanced gastric cancer aged 70 or older were considered eligible for study entry. Patients received weekly oxaliplatin 40 mg/m2, fluorouracil 500 mg/m2 and folinic acid 250 mg/m2. All drugs were given intravenously on a day-1 schedule. Results A total of 42 elderly patients were enrolled. Median age was 73 years and all patients had metastatic disease. The response rate according to RECIST criteria was 45.2% (95% CIs: 30%–56%) with two complete responses, 17 partial responses, 13 stable diseases and 10 progressions, for an overall tumor rate control of 76.2% (32 patients). Toxicity was generally mild and only three patients discontinued treatment because of treatment related adverse events. The most common treatment-related grade 3/4 adverse events were fatigue (7.1%), diarrhoea (4.8%), mucositis (2.4%), neurotoxicity (2.4%) and neutropenia (4.8%). The median response duration was 5.3 months (95% CIs: 2.13 – 7.34), the median time to disease progression was 5.0 months (95% CIs: 3.75 – 6.25) and the median survival time was 9.0 months (95% CIs: 6.18 – 11.82). Conclusion OXALF represents an active and well-tolerated treatment modality for elderly patients with locally advanced and metastatic gastric cancer.

To determine the relationship between p53 overexpression and vascular endothelial growth factor (VEGF) upregulation in liver and abdominal metastases from colon cancer. The analysis in the two metastatic sites was carried out to evaluate the potential role of microenvironment in the molecular regulation of VEGF.Bioptic specimens of liver and abdominal metastases from colon carcinomas were examined by immunohistochemistry for p53 and VEGF expressions. Consecutive cases with assessable tumor tissue were selected.The study population consisted of 24 cases having liver metastases and 34 cases having abdominal metastases. Abdominal metastases showed a higher number of VEGF-positive cases and a higher intensity of VEGF immunoreactivity than liver metastases did (p = 0.01). The combined analysis of p53 and VEGF showed a strong association between the two markers in the 24 liver metastases; 9 cases were VEGF positive/p53 positive and 15 cases were VEGF negative/p53 negative. This relationship was not found in the 34 abdominal metastases, which showed concordance between the two markers in 9 VEGF-positive/p53-positive cases only.Microenvironment factors like hypoxia may have a predominant role in inducing VEGF expression and they can override the molecular control of p53 on VEGF.

PURPOSE: We performed a randomized, double-blind, placebo-controlled trial to assess the efficacy of glutathione (GSH) in the prevention of oxaliplatin-induced neurotoxicity. PATIENTS AND METHODS: Fifty-two patients treated with a bimonthly oxaliplatin-based regimen were randomized to receive GSH (1,500 mg/m2 over a 15-minute infusion period before oxaliplatin) or normal saline solution. Clinical neurologic evaluation and electrophysiologic investigations were performed at baseline and after four (oxaliplatin dose, 400 mg/m2), eight (oxaliplatin dose, 800 mg/m2), and 12 (oxaliplatin dose, 1,200 mg/m2) cycles of treatment. RESULTS: At the fourth cycle, seven patients showed clinically evident neuropathy in the GSH arm, whereas 11 patients in the placebo arm did. After the eighth cycle, nine of 21 assessable patients in the GSH arm suffered from neurotoxicity compared with 15 of 19 in the placebo arm. With regard to grade 2 to 4 National Cancer Institute common toxicity criteria, 11 patients experienced neuropathy in the placebo arm compared with only two patients in the GSH arm (P = .003). After 12 cycles, grade 2 to 4 neurotoxicity was observed in three patients in the GSH arm and in eight patients in the placebo arm (P = .004). The neurophysiologic investigations (sural sensory nerve conduction) showed a statistically significant reduction of the values in the placebo arm but not in the GSH arm. The response rate was 26.9% in the GSH arm and 23.1% in the placebo arm, showing no reduction in activity of oxaliplatin. CONCLUSION: This study provides evidence that GSH is a promising drug for the prevention of oxaliplatin-induced neuropathy, and that it does not reduce the clinical activity of oxaliplatin.

Ifosfamide and cisplatin cause urinary loss of carnitine, which is a fundamental molecule for energy production in mammalian cells. We investigated whether restoration of the carnitine pool might improve chemotherapy-induced fatigue in non-anaemic cancer patients. Consecutive patients with low plasma carnitine levels who experienced fatigue during chemotherapy were considered eligible for study entry. Patients were excluded if they had anaemia or other conditions thought to be causing asthenia. Fatigue was assessed by the Functional Assessment of Cancer Therapy-Fatigue quality of life questionnaire. Treatment consisted of oral levocarnitine 4 g daily, for 7 days. Fifty patients were enrolled; chemotherapy was cisplatin-based in 44 patients and ifosfamide-based in six patients. In the whole group, baseline mean Functional Assessment of Cancer Therapy-Fatigue score was 19.7 (±6.4; standard deviation) and the mean plasma carnitine value was 20.9 μM (±6.8; standard deviation). After 1 week, fatigue ameliorated in 45 patients and the mean Functional Assessment of Cancer Therapy-Fatigue score was 34.9 (±5.4; standard deviation) (P

Background Loss of activity of tumor suppressor genes is considered a fundamental step in a genetic model of carcinogenesis. Altered expression of the p53 and the Deleted in Colon Cancer (DCC) proteins has been described in gastric cancer and this event may have a role in the development of the disease. According to this hypothesis, we investigated the p53 and the DCC proteins expression in different stages of gastric carcinomas. Methods An immunohistochemical analysis for detection of p53 and DCC proteins expression was performed in tumor tissue samples of patients with UICC stage I and II gastric cancer. For the purpose of the analysis, the staining results were related to the pathologic data and compared between stage categories. Results Ninety-four cases of gastric cancer were analyzed. Disease stage categories were pT1N0 in 23 cases, pT2N0 in 20 cases, pT3N0 in 20 cases and pT1-3 with nodal involvment in 31 cases. Stage pT1-2N0 tumors maintained a positive DCC expression while it was abolished in pT3N0 tumors (p Conclusions Altered expression of both DCC and p53 proteins is detectable in gastric carcinomas. It seems that loss of wild-type p53 gene function and consequent p53 overexpression may be involved in early stages of tumor progression while DCC abnormalities are a late event.

Summary Background: The behaviour of colorectal carcinomas may depend on molecular properties of tumors. In node-positive colon cancer, we assessed the S-phase fraction (SPF) index, the vascular endothelial growth factor (VEGF) expression and the TS levels. The combined analysis of SPF/VEGF was studied for predictivity of recurrent disease, the TS quantitation was related to the efficacy of fluorouracil- based adjuvant chemotherapy. Patients and methods: Consecutive patients with surgicallyresected, node-positive colon cancer were studied. Flow cytometry for the SPF and immunohistochemistries for the TS and the VEGF expression were carried out on the primary tumor. Recurrences had to be proven by biopsy or surgery, and they were categorized as early, if occurred within 12 months after surgery, or late if occured 13 months or more. Results: Of 150 evaluable patients, 100 had received fluorouracil-based adjuvant chemotherapy and 50 control patients were untreated. The combined analysis of the VEGF and the SPF showed a strong association between the two markers; 48 patients (32%) had high SPF/VEGF positive tumors and 69 patients (46%) had low SPF/VEGF negative tumors (P < 0.0001). The majority of disease-free patients (73.4%) showed VEGF negative/low SPF tumors (P < 0.0001). Early recurrences occurred more frequently in patients with VEGF positive/high SPF tumors (P < 0.001). In the 100 patients treated with adjuvant chemotherapy, 86% of relapsed patients had TS overexpressin g tumors and 69% of disease-free patients had TS negative tumors (P < 0.001). Also, early recurrences occurred more frequently in TS overexpressing tumors (P < 0.0001). Conclusions: Evidence is supported that node-positive colon cancer constitutes a heterogenous disease. Patients with VEGF positive/high SPF tumors showed an unfavourable outcome compared to patients with VEGF negative/low SPF tumors. The efficacy of fluorouracil-based adjuvant chemotherapy may depend on theTS status.

Although octreotide has been shown to inhibit the growth of gastrointestinal (GI) tumors in vitro and in vivo, preliminary clinical trials have reported disappointing results for this somatostatin analog in patients with GI cancers. The results of these trials probably reflect the difficulty in assessing the therapeutic potential of an agent such as octreotide in GI cancers. Thus, it is possible that treatment with octreotide could be useful in the stabilization of disease if it is associated with an improvement in survival. On the basis of these considerations five randomized trials were carried out to evaluate the therapeutic potential in patients with GI cancers. Four trials (one in patients with colorectal carcinoma and three in patients with carcinoma of the pancreas) did not show any advantage of octreotide in untreated patients; in contrast, one trial reported that octreotide prolonged survival in patients with GI cancers refractory to chemotherapy. Some clinical features of the latter study (treatment with chemotherapy, different schedules) may explain these conflicting results. Although data from randomized trials suggest that octreotide is not effective in untreated asymptomatic advanced GI cancer patients, further studies are warranted to assess the efficacy of octreotide in chemotherapy refractory patients in order to clarify the impact of octreotide in terms of not only survival but also on the patients’ quality of life.

Tumours of patients with node-positive rectal cancer were studied by immunohistochemistry for p53, BAX and vascular endothelial growth factor expressions. Results were correlated to the relapse rate, the pattern of relapse and the event-free survival after radical surgery and adjuvant chemoradiation. After a median follow-up of 60 months, 39 patients remained disease-free and 40 patients relapsed (18 local relapses and 22 distant metastases). The majority of disease-free patients showed p53 negative and vascular endothelial growth factor negative tumours. Local relapses occurred more frequently in patients with p53 overexpressing tumours (P

Summary Background We assessed the hypothesis that a compromised p53 function could account for the non response of colon cancer patients with low thymidylate synthase (TS) expression receiving a bolus 5-fluorouracil (5-FU)-leucovorin (LV) combination. Patients and methods The study population consisted of 41 patients with unresectable metastatic colon cancer, homogeneosuly, treated with bolus 5-FU and LV. Results Twenty-seven patients (66%) showed high levels of TS expression. The difference in the proportion of objective responses between patients with low (CR + PR: 7 of 14, 50%) and high (CR + PR: 0 of 27) TS levels was statistically significant (P = 0.0001, chi-square test). p53 nuclear over-expression was found in 27 of 41 patients (66%). No differences were observed in p53 overexpression in patients with high (66%) or low (66%) TS expression. p53 status was not found to be associated with response even in patients with low TS expression. Conclusions p53 status measured by immunohistochemistry does not seem to be useful to identify unresponsive patients with low TS expression.

4084 Background: Studies on Asian, US, and German patients have moved some criticisms on the validity of the 7th edition of the AJCC classification to discriminate outcome of gastric cancer stages. We investigated the effect of this AJCC classification in a high-quality surgical populations of patients receiving D2 lymphadenectomy. Methods: From the prospective database at San Salvatore Hospital, Pesaro, we identified 515 patientswith gastroesophageal junction (Siewert II and III) or stomach adenocarcinoma who underwent gastrectomy with curative intent from 1998 to 2010. Lymphadenectomy extended to the 3rd level 12p/b nodes (D2/D3) was performed in all patients. Overall survival (OS) probabilities, calculated from the date of surgery to the date of death, from any cause, were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: 58% of patients were male,median age was 73 years (range 36-96). Median number of examined lymph nodes was 32 (range, 1-89), and only 8.9% of patients had less than 15 examined lymph nodes; 96 patients received adjuvant chemo- or chemoradiotherapy. As shown in the table, we proposed a revised staging system (Pesaro Staging System, PSS), which performs better than the 7th edition of AJCC classification in terms of survival differences between stages. Conclusions: This study confirms once again that the 7th edition of the AJCC classification does not discriminate adequately the outcome from stage to stage. In a European population of patients undergoing gastrectomy plus at least D2 lymphadenectomy, the revised staging system, PSS, better defines patient prognosis. [Table: see text]

e11069 Background: Schedules with anthracyclines and taxanes are one of the best options for primary chemotherapy. The addition of trastuzumab showed an impressive percentage of pathological comple...

15169 Background: Currently, there is no established second-line chemotherapy for pts with advanced gastric cancer who failed to respond or progressed after a first-line chemotherapy. Many of these pts still have a good performance status or have symptoms to be palliated at the time of first-line failure and are candidates for second-line chemotherapy. However, phase II trials demonstrate divergent results about pts more likely to benefit from second-line chemotherapy. We retrospectively analyzed the influence of various clinicopathologic factors on the survival of pts treated with second-line chemotherapy. Methods: Analysis is based on the data of 169 pts consecutively treated at 3 oncology department with a second-line chemotherapy. Univariate and multivariate analyses were performed to determine prognostic factors of survival. The variable used for analysis were: sex, age, ECOG performance status, a weight loss > 5 Kg in the last month; site of primary tumor, histopathology; hemoglobin, serum albumin, and CEA levels, number and site of metastatic disease, response to and time-to-progression (TTP) with the first- line chemotherapy. Results: The variables predictive of better survival were: ECOG PS 0–1 (p 10 g/dl (p=0.01), CEA level 4 months (p=0.008). Peritoneal carcinomatosis was predictive of poor survival only when associated with one or more signs or symptoms as vomiting, anorexia, abdominal pain, ascites(p=0.03). Four factors were independently associated with better overall survival: ECOG PS 0–1 (p=0.002; HR 0.46; CI 95%, 0.29–0.75), CEA level 4 months (p=0.02; HR 0.66; CI 95%, 0.45–0.95). Conclusions: In the absence of data deriving from randomized, controlled, clinical trials, this analysis suggests that some clinical factors may help clinicians to better select groups of pts with gastric cancer more likely to benefit from a second-line chemotherapy. No significant financial relationships to disclose.

4041 Background: The aim of our study was to asses the effect on local relapse, and consequently on overall and disease free survival, of a limited or an extended lymphadenectomy, in an homogeneus group of radically resected gastric cancer patients. This analysis was performed in order to identify a subgroup of patients possibly not benefiting from a toxic therapeutic approach such chemoradiation therapy. Methods: Patients with radically resected gastric cancer were eligible for our analysis. We divided our patients into 2 groups according to lymphadenectomy type: group A for limited (25 or less than 25 resected lymph nodes) and group B for extended (more than 25 resected lymph nodes) lymph nodes resection. All major clinical characteristics (age, extension within gastric wall, pN stage and extent of lymphadenectomy) were considered for statistical analysis. Results: Four hundred-eighteen patients were analysed: tumour stage at diagnosis was pT2–3 pN1–3 M0 in 339 patients and pT3 N0 M0 in 79 patients. Med...

Knowledge of the prognostic role of biomarkers in colorectal cancer is limited and the routine determination for clinical practice is not warrented. However, for some of these markers, data are promising enough for further evaluation. This review addresses a comprehensive analysis of prognostic biomarkers in colorectal cancer. Data from published studies were collected and analyzed. A sufficient level of evidence suggests that DNA indexes, angiogenesis indicators and some genetic/biochemical markers identify prognostic differences in patients with early-stage colorectal cancer. High-risk patients could be the target for future adjuvant chemotherapy trials and one or more of these markers may identify prognostic subgroups with the same TNM stage category.