Disentangling functional trait variation and covariation in epiphytic lichens along a continent-wide latitudinal gradient.

Characterizing functional trait variation and covariation, and its drivers, is critical to understand the response of species to changing environmental conditions. Evolutionary and environmental factors determine how traits vary among and within species at multiple scales. However, disentangling their relative contribution is challenging and a comprehensive trait-environment framework addressing such questions is missing in lichens. We investigated the variation in nine traits related to photosynthetic performance, water use and nutrient acquisition applying phylogenetic comparative analyses in lichen epiphytic communities on beech across Europe. These poikilohydric organisms offer a valuable model owing to their inherent limitations to buffer contrasting environmental conditions. Photobiont type and growth form captured differences in certain physiological traits whose variation was largely determined by evolutionary processes (i.e. phylogenetic history), although the intraspecific component was non-negligible. Seasonal temperature fluctuations also had an impact on trait variation, while nitrogen content depended on photobiont type rather than nitrogen deposition. The inconsistency of trait covariation among and within species prevented establishing major resource use strategies in lichens. However, we did identify a general pattern related to the water-use strategy. Thus, to robustly unveil lichen responses under different climatic scenarios, it is necessary to incorporate both among and within-species trait variation and covariation.

Combining spectroscopic techniques and chemometrics for the interpretation of lichen biomonitoring of air pollution.

A screening evaluation of lichen thalli, based on spectroscopic techniques coupled with chemometrics, is proposed as fast, simple and "green" method for the biomonitoring of air pollution. For two consecutive years, lichen thalli of Pseudevernia furfuracea were exposed for three months in selected sites of Liguria (NW-Italy) according to different levels and types of air pollution. At the end of the exposure period, transplanted thalli were analyzed by a set of monitoring techniques, including Front-Face Fluorescence Spectroscopy (FFFS), Near Infrared Spectroscopy (NIRS) and Plant Efficiency Analyser (PEA). Data were compared with values of air pollutants recorded during the exposure period by the Regional Agency for Environmental Protection, in order to relate lichen physiological indicators with the effects of atmospheric concentrations. A chemometric evaluation of the analytical signals, including principal component analysis (PCA) and quadratic discriminant analysis (QDA), was performed; the mean prediction rate of the discriminant models calculated on the FFFS emission spectra ranged from 70 to 75% on the external test sets. Front-face fluorescence spectroscopy proved to be a promising technique for the determination of level and type of pollutants in lichen thalli.

Endotypes of pollen-food syndrome in children with seasonal allergic rhinoconjunctivitis: a molecular classification.

BACKGROUND: Pollen-food syndrome (PFS) is heterogeneous with regard to triggers, severity, natural history, comorbidities, and response to treatment. Our study aimed to classify different endotypes of PFS based on IgE sensitization to panallergens. METHODS: We examined 1271 Italian children (age 4-18 years) with seasonal allergic rhinoconjunctivitis (SAR). Foods triggering PFS were acquired by questionnaire. Skin prick tests were performed with commercial pollen extracts. IgE to panallergens Phl p 12 (profilin), Bet v 1 (PR-10), and Pru p 3 (nsLTP) were tested by ImmunoCAP FEIA. An unsupervised hierarchical agglomerative clustering method was applied within PFS population. RESULTS: PFS was observed in 300/1271 children (24%). Cluster analysis identified five PFS endotypes linked to panallergen IgE sensitization: (i) cosensitization to ≥2 panallergens ('multi-panallergen PFS'); (ii-iv) sensitization to either profilin, or nsLTP, or PR-10 ('mono-panallergen PFS'); (v) no sensitization to panallergens ('no-panallergen PFS'). These endotypes showed peculiar characteristics: (i) 'multi-panallergen PFS': severe disease with frequent allergic comorbidities and multiple offending foods; (ii) 'profilin PFS': oral allergy syndrome (OAS) triggered by Cucurbitaceae; (iii) 'LTP PFS': living in Southern Italy, OAS triggered by hazelnut and peanut; (iv) 'PR-10 PFS': OAS triggered by Rosaceae; and (v) 'no-panallergen PFS': mild disease and OAS triggered by kiwifruit. CONCLUSIONS: In a Mediterranean country characterized by multiple pollen exposures, PFS is a complex and frequent complication of childhood SAR, with five distinct endotypes marked by peculiar profiles of IgE sensitization to panallergens. Prospective studies in cohorts of patients with PFS are now required to test whether this novel classification may be useful for diagnostic and therapeutic purposes in the clinical practice.

The impact of telemonitoring on adherence to nasal corticosteroid treatment in children with seasonal allergic rhinoconjunctivitis.

BACKGROUND: Adherence to controller therapy in allergic diseases is low. Telemonitoring has been proposed to improve adherence to treatment in chronic diseases. However, this strategy has never been tested in allergic rhinoconjunctivitis. OBJECTIVE: To test whether Internet-based telemonitoring during the grass-pollen season of children with allergic rhinoconjunctivitis may enhance adherence to treatment. METHODS: Children and adolescents, 5-18 years old, with moderate-to-severe seasonal allergic rhinoconjunctivitis to grass pollen requiring daily administration of nasal corticosteroid (NCS) (mometasone) were recruited (April 2013) in a paediatric allergy practice. Participants were randomized to Internet-based monitoring (AllergyMonitor(™) , AM) or to usual care (no diary at all, controls) and followed from 13 May (T0) to 15 June 2013 (T2). An intermediate visit (T1) was performed between 31 May and 2 June. Optimal adherence to therapy was expressed as the use of at least 0.190 g/day of mometasone, corresponding to 1 puff/nostril/day, and it was measured by canister weights during (T1) and at the end (T2) of the study period. Main secondary outcomes included the reported disease severity (validated self-questionnaire) and quality of life (AdoIRQLQ questionnaire), disease knowledge (multiple-choice questionnaire), nasal flow and resistance at baseline and at T2. RESULTS: The use of mometasone, expressed as both optimal adherence rate (48.4% vs. 12.5%; P = 0.002) and average daily use (0.20 ± 0.12 g/day vs. 0.15 ± 0.07 g/day; P = 0.037), was higher in the AM group (n = 31) than among controls (n = 32). Disease knowledge improved among the patients using AM (83.3% vs. 68.3%; P < 0.001) but not among controls (68.2% vs. 67.7% right answers; P > 0.05). No differences were observed in the reported severity of disease, nasal flow and resistance and quality of life both at baseline and at follow-up visits. CONCLUSIONS: Internet-based telemonitoring improves adherence to NCS treatment and disease knowledge among children and adolescents with seasonal allergic rhinoconjunctivitis.

Natural history of bone metastasis in colorectal cancer: final results of a large Italian bone metastases study.

BACKGROUND: Data are limited regarding bone metastases from colorectal cancer (CRC). The objective of this study was to survey the natural history of bone metastasis in CRC. PATIENTS AND METHODS: This retrospective, multicenter, observational study of 264 patients with CRC involving bone examined cancer treatments, bone metastases characteristics, skeletal-related event (SRE) type and frequency, zoledronic acid therapy, and disease outcomes. RESULTS: Most patients with bone metastases had pathologic T3/4 disease at CRC diagnosis. The spine was the most common site involved (65%), followed by hip/pelvis (34%), long bones (26%), and other sites (17%). Median time from CRC diagnosis to bone metastases was 11.00 months; median time to first SRE thereafter was 2.00 months. Radiation and pathologic fractures affected 45% and 10% of patients, respectively; 32% of patients had no reported SREs. Patients survived for a median of 7.00 months after bone metastases diagnosis; SREs did not significantly affect survival. Subgroup analyses revealed that zoledronic acid significantly prolonged median time to first SRE (2.00 months versus 1.00 month, respectively, P=0.009) and produced a trend toward improved overall survival versus no zoledronic acid. CONCLUSION: This study illustrates the burden of bone metastases from CRC and supports the use of zoledronic acid in this setting.

Prognosis of mucinous histology for patients with radically resected stage II and III colon cancer.

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.

"Short Course" of Nonpegylated Liposomal Doxorubicin Plus Paclitaxel and Trastuzumb as Primary Systemic Therapy for Operable and Locally-Advanced Breast Cancer: A Phase II Study (PacLiDox 07).

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 complete responses in Buzdar trial (66.7%). Recently, nonpegylated liposome-encapsulated doxorubicin (NLD) has been widely used in advanced breast cancer with high response rates (98.1 % in Cortes study). The aims of our study were to assess pathological responses and toxicity of NLD plus paclitaxel (and trastuzumab in patients with HER2 overexpression). METHODS: Thirty patients entered the study: 9 locally advanced and 21 operable. Median age was 58.5 years (range: 31-73). 23 patients without HER2 overexpression (or FISH not amplified) were treated with NLD 50 mg/m2 every three weeks for 3 courses and weekly paclitaxel 80 mg/m2 for 8 courses. 7 patients with HER2 overexpression or FISH amplified were treated with the same schedules plus trastuzumab (Herceptin) 4 mg/kg for the first administration and 2 mg/kg for the following 7 weekly administrations. RESULTS: Pathological complete response (pCR) was documented in 1 patient (treated with trastuzumab); no residual tumor (infiltrating or "in situ") on breast was documented in other 2 patients. Objective clinical responses were documented in 22 patients (73.3%): 8 complete, 10 partial and 4 "minimal" responses. 7 patients have shown stable and 1 progressive disease. Clinical response in patients with HER2 overexpression treated with trastuzumab was 100% (4 complete and 3 partial responses). Conservative surgery was performed in 8 (38%) and mastectomy in 13 (62%) out of 21 operable patients; however, 7 out of 14 responding patients with operable disease underwent quadrantectomy (50%). Main toxicity was neutropenia: febrile in 2 patients (7%) and gr. 3-4 in 13 (43%). Other grade 3 toxicities were as follows: vomiting in 1 patient, asthenia in 1 patient, joint symptom in 1 patient. 3 patients were withdrawn from the study. No episodes of left ventricular ejection fraction (LVEF) < 50% were recorded (with a median reduction of 8%). CONCLUSIONS: A "short course" of paclitaxel and NLD is active in terms of clinical response and conservative surgery for patients with potentially operable and locally advanced breast cancer; toxicity was manageable. High activity of the combination with trastuzumab has been confirmed. However, with this "short course" schedule, the result in term of clinical responses didn't turn into complete pathological responses.

Genetic modulation of the Let-7 microRNA binding to KRAS 3'-untranslated region and survival of metastatic colorectal cancer patients treated with salvage cetuximab-irinotecan.

There is increasing evidence that the Let-7 microRNA (miRNA) exerts an effect as a tumor suppressor by targeting the KRAS mRNA. The Let-7 complementary site (LCS6) T>G variant in the KRAS 3'-untranslated region weakens Let-7 binding. We analyzed whether the LCS6 variant may be clinically relevant to patients with metastatic colorectal cancer (MCRC) treated with anti-epidermal growth factor receptor (EGFR) therapy. LCS6 genotypes and KRAS/BRAF mutations were determined in the tumor DNA of 134 patients with MCRC who underwent salvage cetuximab-irinotecan therapy. There were 34 G-allele (T/G+G/G) carriers (25%) and 100 T/T genotype carriers (75%). G-allele carriers were significantly more frequent in the KRAS mutation group than in patients with KRAS wild type (P=0.004). In the 121 patients without BRAF V600E mutation, overall survival (OS) and progression-free survival (PFS) times were compared between carriers of the LCS6 G-allele genotypes and carriers of the wild-type T/T genotype. LCS6 G-allele carriers showed worse OS (P=0.001) and PFS (P=0.004) than T/T genotype carriers (confirmed in the multivariate model including the KRAS status). In the exploratory analysis of the 55 unresponsive patients with KRAS mutation, LCS6 G-allele carriers showed adverse OS and PFS times. These findings deserve additional investigations as they may open novel perspectives for the treatment of patients with MCRC.

Mucinous histology predicts for poor response rate and overall survival of patients with colorectal cancer and treated with first-line oxaliplatin- and/or irinotecan-based chemotherapy.

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 sites > or =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.

Second-line chemotherapy for patients with advanced gastric cancer: who may benefit?

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 50 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

Liver-only metastatic colorectal cancer patients and thymidylate synthase polymorphisms for predicting response to 5-fluorouracil-based chemotherapy.

We investigated the association between thymidylate synthase (TS) germline polymorphisms and response to 5-fluorouracil-based chemotherapy in 80 patients with liver-only metastatic colorectal cancer (MCRC). The tandem repeat polymorphism (VNTR) in TS 5'-untranslated region (5'-UTR), which consists of two (2R) or three (3R) 28-bp repeated sequences, with or without a G/C nucleotide change in 3R carriers (3G or 3C) and a 6-bp insertion/deletion (6+/6-) in the TS 3'-UTR, was studied. The distinction between high (2R/3G, 3C/3G and 3G/3G) and low (2R/2R, 2R/3C and 3C/3C) TS expression genotypes according to the 5'-UTR VNTR+G/C nucleotide change showed significant association with tumour response (P=0.01). In particular, high TS expression genotypes were found in 8 out of 34 patients (23.5%) with complete or partial response and in 24 out of 46 patients (52%) with stable disease and disease progression. Liver-only MCRC patients are a homogeneous and clinical relevant subgroup that may represent an ideal setting for studying the actual influence of TS polymorphisms.

Lichens from Antalya, Cankiri, Konya and Nevsehir Provinces (Turkey).

A contribution to the lichen flora of Turkey is performed. A total of 171 lichen taxa (including 2 subspecies and 2 varieties) and 1 lichenicolous fungus are determined from 14 localities in Antalya, Cankiri, Konya and Nevsehir provinces of Turkey. Caloplaca scrobiculata H. Magn. is new to Turkey. Besides Caloplaca scrobiculata H. Magn. and Xanthoria sorediata (Vain.) Poelt were found for the second time in Asia. Carbonea vitellinaria (Nyl.) Hertel was found to grow on Candelariella vitellina (Hoffm.) Müll. Arg. while Muellerella pymaea (Körb.) D. Hawksw. var. athallina (Müll. Arg.) Triebel (lichenicolous fungus) on Tephromela atra (Huds.) Hafellner as parasitic. All lichen taxa found in Cankiri are new to this province (92 intraspecific taxa), while 39 new to Nevsehir, 8 new to Konya and 5 new to Antalya provinces. For every each taxon, the habitat pattern and distribution data are presented.

Lymphatic, blood vessel and perineural invasion identifies early-stage high-risk radically resected gastric cancer patients.

The availability of different treatment options for radically resectable gastric cancer reopened the question of treatment selection and correct definition of high-risk categories. Lymphatic, blood vessel and perineural invasion (LBVI/PNI) seem to possess the necessary potential to provide useful information for the clinical management of this disease. Seven hundred and thirty-four patients with advanced gastric cancer who underwent curative gastrectomy were analysed according to the presence of LBVI/PNI. Patients were divided into two groups: group A for patients with LBVI/PNI (189 patients 26%) and group B for patients without LBVI/PNI (545 patients, 74%). The disease-free survival (DFS) for patients in group A was 32.1 months, whereas it was not reached for patients in group B (P=0.0001); the median overall survival was 45.5 months for patients in group A, whereas it was not reached for patients in group B (P=0.0001). At multivariate analysis, the presence of LBVI/PNI appeared an independent prognostic factor for DFS and OS. Our results were confirmed in subgroup analysis, separately considering stage I and early gastric cancer patients with and without LBVI/PNI. Taken together, our findings suggest the importance of LBVI/PNI in gastric cancer as it may provide additional information for identifying patients at high risk, who may be candidates for further medical treatment after or before surgery.

Weekly oxaliplatin, 5-fluorouracil and folinic acid (OXALF) as first-line chemotherapy for elderly patients with advanced gastric cancer: results of a phase II trial.

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.

Reliability of different sampling densities for estimating and mapping lichen diversity in biomonitoring studies.

Sampling requirements related to lichen biomonitoring include optimal sampling density for obtaining precise and unbiased estimates of population parameters and maps of known reliability. Two available datasets on a sub-national scale in Italy were used to determine a cost-effective sampling density to be adopted in medium-to-large-scale biomonitoring studies. As expected, the relative error in the mean Lichen Biodiversity (Italian acronym: BL) values and the error associated with the interpolation of BL values for (unmeasured) grid cells increased as the sampling density decreased. However, the increase in size of the error was not linear and even a considerable reduction (up to 50%) in the original sampling effort led to a far smaller increase in errors in the mean estimates (<6%) and in mapping (<18%) as compared with the original sampling densities. A reduction in the sampling effort can result in considerable savings of resources, which can then be used for a more detailed investigation of potentially problematic areas. It is, however, necessary to decide the acceptable level of precision at the design stage of the investigation, so as to select the proper sampling density.

Thymidylate synthase protein expression in colorectal cancer metastases predicts for clinical outcome to leucovorin-modulated bolus or infusional 5-fluorouracil but not methotrexate-modulated bolus 5-fluorouracil.

BACKGROUND: Different 5-fluorouracil (5-FU) schedules and/or biochemical modulators may result in different mechanisms of cytotoxicity, potentially affecting the correlation between thymidylate synthase (TS) expression and the clinical response to the fluoropyrimidine. PATIENTS AND METHODS: TS levels were measured immunohistochemically on archival specimens of colorectal cancer metastases from 124 patients homogeneously treated in a series of clinical trials at our institutions with: (A) leucovorin (LV)-modulated infusional 5-FU (n = 48); (B) LV-modulated bolus 5-FU (n = 41); (C) methotrexate (MTX)-modulated bolus 5-FU (n = 35). RESULTS: A statistically significant correlation between TS levels and the clinical response was observed with the regimens involving continuous infusion and/or LV modulation (response rate in patients with low and high TS: 66% versus 24%, P = 0.003, and 50% versus 0%, P = 0.0001, in group A and B, respectively). Conversely, TS levels failed to predict the clinical response within the group of patients treated with MTX-modulated bolus 5-FU (response rate 21% versus 13%, P = 0.50, with low and high TS, respectively). Consistently, the median time to progression/overall survival time in patients with low and high TS were 9 versus 6 months/19 versus 14 months (P = 0.009/0.035, group A), 8 versus 2 months/12 versus 6 months (P = 0.002/0.0006, group B) and 3 versus 2 months/12 versus 13 months (P = 0.14/0.74, group C). CONCLUSIONS: The correlation between intratumoral TS levels and the clinical response to 5-FU depends strongly on the schedule of administration/biochemical modulators that are used in different 5-FU regimens. These data strengthen the notion that different 5-FU schedules have different mechanisms of cytotoxicity.

Efficacy of anthracyclines and paclitaxel as first line chemotherapy in patients with visceral metastases of breast cancer.

BACKGROUND: Anthracyclines combined with paclitaxel are one of the most active schedules in patients with advanced breast cancer: response rates range from 40 to 80%, considering all metastatic sites (visceral and soft tissues). We performed a non-randomized phase II trial with anthracyclines/paclitaxel combination to evaluate response and toxicity only in patients with visceral metastases. METHODS: Twenty-seven patients (median age 50 years; range 30-72) with visceral metastases of breast cancer were enrolled in this study. Overall, 11 patients had lung metastases (41%), 10 liver (37%), 4 liver-lung metastases (15%) and 2 peritoneal carcinosis (7%). 7 patients had received adjuvant anthracycline-based chemotherapy (26%) and 10 patients adjuvant CMF combination chemotherapy (37%); 10 patients (37%) received hormonal therapy for advanced disease. Treatment schedules were: group A) 17 patients, Adriamicyn 50 mg/m2 on day 1 i.v. bolus and Paclitaxel 175 mg/m2 on day 2 i.v. 3 hours infusion, every 3 weeks; group B) 10 patients, epirubicin 90 mg/m2 on day 1 i.v. bolus and paclitaxel 200 mg/m2 on day 2 i.v., 3 hours infusion, every 3 weeks. The number of cycles administered was 141 with a median of 5 (range 3-9). RESULTS: All patients were evaluable for response and toxicity. The objective response rate was 59% - 16 patients - (15% complete and 44% partial remission), 95% C.I. 40.7-77%; 10/17 in group A and 7/10 in group B. Stable disease 30% (8 patients) and progressive disease 11% (3 patients). The median duration of response was 5 months (range 1-16); median time to progression 13 months (range 3-18) and median survival 17 months (range 4-24). The main toxicity was neutropenia, occurred in 16 patients (59%; grade IV in 7 patients, of whom 2 febrile neutropenia, and grade III in 9 patients); grade III gastrointestinal toxicity in 2 patients; grade III neurological toxicity in 1 patient; grade III stomatitis in 2 patients. No congestive hearth failure or treatment death related was observed. CONCLUSIONS: These schedules of anthracyclines and paclitaxel confirmed their efficacy in metastatic breast cancer even in patients with visceral disease. Neutropenia was the main toxicity; grade IV neutropenia was more frequently observed in epirubicin/paclitaxel arm.

Raltitrexed plus oxaliplatin (TOMOX) as first-line chemotherapy for metastatic colorectal cancer. A phase II study of the Italian Group for the Study of Gastrointestinal Tract Carcinomas (GISCAD).

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/m2 plus oxaliplatin 100 mg/m2, 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 intention-to-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 repeated and prolonged fluorouracil infusions.

Potential role of levocarnitine supplementation for the treatment of chemotherapy-induced fatigue in non-anaemic cancer patients.

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 microM (+/-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<.001). All patients achieved normal plasma carnitine levels. Patients maintained the improved Functional Assessment of Cancer Therapy-Fatigue score until the next cycle of chemotherapy. In selected patients, levocarnitine supplementation may be effective in alleviating chemotherapy-induced fatigue. This compound deserves further investigations in a randomised, placebo-controlled study.

Infusional 5-fluorouracil, cisplatin and mitomycin C in advanced gastric cancer: a low cost effective regimen.

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.