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Immune checkpoint inhibitors have not shown clinical benefit to patients with metastatic colorectal cancer who had proficient mismatch repair (pMMR) or microsatellite stable (MSS) tumours in previous studies. Both an active combination chemotherapy (FOLFOXIRI; fluorouracil, leucovorin, oxaliplatin, and irinotecan) and bevacizumab seem able to increase the immunogenicity of pMMR or MSS tumours. We aimed to provide preliminary evidence of benefit from the addition of the anti-PD-L1 agent atezolizumab to first-line FOLFOXIRI plus bevacizumab in patients with metastatic colorectal cancer.AtezoTRIBE was a multicentre, open-label, randomised, controlled, phase 2 study of patients (aged 18-70 years with an Eastern Cooperative Oncology Group [ECOG] performance status of 0-2 and aged 71-75 years with an ECOG performance status of 0) with histologically confirmed, unresectable, previously untreated metastatic colorectal cancer and adequate organ function, who were recruited from 22 oncology centres in Italy. Patients were stratified according to centre, ECOG performance status, primary tumour site, and previous adjuvant therapy. A randomisation system incorporating a minimisation algorithm randomly assigned (1:2) patients via a masked web-based allocation procedure to two groups: the control group received first-line FOLFOXIRI (intravenous 165 mg/mBetween Nov 30, 2018, and Feb 26, 2020, 218 patients were randomly assigned and received treatment (73 in the control group and 145 in the atezolizumab group). At the data cutoff (Aug 1, 2021), median follow-up was 19·9 months (IQR 17·3-23·9). Median progression-free survival was 13·1 months (80% CI 12·5-13·8) in the atezolizumab group and 11·5 months (10·0-12·6) in the control group (hazard ratio [HR] 0·69 [80% CI 0·56-0·85]; p=0·012; adjusted HR 0·70 [80% CI 0·57-0·87]; log-rank test p=0·018). The most frequent all-cause grade 3-4 adverse events were neutropenia (59 [42%] of 142 patients in the atezolizumab group vs 26 [36%] of 72 patients in the control group), diarrhoea (21 [15%] vs nine [13%]), and febrile neutropenia (14 [10%] vs seven [10%]). Serious adverse events were reported in 39 (27%) patients in the atezolizumab group and in 19 (26%) patients in the control group. Two (1%) treatment-related deaths (due to acute myocardial infarction and bronchopulmonary haemorrhage) were reported in the atezolizumab group; none were reported in the control group.The addition of atezolizumab to first-line FOLFOXIRI plus bevacizumab is safe and improved progression-free survival in patients with previously untreated metastatic colorectal cancer.GONO Foundation, ARCO Foundation, F Hoffmann-La Roche, and Roche.

Background Alectinib is a potent anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) which is currently used in the first-line setting of advanced ALK+ non-small cell lung cancer (NSCLC). Despite favorable results in the metastatic setting, the activity of alectinib in locally-advanced ALK+ NSCLC as a neoadjuvant treatment remains to be assessed. We report the case of a patient with stage IIIA ALK+ NSCLC (cT2aN2) who received alectinib as neoadjuvant treatment, achieving major pathological response (MPR) at pathologic examination. Hence we present the treatment rationale and study design of a phase II, open-label, single-arm, multicenter clinical trial (ALNEO study, EUDRACT number 2020-003432-25). Materials and Methods Patients with potentially resectable stage III ALK+ NSCLC (any T with N2, T4N0-1) will be registered to receive oral alectinib 600 mg twice daily for 2 cycles of 4 weeks each (8 weeks totally) during the neoadjuvant phase. After definitive surgery, patients will enter in the adjuvant setting, during which they will receive alectinib 600 mg twice daily for 24 cycles (96 weeks). The primary endpoint is MPR, defined as ≤10% residual viable tumor cells histologically detected in the resected primary tumor and all resected lymph nodes after surgery. Secondary endpoints include pathological complete response, objective response, event-free survival, disease-free survival, overall survival, adverse events. Conclusions Our case report supports the feasibility of alectinib as neoadjuvant treatment. ALNEO study will further explore the activity and safety of this novel treatment strategy.

Background The mitral valve is often structurally abnormal in hypertrophic cardiomyopathy (HCM). However, the mechanisms responsible for these abnormalities remain controversial. In 2016 we identified, at myectomy, muscular mitral-aortic discontinuity in 5 young patients with obstructive HCM. Objectives This study sought to confirm our preliminary findings and assess the prevalence of muscular mitral-aortic discontinuity in obstructive HCM. Methods At our center, from January 2017 to April 2018, the area between the anterior mitral leaflet and aortic valve was inspected at myectomy in 106 consecutive patients with HCM. Results Muscular mitral-aortic discontinuity was identified in 28 (26%) patients and was significantly more common in younger than older patients (age 39 ± 13 years vs. 58 ± 11 years; p Conclusions We report, for the first time, muscular mitral-aortic discontinuity in HCM. At myectomy, a long muscular discontinuity displaced the anterior mitral leaflet toward the apex in most young patients, was significantly associated with sarcomere mutations independent of age, and was extremely uncommon in older patients. These findings suggest that a long muscular mitral-aortic discontinuity could predispose to the development of outflow obstruction in young patients with sarcomere mutations.

Background and objectives Despite low incidence of early-onset sepsis, the majority of preterm newborns receive early antibiotic prophylaxis. Our aim was to assess reference ranges of Presepsin during the first 48 h of life in preterm infants and to evaluate the possible influence of neonatal and maternal factors on its values. Methods This observational study consecutively enrolled newborns ≤ 32 weeks of GA at 0–6 h of life. Enrolled infants were sampled for blood culture, complete white blood cell (WBC) count, and P-SEP at 0–6 (T0) h of life and for P-SEP at 12 ± 3 (T1), 24 ± 3 (T2), and 48 ± 6 (T3) h of life. Cases of EOS were not considered for the statistical analysis. Results Data analysis was performed for 183 patients. P-SEP median values were 583 ng/L at T0 (IQR 405–800 ng/L, 5th and 95th percentiles 204 and 1200 ng/L), 614 ng/L at T1 (IQR 450–812 ng/L, 5th and 95th percentiles 262 and 1171 ng/L), 604 ng/L at T2 (IQR 445–825 ng/L, 5th and 95th percentiles 292 and 1302 ng/L) and 513 ng/L at T3 (IQR 371–734 ng/L, 5th and 95th percentiles 249 and 1278 ng/L). P-SEP values are negatively associated to gestational age (GA) at T0, T1, and T2. Conclusions We determined for the first time the reference ranges of P-SEP during the first 48 h of life in very preterm infants and provided its percentile distribution at T0, T1, T2 and T3. P-SEP measurement was affected by GA at T0, T1, T2.

Summary Background The triplet FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes for patients with metastatic colorectal cancer, compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. However, the actual benefit of the upfront exposure to the three cytotoxic drugs compared with a preplanned sequential strategy of doublets was not clear, and neither was the feasibility or efficacy of therapies after disease progression. We aimed to compare a preplanned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression versus a sequence of mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) and FOLFIRI doublets, in combination with bevacizumab. Methods TRIBE2 was an open-label, phase 3, randomised study of patients aged 18–75 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, with unresectable, previously untreated metastatic colorectal cancer, recruited from 58 Italian oncology units. Patients were stratified according to centre, ECOG performance status, primary tumour location, and previous adjuvant chemotherapy. A randomisation system incorporating a minimisation algorithm was used to randomly assign patients (1:1) via a masked web-based allocation procedure to two different treatment strategies. In the control group, patients received first-line mFOLFOX6 (85 mg/m2 of intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab (5 mg/kg intravenously over 30 min) followed by FOLFIRI (180 mg/m2 of intravenous irinotecan over 120 min concurrently with 200 mg/m2 of leucovorin; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab after disease progression. In the experimental group, patients received FOLFOXIRI (165 mg/m2 of intravenous irinotecan over 60 min; 85 mg/m2 intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 3200 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab followed by the reintroduction of the same regimen after disease progression. Combination treatments were repeated every 14 days for up to eight cycles followed by fluorouracil and leucovorin (at the same dose administered at the last induction cycle) plus bevacizumab maintenance until disease progression, unacceptable adverse events, or consent withdrawal. Patients and investigators were not masked. The primary endpoint was progression-free survival 2, defined as the time from randomisation to disease progression on any treatment given after first disease progression, or death, analysed by intention to treat. Safety was assessed in patients who received at least one dose of their assigned treatment. Study recruitment is complete and follow-up is ongoing. This trial is registered with Clinicaltrials.gov , NCT02339116 . Findings Between Feb 26, 2015, and May 15, 2017, 679 patients were randomly assigned and received treatment (340 in the control group and 339 in the experimental group). At data cut-off (July 30, 2019) median follow-up was 35·9 months (IQR 30·1–41·4). Median progression-free survival 2 was 19·2 months (95% CI 17·3–21·4) in the experimental group and 16·4 months (15·1–17·5) in the control group (hazard ratio [HR] 0·74, 95% CI 0·63–0·88; p=0·0005). During the first-line treatment, the most frequent of all-cause grade 3–4 events were diarrhoea (57 [17%] vs 18 [5%]), neutropenia (168 [50%] vs 71 [21%]), and arterial hypertension (25 [7%] vs 35 [10%]) in the experimental group compared with the control group. Serious adverse events occurred in 84 (25%) patients in the experimental group and in 56 (17%) patients in the control group. Eight treatment-related deaths were reported in the experimental group (two intestinal occlusions, two intestinal perforations, two sepsis, one myocardial infarction, and one bleeding) and four in the control group (two occlusions, one perforation, and one pulmonary embolism). After first disease progression, no substantial differences in the incidence of grade 3 or 4 adverse events were reported between the control and experimental groups, with the exception of neurotoxicity, which was only reported in the experimental group (six [5%] of 132 patients). Serious adverse events after disease progression occurred in 20 (15%) patients in the experimental group and 25 (12%) in the control group. Three treatment-related deaths after first disease progression were reported in the experimental group (two intestinal occlusions and one sepsis) and four in the control group (one intestinal occlusion, one intestinal perforation, one cerebrovascular event, and one sepsis). Interpretation Upfront FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen after disease progression seems to be a preferable therapeutic strategy to sequential administration of chemotherapy doublets, in combination with bevacizumab, for patients with metastatic colorectal cancer selected according to the study criteria. Funding The GONO Cooperative Group, the ARCO Foundation, and F Hoffmann–La Roche.

Background Alternating induction and maintenance phases is a common strategy in metastatic colorectal cancer (mCRC). Metronomic chemotherapy (metroCT) may represent a well-tolerated chemotherapy backbone for maximising bevacizumab effect during maintenance. The MOMA trial was designed to compare metroCT plus bevacizumab versus bevacizumab alone as maintenance following 4 months of induction with FOLFOXIRI plus bevacizumab. Patients and methods In this phase II study, patients with unresectable mCRC were randomised to receive up to 8 cycles of FOLFOXIRI plus bevacizumab, followed by bevacizumab (arm A) or the same regimen followed by bevacizumab plus metroCT (capecitabine 500 mg/three times per day and cyclophosphamide 50 mg/die, arm B) until disease progression. The primary end-point was progression-free survival (PFS). According to the Rubinstein and Korn's design, to detect a hazard ratio[HR] of 0.75 favouring arm B, with 1 sided-alpha and beta errors of 15% and 80%, 173 events and 222 patients were required. Results Between May 2012 and March 2015, 232 patients, mostly with RAS (65%) or BRAF (9%) mutant tumours, were randomised in 16 Italian centres. At a median follow-up of 47.8 months, 210 and 164 progression and death events were registered. The primary end-point was not met. Median PFS was 10.3 and 9.4 months in arm B and A, respectively (HR: 0.94 [70% confidence interval {CI}: 0.82–1.09], p = 0.680). No significant differences were reported in terms of overall survival (OS) (median OS arm B/A: 22.5/28 months; HR: 1.16 [95%CI: 0.99–1.37], p = 0.336). Response rate with FOLFOXIRI plus bevacizumab was 63% (arm B/A: 58%/68%). In the liver-limited subgroup, the secondary resection rate was 49% (arm B/A: 45%/55%). Conclusions The addition of metroCT to maintenance with bevacizumab does not significantly improve PFS of mCRC patients. The activity of FOLFOXIRI plus bevacizumab is confirmed in a population with high prevalence of RAS/BRAF mutations treated with a 4-months induction. Trial registration www.clinicaltrials.gov NCT02271464.

Background The activity of palbociclib as a single agent in advanced breast cancer has not been extensively studied, with the only available clinical data limited to heavily pretreated patients. Preclinical data suggests palbociclib may partially reverse endocrine resistance, though this hypothesis has not been evaluated in previous clinical studies. This phase II, open-label, multicenter study examined the activity of palbociclib monotherapy, as well as palbociclib given in combination with the same endocrine therapy (ET) that was received prior to disease progression, in postmenopausal women with moderately pretreated, estrogen receptor-positive, HER2 negative advanced breast cancer. Patients and methods Eligible women with advanced disease which had progressed on one or two prior ETs were randomized 1 : 1 to receive either palbociclib alone, or palbociclib in combination with the ET as previously received. Primary end point was clinical benefit rate (CBR); secondary end points included progression-free survival (PFS). Results Between October 2012 and July 2016, a total of 115 patients were randomized. The CBR was 54% [95% confidence interval (CI): 41.5–63.7] for combination therapy, and 60% (95% CI: 47.8–72.9) for monotherapy. Median PFS was 10.8 months (95% CI: 5.6–12.7) for combination therapy, and 6.5 months (95% CI: 5.4–8.5) for monotherapy [hazard ratio (HR) 0.69; 95% CI: 0.4–1.1, exploratory P-value = 0.12]. Exploratory analyses revealed the PFS advantage for combination therapy was seen in the subgroup of patients who received prior ET for >6 months (HR 0.53; 95% CI: 0.3–0.9, exploratory P-value = 0.02), but not in those who received prior ET for ≤6 months. Conclusion Palbociclib has clinical activity as a single agent in women with moderately pretreated, oestrogen receptor-positive, HER2-negative advanced breast cancer. Palbociclib may have potential to reverse endocrine resistance in patients with a history of previous durable response to ET. Clinical trial information NCT02549430

Background: The triplet FOLFOXIRI (fluorouracil, L-leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes of patients with metastatic colorectal cancer, when compared to FOLFIRI (fluorouracil, Lleucovorin, and irinotecan) plus bevacizumab. However, the actual benefit of the upfront exposure to the three cytotoxics when compared with a preplanned sequential strategy of doublets was not clear, as well as the feasibility and efficacy of therapies after progression. To this purpose, we aimed at comparing a pre-planned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression to a sequence of mFOLFOX6 (fluorouracil, L-leucovorin, and oxaliplatin) and FOLFIRI doublets, in combination with bevacizumab. Methods: TRIBE2 was an open-label, prospective, phase 3 randomised study of patients (aged 18-70 years with Eastern Cooperative Oncology Group [ECOG] performance status of 2 or less and aged 71-75 years with an ECOG performance status of 0), with unresectable, previously untreated metastatic colorectal cancer, who were recruited from 58 Italian Oncology Units. Patients were stratified according to center, ECOG performance status, primary tumour location and previous adjuvant chemotherapy, and randomly assigned (1:1) via a web-based procedure to two different strategies: first-line mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab after disease progression (control group) or FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen after disease progression (experimental group). Combination treatments were administered up to 8 cycles followed by fluorouracil/L-leucovorin plus bevacizumab maintenance until disease progression, unacceptable adverse events, or consent withdrawal. Both patients and investigators were aware of treatment assignment. The primary endpoint was progression-free survival 2, defined as the time from randomization to disease progression on any treatment given after first disease progression or death, analysed by intention to treat. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. The study recruitment was completed, and follow-up of participants is still ongoing. Findings: Between February 26, 2015, and May 15, 2017, 679 patients were randomly assigned and received treatment (340 in the control group and 339 in the experimental group). 81% of enrolled patients had a right-sided and/or RAS or BRAF mutated tumour. At data cut-off (July 30, 2019) the median follow-up was 35·9 months (IQR 30·1-41·4). Median progression-free survival 2 was 19·2 months (95% CI 17·3-21·4) in the experimental group and 16·4 months (95% CI 15·1-17·5) in the control group (hazard ratio [HR] 0·74, 95% CI 0·63-0·88; p

Background: In search of novel biomarkers of response to bevacizumab in metastatic colorectal cancer (mCRC), we analyzed the expression and prognostic role of several proteins related to angiogenesis. Methods: A retrospective, multicenter study on 80 surgical samples from mCRC patients treated in first line with bevacizumab plus chemotherapy was accomplished. The following proteins were analyzed by immunohistochemistry: hERG1 potassium channel, β1-integrin, pAKT, NFkB, HIF-1α, HIF-2α, p53, VEGF-A, GLUT-1, and CA-IX. Data were analyzed in conjunction with the clinicopathological characteristics of the patients, KRAS status, response to bevacizumab, and follow-up. Results: (1) All the proteins were expressed in the samples, with statistically significant associations between HIF-1α and gender, HIF-2α and left colon, hERG1 and VEGF-A, β1-integrin and HIF-2α, GLUT-1 and both HIF-1α and HIF-2α, and CA-IX and VEGF-A. (2) At the univariate analysis, positivity for hERG1, VEGF-A, and the active form of HIF-2α (aHIF-2α), and the G3 histological grade showed a positive impact on progression-free survival (PFS). (3) hERG1 and aHIF-2α maintained their positive impact on PFS at the multivariate analysis. (4) hERG1 behaved as a protective factor for PFS independently on KRAS status. Conclusions: hERG1 and aHIF-2α might help to identify patients who would benefit from bevacizumab treatment.

BACKGROUND First-line sunitinib is recommended in metastatic renal cell carcinoma (mRCC), but it is frequently associated with relevant toxicities and subsequent dose reductions. Alternative schedules, such as 2-week-on treatment and 1-week-off (2/1 schedule), might improve tolerability. We evaluated the safety and outcomes of this schedule in a large multicenter analysis. PATIENTS AND METHODS Retrospective, multicenter analysis of mRCC patients treated with first-line sunitinib on a 2/1 schedule. Data of 249 patients were reviewed: 208 cases who started sunitinib on the 4/2 schedule (full dosage: 188/208, 90.4%) and thereafter switched to the 2/1 schedule for toxicity (group 4/2 → 2/1) and 41 patients who started first-line sunitinib with the 2/1 schedule because of suboptimal clinical conditions (group 2/1). A total of 211 consecutive patients treated with the 4/2 schedule in another institution served as external controls. Safety was the primary end point. Treatment duration (TD), progression-free survival (PFS) and overall survival (OS) were also analyzed. RESULTS In group 4/2 → 2/1, the overall incidence of grade ≥ 3 toxicities was significantly reduced (from 45.7% to 8.2%, P < 0.001) after the switch to 2/1 schedule. This advantage was maintained also in the 106/188 cases (56.4%) who maintained the full dosage. Fatigue, hypertension, hand-foot syndrome and thrombocytopenia were less frequent. The incidence of grade ≥ 3 adverse events in the negatively selected group 2/1 (only 73.2% starting at full dose) was 26.8%, similar to what observed in the external control group (29.4%). Median TD was 28.2 months in the 4/2 → 2/1 group (total time spent with both schedules), 7.8 months in the 2/1 group and 9.7 months in external controls. Median PFS was 30.2, 10.4 and 9.7 months, respectively. Median OS was not reached, 23.2 and 27.8 months, respectively. CONCLUSIONS mRCC patients who moved to a modified 2/1 schedule of sunitinib experience an improved safety profile compared with that observed during the initial 4/2 schedule.

Background Neoangiogenesis is particularly abundant in small-cell lung cancer (SCLC) and is associated with poor prognosis. As a result of the promising nature of phase II studies, a randomized phase III trial was designed to assess the efficacy of adding bevacizumab to first-line chemotherapy with cisplatin-etoposide for treatment of extensive disease SCLC. We present the treatment rationale and study design of GOIRC trial (FARM6PMFJM study), a multicenter randomized phase III study, supported by AIFA (Agenzia Italiana del Farmaco). Patients and Methods Patients are randomized to receive either cisplatin 25 mg/m2 and etoposide 100 mg/m2 intravenously on days 1 to 3 (control arm) or the same chemotherapy combined with bevacizumab 7.5 mg/kg intravenously on day 1 (experimental arm). Treatment is repeated every 3 weeks and for a maximum of 6 courses. Patients randomized to the experimental arm in the absence of disease progression after 6 cycles continue bevacizumab alone until progression or for a maximum of 18 courses. Tumor assessment is done every 3 cycles. Major eligibility criteria are: age ≥ 18 years; histologically or cytologically documented extensive disease SCLC; Eastern Cooperative Oncology Group performance status ≤ 2; adequate hematological, hepatic and renal functions; no history of grade 2 or higher hemoptysis; and no evidence of tumor cavitation. The primary end point of this study is overall survival. Secondary end points include response rate, time to progression, and toxicity. Conclusion An interim futility analysis was performed by an Independent Data Monitoring Committee in September 2013 and the trial obtained approval to continue. As of July 31, 2014, 171 patients of 206 planned have been randomized.

Objectives Customized chemotherapy has several advantages: patients are more likely to be treated with the most effective agents and can be spared the toxicity of ineffective drugs. Based on the literature, excision repair cross complementation group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) genes represent predictive biomarkers of response to platinum compound and gemcitabine, in NSCLC. Materials and methods We had planned a phase II trial (Simon design) to evaluate combination chemotherapy according to single nucleotide polymorphisms (SNPs) of ERCC1 (118T/C and 8092C/A) and RRM1 (−37C/A and −524T/C) in naive patients affected by advanced NSCLC. ERCC1 and RRM1 SNPs assessment was performed in peripheral blood lymphocytes (PBLs). Combination chemotherapy was selected based on ERCC1 and RRM1 SNPs: we assume that patients with one or two C alleles at position 118 and with one or two A alleles at position 8092 in ERCC1 gene would correspond to Cisplatin non-responder and than with two A alleles at −37 and two C alleles at −524 in RRM1 gene to gemcitabine non-responder. Four schedules were provided: cisplatin + gemcitabine, cisplatin + docetaxel, gemcitabine + docetaxel; docetaxel + vinorelbine. Primary endpoint was overall response (ORR) in the intention-to-treat population. Results 42 patients were enrolled from January 2010 to November 2011; 40 patients received at least 1 cycle of chemotherapy; median age was 66 years (range: 47–72); 36(90%) had stage IV, 4(10%) IIIB; 23(58%) had adenocarcinoma, 14(35%) squamous carcinoma. Twenty-five (62%) patients received treatment A, 3(8%) treatment B, 11(28%) treatment C, 1(23%) treatment D. ORR was 55%, analysis in squamous patients subgroups showed 71.4% ORR. The median follow-up was 19.7 months, PFS was 23 weeks (95% CI = 15–26) and OS was 40.4 weeks (95% CI = 32–55). Treatment was well tolerated. Conclusion We observed an increase of ORR in NSCLC patients when they were treated with chemotherapy according to ERCC1 and RRM1 SNPs status.

BACKGROUND: There is a need to identify new markers to assess recurrence risk in early-stage colorectal cancer (CRC) patients. We explored the prognostic impact of ether-a-gò-gò-related gene 1 channels and some hypoxia markers, in patients with nonmetastatic (stage I, II, and III) CRC. METHODS: The expression of hERG1, vascular endothelial growth factor A (VEGF-A), glucose transporter 1, carbonic anhydrase IX (CA-IX), epidermal growth factor receptor (EGF-R), and p53 was tested by immunohistochemistry in 135 patients. The median follow-up was 35 months. Clinicopathologic parameters and overall survival were evaluated. RESULTS: hERG1 displayed a statistically significant association with Glut-1, VEGF-A, CA-IX, and EGF-R; p53 with VEGF-A and CA-IX; Glut-1 with the age of the patients; and EGF-R with TNM and mucin content. TNM and CA-IX were prognostic factors at the univariate analysis; TNM, hERG1, and Glut-1, at the multivariate analysis. Risk scores calculated from the final multivariate model allowed to stratify patients into four different risk groups: A) stage I-II, Glut-1 positivity, any hERG1; B) stage I-II, Glut-1 and hERG1 negativity; C) stage I-II, Glut-1 negativity, hERG1 positivity; D) stage III, any Glut-1 and any hERG1. CONCLUSIONS: hERG1 positivity with Glut-1 negativity identifies a patient group with poor prognosis within stage I-II CRC. The possibility that these patients might benefit from adjuvant therapy, independently from the TNM stage, is discussed. IMPACT: More robust prognostic and predictive markers, supplementing standard clinical and pathologic staging, are needed for node-negative patients.

A number of different clinical characteristics and molecular markers related to epidermal growth factor receptor (EGFR) activation have been reported to singly correlate with therapeutic activity of EGFR tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC). This study was designed to evaluate the predictive value on gefitinib outcomes of a comprehensive panel of molecular parameters in advanced NSCLC patients EGFR and K-ras mutations were detected by direct sequencing on tumor DNA from paraffin embedded samples EGFR and HER2 gene copy number was assessed by FISH EGFR protein expression was quantified by immunohistochemistry. EGFR gene intron 1 polymorphism was assessed on genomic DNA isolated from venous whole blood samples Ninety-one patients were prospectively enrolled and the overall gefitinib response rate was 18 7% (2 complete and 15 partial responses) Sex (p = 0005), non-smoking status (p = 0010). skin toxicity (p = 0020). EGFR gene mutations (p

Background: Standard methods to prevent chemotherapy-induced early menopause in young, breast cancer patients are unavailable to date. Preclinical data has suggested that luteinising hormone-releasing hormone (LH-RH) analogs given during treatment can decrease the gonado-toxicity induced by chemotherapy. This phase II study aimed to assess the activity of such a method in young, breast cancer patients undergoing adjuvant chemotherapy. Patients and methods: Premenopausal patients received the LH-RH analog goserelin 3.6 mg every 4 weeks before and during chemotherapy. According to two-stage optimal phase II Simon design, treatment was considered clinically interesting if it was able to prevent menopause in 19 out of 29 patients of the study population. The resumption of ovarian function was defined by a resumption of menstrual activity or by a follicle-stimulating hormone (FSH) value ≤40 IU/I within 12 months after the last cycle of chemotherapy. Results: Thirty patients were enrolled and 29 were evaluable. Median age was 38 years (range 29-47). All but one patient received CEF regimen (cyclophosphamide, epirubicin, 5-fluorouracil). Resumption of menstrual activity was observed in 21 patients (72%; 95% Cl 52% to 87%) and a FSH value

Embryonal carcinoma (EC) cells, stem cells of teratocarcinoma, represent an excellent model to study the developmental mechanisms that, inappropriately reactivated, can drive tumorigenesis. EC cells are very aggressive, and grow rapidly when injected into adult syngeneic mice. However, when injected into blastocysts, they revert to normality, giving rise to chimeric animals. In order to study the ability of postimplantation embryonic environment to "normalize" tumorigenic cells, and to study their homing, we transplanted F9, Nulli-SCC1, and P19 EC cells into 8 to 15-day allogenic CD1 mouse embryos, into allogenic CD1 newborns, and into syngeneic adult mice, and evaluated tumor formation, spreading, and homing. We found that, although at all embryonic stages successful transplantation occurred, the chances of developing tumors after birth increased with the time of injection of EC cells into the embryo. In addition, using enhanced green fluorescent protein-expressing F9 cells, we demonstrated that the cells not giving rise to tumors remained latent and could be tracked down in tissues during adulthood. Our data indicate that the embryonic environment retains a certain ability to "normalize" tumor cells also during post-implantation development. This could occur through yet unknown epigenetic signals triggering EC cells' differentiation.

Recent evidence suggests that the cut-off for age utilized in neuroblastoma risk groups should be increased from the 365-day cut-off currently in use. Separate cooperative group analyses were performed by German and Italian groups and two analyses by the Children's Oncology Group (North America, Australia, New Zealand, Switzerland, Netherlands). In general, the results are in agreement regarding the prognostic contribution of age. There is strong evidence to support an increase in the age cut-off to a value in the range of 15-18 months based on the results from the German analysis and two COG analyses. However, Italian results in INSS stage 4 patients show that outcome in patients 12-17 months is not better than that of older patients. Further analyses are warrented.

The objective of this investigation was to determine factors predictive of bacteraemia at presentation in febrile, granulocytopenic cancer patients in order to estimate the probability of bacteraemia in each patient, and to compare factors associated with a diagnosis of gram-positive or gram-negative bacteraemia. Retrospective analysis of two sets of data (derivation and validation sets) randomly obtained from a large prospective study was conducted in a multicentre study of febrile, granulocytopenic cancer patients admitted for empiric antibacterial therapy. Within the derivation set, prognostic factors (clinical and laboratory data) likely to be associated with a generic diagnosis of bacteraemia and with a specific diagnosis of gram-positive or gram-negative bacteraemia were analysed by means of three backward, stepwise, logistic regression analyses. The predictive probability of bacteraemia was calculated using the logistic equation. The discriminating ability of the model in predicting bacteraemia was evaluated in the derivation and validation sets using receiver-operating characteristic curves. The predictive probability of gram-positive or gram-negative bacteraemia was not calculated. In the derivation set, 157 of 558 episodes (28%) were microbiologically documented bacteraemias. Predicting factors were antifungal prophylaxis, duration of granulocytopenia before fever, platelet count, highest fever, shock and presence and location of initial signs of infection. The variables institution, antibacterial prophylaxis and underlying disease showed borderline associations with bacteraemia. Shock was associated with gram-negative bacteraemia, while signs of infection at catheter site were predictive of gram-positive bacteraemia. Quinolone prophylaxis was negatively associated with gram-negative bacteraemia. When tested in the validation set, the model was poorly predictive, although a small subgroup of episodes (representing only 16% of the total sample size) with low risk of bacteraemia was identified. Factors predictive of bacteraemia can be identified, with discrimination between gram-positive and gram-negative aetiology. Further studies are warranted in order to improve the discriminant ability of the model.

A special computer network has been specifically designed and realized to connect 36 Italian cardiological institutions to a central core laboratory. This network, which has been created to run the CEDIM Multicenter Trial (effects of L-carnitine on left ventricular function in patients with myocardial infarction assessed by digital echocardiography), enables automatic verification, via computer, 24 hours a day, of patient eligibility criteria, randomization, transmission, and filing of real-time left ventricular echocardiographic examinations. All the investigators participating in the CEDIM trial underwent several training courses as well as dummy run procedures to achieve optimal performance of all the operational procedures required for the network to function smoothly and correctly. This paper describes the aims of this special network, its technical characteristics, and the investigator training and dummy run procedures.

The Doppler echocardiographic pattern of restrictive left ventricular (LV) filling has proved to be an important predictor of clinical course and prognosis in dilated cardiomyopathy. However, the relation between restrictive filling pattern and clinical course has not been systematically investigated in hypertrophic cardiomyopathy (HC). We assessed the prognostic implications of the Doppler restrictive filling pattern in 239 consecutive patients with HC in whom Doppler measurements of LV filling had been systematically recorded at initial evaluation and during follow-up. Restrictive LV filling was identified in 14 patients (5.9%) at initial evaluation and developed in 22 (9.2%) during follow-up. A close relation was identified between restrictive filling pattern and end-stage HC, with patients with restrictive filling showing a sixfold increase in risk of developing end-stage HC (hazard ratio 6.25, 95% confidence interval 1.90 to 20.57, p = 0.003). Over a median follow-up of 9.7 years, 22 patients (9.2%) died suddenly or received appropriate cardioverter-defibrillator interventions, and 54 (22.6%) had HC-related death or underwent heart transplantation. In a set of univariate and multivariate analyses including each of the generally accepted risk factors for cardiac death in HC, the restrictive filling pattern was a strong and independent marker of increased risk (hazard ratio for sudden cardiac events 3.51, 95% confidence interval 1.37 to 8.95, p = 0.009; hazard ratio for HC-related death or heart transplantation 3.54, 95% confidence interval 1.91 to 6.57, p