HER2 loss in HER2-positive gastric or gastroesophageal cancer after trastuzumab therapy: Implication for further clinical research.

Mechanisms of acquired resistance to trastuzumab-based treatment in gastric cancer are largely unknown. In this study, we analyzed 22 pairs of tumor samples taken at baseline and post-progression in patients receiving chemotherapy and trastuzumab for advanced HER2-positive [immunohistochemistry (IHC) 3+ or 2+ with in-situ hybridization (ISH) amplification] gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over-expression were defined as post-trastuzumab IHC score <3+ and absence of ISH amplification, and IHC "downscoring" from 2+/3+ to 0/1+, respectively. HER2 IHC was always performed, while ISH was missing in 3 post-progression samples. Patients with initial HER2 IHC score 3+ and 2+ were 14 (64%) and 8 (36%), respectively. Loss of HER2 positivity and HER2 over-expression was observed in 32 and 32% samples, respectively. The chance of HER2 loss was not associated with any of the baseline clinicopathological variables. The only exception was in patients with initial IHC score 2+ versus 3+, for both endpoints of HER2 positivity (80 vs. 14%; p = 0.008) and HER2 over-expression (63 vs. 14%; p = 0.025). As already shown in breast cancer, loss of HER2 may be observed also in gastric cancers patients treated with trastuzumab-based chemotherapy in the clinical practice. This phenomenon may be one of the biological reasons explaining the failure of anti-HER2 second-line strategies in initially HER2-positive disease.

Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial.

BACKGROUND: The combination of bevacizumab with fluorouracil-based chemotherapy is a standard first-line treatment option in metastatic colorectal cancer (mCRC). We studied the efficacy of continuing or reintroducing bevacizumab in combination with second-line chemotherapy after progression to bevacizumab-based first-line therapy. PATIENTS AND METHODS: In this phase III study, patients with mCRC treated with fluoropyrimidine-based first-line chemotherapy plus bevacizumab were randomized to receive in second-line mFOLFOX-6 or FOLFIRI (depending on first-line regimen) with or without bevacizumab. The primary end point was progression-free survival. To detect a hazard ratio (HR) for progression of 0.70 with an α and ß error of 0.05 and 0.20, respectively, 262 patients were required. RESULTS: In consideration of the results of the ML18147 trial, the study was prematurely stopped. Between April 2008 and May 2012, a total of 185 patients were randomized. Bevacizumab-free interval was longer than 3 months in 43% of patients in chemotherapy alone arm and in 50% of patients in the bevacizumab arm. At a median follow-up of 45.3 months, the median progression-free survival was 5.0 months in the chemotherapy group and 6.8 months in the bevacizumab group [adjusted HR = 0.70; 95% confidence interval (CI) 0.52-0.95; stratified log-rank P = 0.010]. Subgroup analyses showed a consistent benefit in all subgroups analyzed and in particular in patients who had continued or reintroduced bevacizumab. An improved overall survival was also observed in the bevacizumab arm (adjusted HR = 0.77; 95% CI 0.56-1.06; stratified log-rank P = 0.043). Responses (RECIST 1.0) were similar in the chemotherapy and bevacizumab groups (17% and 21%; P = 0.573). Toxicity profile was consistent with previously reported data. CONCLUSIONS: This study demonstrates that the continuation or the reintroduction of bevacizumab with second-line chemotherapy beyond first progression improves the outcome and supports the use of this strategy in the treatment of mCRC. ClinicalTrials.gov number: NCT00720512.

Multivariate prognostic factors analysis for second-line chemotherapy in advanced biliary tract cancer.

BACKGROUND: The role of second-line chemotherapy (CT) is not established in advanced biliary tract cancer (aBTC). We investigated the outcome of aBTC patients treated with second-line CT and devised a prognostic model. METHODS: Baseline clinical and laboratory data of 300 consecutive aBTC patients were collected and association with overall survival (OS) was investigated by multivariable Cox models. RESULTS: The following parameters resulted independently associated with longer OS: Eastern Cooperative Oncology Group performance status of 0 (P<0.001; hazard ratio (HR), 0.348; 95% confidence interval (CI) 0.215-0.562), CA19.9 lower than median (P=0.013; HR, 0.574; 95% CI 0.370-0.891), progression-free survival after first-line CT ≥ 6 months (P=0.027; HR, 0.633; 95% CI 0.422-0.949) and previous surgery on primary tumour (P=0.027; HR, 0.609; 95% CI 0.392-0.945). We grouped the 249 patients with complete data available into three categories according to the number of fulfilled risk factors: median OS times for good-risk (zero to one factors), intermediate-risk (two factors) and poor-risk (three to four factors) groups were 13.1, 6.6 and 3.7 months, respectively (P<0.001). CONCLUSIONS: Easily available clinical and laboratory factors predict prognosis of aBTC patients undergoing second-line CT. This model allows individual patient-risk stratification and may help in treatment decision and trial design.

FOLFOXIRI in combination with panitumumab as first-line treatment in quadruple wild-type (KRAS, NRAS, HRAS, BRAF) metastatic colorectal cancer patients: a phase II trial by the Gruppo Oncologico Nord Ovest (GONO).

BACKGROUND: The FOLFOXIRI regimen developed by the Gruppo Oncologico Nord Ovest (GONO) demonstrated higher activity and efficacy compared with FOLFIRI in metastatic colorectal cancer (mCRC). Panitumumab is effective in some patients with KRAS codon 12-13 wild-type mCRC. KRAS codon 61, HRAS, NRAS, and BRAF V600E mutations might predict resistance to anti-epidermal growth factor receptor antibodies. PATIENTS AND METHODS: We conducted a phase II study evaluating the combination of panitumumab (6 mg/kg on day 1) with a slightly modified GONO-FOLFOXIRI (irinotecan 150 mg/m², oxaliplatin 85 mg/m², and folinate 200 mg/m² on day 1, followed by fluorouracil 3000 mg/m² as a 48-h continuous infusion starting on day 1) repeated every 2 weeks as first-line treatment of wild-type KRAS, HRAS, NRAS (codon 12-13-61), and BRAF unresectable mCRC patients. Fluorouracil dose was reduced to 2400 mg/m² after two of the first three patients reported grade 3-4 diarrhoea (in one case with febrile neutropenia). Induction treatment was scheduled for a maximum of 12 cycles, followed by panitumumab ± fluorouracil/folinate maintenance until progression. Primary end point was overall response rate (ORR). RESULTS: Eighty-seven patients were screened and 37 were enrolled. Thirty-three patients achieved an objective response (ORR: 89%; 95% CI 75% to 96%). Sixteen patients (43%) underwent secondary surgery of metastases, and R0 resection was achieved in 13 cases (35%). At a median follow-up of 17.7 months, median progression-free survival was 11.3 months (95% CI 9.7-12.9 months). After amendment, most common grade 3-4 adverse events reported during induction treatment were neutropenia (48%; febrile neutropenia: 5%), diarrhoea (35%), asthenia (27%), stomatitis (14%), and skin toxic effect (14%). One treatment-related death was registered. CONCLUSIONS: Adding panitumumab to FOLFOXIRI is feasible decreasing the dose of fluorouracil and irinotecan to reduce the risk of diarrhoea. Activity and secondary resectability of metastases among Ras-BRAF wild-type patients are promising.

An EZH2 polymorphism is associated with clinical outcome in metastatic colorectal cancer patients.

BACKGROUND: Despite therapeutic innovations, metastatic colorectal cancer (mCRC) is still characterized by poor prognosis and few molecular markers predict the risk of progression. Polycomb group genes (PcGs) are epigenetic modifiers involved in tumor suppressor gene silencing. PcG member EZH2 mediates gene silencing through histone-H3 lysine-27 methylation. In colorectal cancer (CRC), EZH2 overexpression predicts shorter survival. Recently, four EZH2 single-nucleotide polymorphisms (SNPs) have been described. The present study was aimed at evaluating the correlation between EZH2 SNPs and outcome parameters in mCRC patients. PATIENTS AND METHODS: DNA was extracted from blood samples of 110 mCRC patients treated with first-line 5-fluorouracil, folinic acid, irinotecan (FOLFIRI) and bevacizumab. Genotyping was carried out by real-time PCR. Genotype was used to predict objective response, progression-free survival (PFS) and overall survival (OS). EZH2 messenger RNA levels were evaluated on lymphocytes of a parallel cohort of 50 CRC patients. RESULTS: One allelic variant (rs3757441 C/C versus C/T or T/T) was significantly associated with shorter PFS and OS (P < 0.01 and P < 0.05, respectively). At multivariate analysis, the same variant resulted an independent predictor of PFS and OS (P < 0.05). The C/C variant was associated with significantly higher EZH2 expression (P < 0.05). CONCLUSION: An EZH2 SNP may be useful to predict clinical outcome in mCRC patients.

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.

Trifluridine/tipiracil versus placebo for third or later lines of treatment in metastatic gastric cancer: an exploratory subgroup analysis from the TAGS study.

BACKGROUND: Metastatic gastric cancer and cancer of the esophagogastric junction (GC/EGJ) is an aggressive disease with poor prognosis. In the TAGS study, trifluridine/tipiracil (FTD/TPI) improved overall survival (OS) compared with placebo in heavily pre-treated patients. This unplanned, exploratory subgroup analysis of the TAGS study aimed to clarify outcomes when FTD/TPI was used as third-line (3L) treatment and fourth- or later-line (4L+) treatment. PATIENTS AND METHODS: Patients were divided into a 3L group (126 and 64 in FTD/TPI and placebo arms, respectively) and 4L+ group (211 and 106 in FTD/TPI and placebo arms, respectively). Endpoints included OS, progression-free survival (PFS), time to Eastern Cooperative Oncology Group performance status (ECOG PS) deterioration to ≥2, and safety. RESULTS: Baseline characteristics were generally well balanced between FTD/TPI and placebo for 3L and 4L+ treatment. Median OS (mOS) for FTD/TPI versus placebo was: 6.8 versus 3.2 months {hazard ratio (HR) [95% confidence interval (CI)] = 0.68 (0.47-0.97), P = 0.0318} in the 3L group; and 5.2 versus 3.7 months [0.73 (0.55-0.95), P = 0.0192] in the 4L+ group. Median PFS for FTD/TPI versus placebo was 3.1 versus 1.9 months [0.54 (0.38-0.77), P = 0.0004] in the 3L group; and 1.9 versus 1.8 months [0.57 (0.44-0.74), P < 0.0001] in the 4L+ group. Time to deterioration of ECOG PS to ≥2 for FTD/TPI versus placebo was 4.8 versus 2.0 months [HR (95% CI) = 0.60 (0.42-0.86), P = 0.0049] in the 3L group; and 4.0 versus 2.5 months [0.75 (0.57-0.98), P = 0.0329] in the 4L+ group. The safety of FTD/TPI was consistent in all subgroups. CONCLUSIONS: This analysis confirms the efficacy and safety of FTD/TPI in patients with GC/EGJ in third and later lines with a survival benefit that seems slightly superior in 3L treatment. When FTD/TPI is taken in 3L as recommended in the international guidelines, physicians can expect to provide patients with an mOS of 6.8 months.

The effect of agricultural intensification and water-locking on the world's largest coastal lagoonal system.

The palaeolimnological conditions of Mirim Lagoon, a large coastal shallow lagoon under the influence of historical human impacts related to the development of the primary sector of the economy were reconstructed. The first significant human impact consisted of locking the estuarine system to induce the transition from brackish to freshwater conditions. During this transition, the sedimentation rate consistently increased from pre-disturbance values of 0.25 cm yr-1 to >1 cm yr-1. A concomitant increase in nitrogen and carbon values was recorded indicating a related eutrophication process. The highest nutrient levels were achieved during the 1990s after the incorporation of cutting-edge technologies for agricultural production such as high-yielding varieties of rice resistant to climate variability and pests, and the use of inorganic fertilisers, pesticides and water supply controlled by irrigation. After 2011, the soybean production boosted and the area cultivated with this oilseed equalled the area of rice paddies, i.e., 2 × 105 ha. A sharp decrease in δ13C from -19 to -24‰ and in δ15N from 6 to 2‰ were observed in the sedimentary record, indicating a major shift in the composition of the organic matter after the agricultural intensification. Trace elements Cr, Cu, Ni and Zn showed a high positive correlation with Al and Fe, and enrichment factors near 1, indicating a natural and terrigenous source of these elements and also unpolluted conditions. However, the increase of As after 1990 and the positive correlation with Pb was associated with agricultural practices. All elemental ratios (K/Al, Ti/Al and V/Cr) showed constant pre-disturbance trends and a turning point ca. the 1990s. Microplastics were detected from the beginning of the 1990s and increased towards recent sediments, thus corroborating an anthropogenically impacted scenario. Therefore, the development of the primary sector of the economy exerted clear impacts on the environmental quality of the system.

210Po levels and distribution in different environmental compartments from a coastal lagoon. The case of Briozzo lagoon, Uruguay.

This paper presents the levels and distribution of 210Po in different compartments of a coastal lagoon on the east coast of Uruguay (South America). Activity concentrations of 210Po have been obtained in different matrices, such as water, superficial sediments, clams (Diplodon sp.), freshwaters snails (Pomacea sp.), zooplankton, and fishes (Jenynsia sp.), collected at different points of the lagoon and during several sampling campaigns. In addition, the organic matter content of the sediment was determined to study the variation of 210Po along the lagoon. The activity concentrations of 210Po in the water samples are in the range between 1.1 ± 0.2-3.5 ± 0.4 mBq/L while in the sediment samples vary between 17.1 ± 1.4 and 540 ± 12 Bq/kg, DW. In the case of biota, the ranges obtained were 182 ± 5-265 ± 6 Bq/kg, DW in clams and 134 ± 4-1245 ± 16 Bq/kg, DW in snail samples. A good correlation of 210Po with the organic fractions of the sediment was observed (r = 0.8798, p-value < 0.001), being obtained high values for the distribution coefficient Kd (104 -105). In the biota samples, a clear difference was observed in the 210Po concentration values in both species, mainly due to the different feeding habits of both aquatic organisms, as it is reflected in the associated concentration ratios (CR). In this paper, a good set of results of 210Po, Kd, and CR have been obtained in different matrices, enhancing the limited archives available for modelers concerning these parameters for 210Po and freshwater systems.

A multicenter phase II study of the combination of oxaliplatin, irinotecan and capecitabine in the first-line treatment of metastatic colorectal cancer.

The triple drug combination consisting of irinotecan, oxaliplatin and 5-fluorouracil (FOLFOXIRI) has demonstrated higher activity and efficacy compared to the doublet FOLFIRI. 5-Fluorouracil could be substituted in FOLFOXIRI regimen by capecitabine, an oral fluoropyrimidine with similar efficacy. Recently, a dose-finding trial has demonstrated the feasibility of the combination of irinotecan, oxaliplatin and capecitabine (XELOXIRI) and established their recommended doses. The aim of this study was to evaluate the activity of XELOXIRI. A total of 36 patients with unresectable metastatic colorectal cancer received irinotecan 165 mg m(-2) and oxaliplatin 85 mg m(-2) on day 1 plus capecitabine 2000 mg m(-2) per day orally in two doses from day 1 to day 7, every 2 weeks. Grade 3-4 toxicities were infrequent, expect for neutropenia and diarrhoea, which were each observed in 30% of patients. Two complete and twenty-two partial responses were obtained, corresponding to an overall response rate of 67% (95% CI 51.4-82%). After a median follow-up of 17.7 months, the median progression-free and overall survival were 10.1 and 17.9 months, respectively. The substitution of 5-fluorouracil with capecitabine, in combination with irinotecan and oxaliplatin, is feasible and does not impair the activity of the regimen. However, the XELOXIRI combination is associated with a high incidence of diarrhoea and, therefore, should be considered as a not preferable alternative to FOLFOXIRI.

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.

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.

Treatment of squamous cell carcinoma of the anal canal: A new strategies with anti-EGFR therapy and immunotherapy.

The incidence of squamous cell carcinoma of the anal canal (SCAC) is increasing in both sexes but the standard treatment remains that of 20 years ago. However, interesting data have recently emerged on the use of anti-epidermal growth factor receptor (EGFR) agents and immunotherapy in advanced disease. Thus, new avenues of research are opening up that will hopefully lead to more effective therapeutic strategies. We provide an overview of the latest studies published on this tumor and discuss the possible future therapeutic options for combination therapy, anti-EGFR treatment and radiotherapy.

Bone metastases in biliary cancers: A multicenter retrospective survey.

•Natural history of biliary cancers metastatic to bone•The role of skeletal events in patients with biliary cancer•Biliary cancer and bone metastases: role of bisphosphonates.

Determinants of on-the-job-barriers in employed persons with multiple sclerosis: the role of disability severity and cognitive indices.

BACKGROUND: Literature has shown that work maintenance is central in order to guarantee participation to persons with disability. Knowledge about potential sources of difficulties and obstacles is then crucial in order to prevent barriers and facilitate work maintenance and career development for persons with disabilities. OBJECTIVE: Studies analyzing on-the-job barriers among employed people with multiple sclerosis (MS) have found evidence for a role of clinical determinants. The aim of this study was to describe in more detail the role of disability severity and of cognitive indices on work barriers. PARTICIPANTS: Thirty-two employed adults with a diagnosis of MS with mild to moderate disability severity were included in the study. They were involved in the descriptive study while attending their planned care in the MS unit. METHODS: Subjects completed neurocognitive tasks, a self-report measure of executive functioning and a face-to-face semi-structured interview exploring their perception of barriers at work. RESULTS: Regression analyses showed a specific role of disability severity on perception of barriers due to physical, cognitive and interpersonal relationships; cognitive indices, on the other hand, predicted barriers ascribed to company policy (cognitive score), to accessibility (planning score) or difficulties in cognitive and task related abilities (self-rated executive functioning). CONCLUSION: These findings underline the relevance of objective tasks and self-report questionnaire, direct and indirect multi-dimensional assessment of functioning for an early intervention planning. An ecological model of career development in adults with disabilities is also supported.