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Colorectal cancer (CRC) is one of the most common cancers; ∼20% of patients have metastases at diagnosis, and 50%-60% subsequently develop metachronous metastases. Bone involvement, despite being rare, is usually associated with higher disease burden, worse prognosis, impaired quality of life, and significant health-related cost. In the last few years, following the positive results of the TRIBE and TRIBE2 trials, the association of FOLFOXIRI plus bevacizumab has become the new standard of care for metastatic CRC. Despite being highly efficacious in all subgroups, little is known about the activity of this regimen in patients with bone metastases.We carried out a pooled analysis of TRIBE and TRIBE2 studies focusing on patients with skeletal deposits.Our analyses on the whole population showed that patients with baseline bone involvement reported shorter overall survival [OS; 14.0 versus 26.2 months; hazard ratio (HR) 2.04, 95% confidence interval (CI) 1.46-2.87; P0.001] and progression-free survival (PFS; 6.2 versus 11.1 months; HR 1.96, 95% CI 1.42-2.69; P0.001) compared with those without bone metastases; no significant interaction with the treatment was reported for PFS (P = 0.094) and OS (P = 0.38). Bone metastases had a negative prognostic implication in the multivariate analysis (HR 2.24, 95% CI 1.54-3.26; P 0.001). Furthermore, patients with bone lesions at first radiological progression (including those with baseline bone metastases) had a shorter OS compared with those who progressed in other sites (10.4 versus 13.2 months; HR 1.48, 95% CI 1.15-1.91; P = 0.002). A trend toward inferior OS (7.5 versus 11 months, HR 1.50, 95% CI 0.92-2.45; P = 0.10) appeared in patients with basal skeletal deposits compared with those with bone involvement at first radiological progression.Our study confirmed the negative prognostic impact of bone metastases in CRC. Furthermore, we demonstrated for the first time that the survival advantage of triplet chemotherapy plus bevacizumab is maintained even in this prognostically unfavorable subgroup.

Objectives Pheochromocytomas are rare tumors which can present with heterogeneous secretion profiles, clinical manifestations, and radiologic appearance. Under a histopathological point of view, they can be characterized as more or less aggressive with the Pheochromocytoma of the Adrenal gland Scaled Score (PASS) and the Grading system for Adrenal Pheochromocytoma and Paraganglioma (GAPP) score. The aim of this study is to analyze the texture analysis characteristics of pheochromocytoma and identify whether the texture analysis can yield information aiding in the diagnosis and the characterization of those tumors. Methods Radiological, biochemical, and histopathological data regarding 30 consecutive patients with histologically confirmed pheochromocytoma were analyzed. Images obtained in the unenhanced, late arterial, venous, and delayed phases were used for the texture analysis. Results Urinary epinephrine and metanephrine levels showed a significant correlation (R2 = 0.946; R2 = 699) in the multivariate linear model with texture features, as well as Ki-67 (R2 = 0.397), PASS score (R2 = 0.182), GAPP score (R2 = 0.705), and cellularity showed a significant correlation (R2 = 0.389). The cluster analysis based on radiomic features resulted in 2 clusters, with significative differences in terms of systolic and diastolic blood pressure values at the time of diagnosis (p = 0.025), GAPP score (4 vs 6, p = 0.05), histological pattern (1–2, p = 0.039), and comedonecrosis (0% vs 50%, p = 0.013). Conclusion In conclusion, our study provides the proof of concept for the use of texture analysis on contrast-enhanced CT images as a noninvasive, quantitative tool for helping in the characterization of the clinical, biochemical, and histopathological features of pheochromocytoma.

The incidence of cholangiocarcinoma (CCA) has steadily increased during the past 20 years, and mortality is increasing. The majority of patients with CCA have advanced or metastatic disease at diagnosis, and treatment options for unresectable disease are limited, resulting in poor prognosis. However, recent identification of targetable genomic alterations has expanded treatment options for eligible patients. Given the importance of early and accurate diagnosis in optimizing patient outcomes, this review discusses best practices in CCA diagnosis, with a focus on categorizing molecular genetics and available targeted therapies. Imaging and staging of CCAs are discussed, as well as recommended biopsy collection techniques, and molecular and genomic profiling methodologies, which have become increasingly important as molecular biomarker data accumulate. Approved agents targeting actionable genomic alterations specifically in patients with CCA include ivosidenib for tumors harboring IDH1 mutations, and infigratinib and pemigatinib for those with FGFR2 fusions. Other agents currently under development in this indication have shown promising results, which are presented here.

Metronomic chemotherapy (mCHT) refers to the minimum biologically effective dose of a chemotherapy agent given as a continuous dosing regimen, with no prolonged drug-free breaks, that leads to antitumor activity. Aim of the present study is to describe the use of mCHT in a retrospective cohort of metastatic breast cancer (MBC) patients in order to collect data regarding the different types and regimens of drugs employed, their efficacy and safety. Between January 2011 and December 2016, data of 584 metastatic breast cancer patients treated with mCHT were collected. The use of VRL-based regimens increased during the time of observation (2011: 16.8% - 2016: 29.8%), as well as CTX-based ones (2011: 17.1% - 2016: 25.6%), whereas CAPE-based and MTX-based regimens remained stable. In the 1st-line setting, the highest ORR and DCR were observed for VRL-based regimens (single agent: 44% and 88%; combination: 36.7% and 82.4%, respectively). Assuming VRL-single agent as the referee treatment (median PFS: 7.2 months, 95% CI: 5.3–10.3), the longest median PFS were observed in VRL-combination regimens (9.5, 95%CI 88.8–11.3, HR = 0.72) and in CAPE-single agent (10.7, 95%CI 8.3–15.8, HR = 0.70). The VICTOR-6 study provides new data coming from the real-life setting, by adding new information regarding the use of mCHT as an option of treatment for MBC patients.

Documenting successful remediation of polychlorinated biphenyl (PCB)-contaminated sediments is limited; potentially due to inadequate monitoring methods, complexities associated with the environment, and selected remedial techniques. At some sites, absence of appropriate baseline and postremoval monitoring limits proper evaluation of remedial efficacy. Accurate interpretation of interactions between media, space, time, species, lipid content, and remedial technique requires robust study design and data. This article presents baseline and postremoval data documenting reduced PCB concentrations in fish tissue, surface water, and sediment in response to the US Environmental Protection Agency (USEPA) time-critical removal action (TCRA) that was conducted at the former Bryant Mill Pond (BMP) on Portage Creek in Kalamazoo, Michigan. The BMP is part of an operable unit (OU) within the Allied Paper, Inc./Portage Creek/Kalamazoo River Superfund Site. PCBs discharged to the creek as a byproduct of carbonless copy paper recycling are the primary contaminant of concern. Paper waste residuals commonly appear as gray to light gray clays in river sediments and floodplain soils. The cleanup criterion was 10 mg/kg, with a residual PCB concentration goal of 1 mg/kg. Because the PCB-containing waste is (generally) associated with readily visible light gray clay, excavation of all visibly contaminated current or formerly impounded sediment served as a surrogate for the cleanup criteria and goal. Sediment was wet excavated and backfilled after diversion of the creek. After confirmation that PCB concentrations met cleanup criteria, the stream was diverted to the excavated side, and excavation and backfilling were completed. Overall, 146 000 cubic yards of material including PCB-contaminated sediments were removed from the BMP. The long-term monitoring (LTM) program implemented by the Michigan Department of Environmental Quality (MDEQ), and historic data from a variety of sources (federal, state, and local agencies and responsible parties) provided data demonstrating TCRA effectiveness. Before TCRA, surface sediment PCB concentration in instream and formerly inundated sediment combined was 83 mg/kg (with a maximum of 700 mg/kg). Instream sediments that are more representative of fish exposures had a pre-TCRA surface weighted average concentration (SWAC) of 27 mg/kg. The post-TCRA SWAC for instream and floodplain sediments combined was 0.26 mg/kg. Average surface water concentrations at the downstream end of the BMP were reduced from 0.11 µg/L pre-TCRA to 0.0025 µg/L post-TCRA. Tissue samples for adult carp fillets decreased from 4 mg/kg pre-TCRA to 0.26 mg/kg post-TCRA; whole body white suckers from 3 mg/kg pre-TCRA to 0.1 mg/kg post-TCRA; whole body channel catfish from 39 mg/kg-L pre-TCRA to 2.6 mg/kg-L post-TCRA. Concentrations of PCBs in 2 species of resident fish (carp and white suckers), caged channel catfish, surface water, and sediment were reduced by over 1 order of magnitude within 1 year of completion, substantively accelerating natural recovery processes. A slight increase in PCB concentration was observed in both whole body suckers and adult carp fillets in the second monitoring period post-TCRA; however, these concentrations are still near an order of magnitude less than pre-TCRA concentrations and appear to be currently stable or on a slight downward trend. Integr Environ Assess Manag 2015;11:161–170. © 2014 SETAC

In the Illinois River watershed (Arkansas and Oklahoma) poultry litter is routinely applied to pasture lands as fertilizer supplements. The objective of this study was to quantify the impacts of this practice on water quality in small streams in the watershed. Total phosphorus concentrations in small streams were quantified during a 15 month intensive sampling program for small tributaries, un-impacted by point sources, and covering a range of upstream poultry farming intensities throughout the watershed. Base flow samples were also collected from the tributaries during multiple dry weather sampling events. Correlation analysis was performed for various measurable drainage basin characteristics and phosphorus concentrations. Results show significant positive correlations between total phosphorus concentrations and the intensity of poultry farm operations upstream of sample sites. This relationship is supported by a supplemental synoptic sampling event upstream and downstream of a field applied with poultry litter and by a watershed-scale mass balance analysis. The latter identifies poultry as the single largest contributor of phosphorus inputs to the basin, accounting for over 76 % of the total watershed load. Study results also show significant, but generally weaker, positive correlations between phosphorus and upstream density of septic tanks and soil conservation service curve number of the drainage basin, but these appear likely to be primarily due to cross-correlations with poultry farm presence. This study demonstrates the use of readily-observed basin characteristics in simple water quality predictive tools and has implications for management of poultry-dominated watersheds.

Aims and Background Rarely are conclusions from clinical trials summarized in international consensus conferences and promptly transferred to patient care. The adjuvant therapy for colorectal cancer used in daily clinical practice in Italy is described and compared with the recommendations of the 1990 NIH Consensus Conference. Patients and Methods We audited prescriptions of adjuvant systemic therapies for Italian colorectal cancer patients in 82 centers during a fixed one-week period. Results Among 434 patients receiving adjuvant chemotherapy there were 139 (42.5%) colon cancer patients with N- and 169 (51.7%) with N+ regional nodal involvement. Treatment at academic centers, a young age, T4 and a low total number of lymph nodes removed at surgery were the factors potentially justifying the decision for adjuvant chemotherapy in stage II colon cancer patients. The most common chemotherapy used was a bolus of 5-fluorouracil/folinic acid for 6 months (75.8%). Adjuvant radiotherapy was not administered to 37 (38.5%) of 96 patients with stage II and III rectal cancer. Conclusions The study shows that a substantial proportion of patients on adjuvant treatment at a certain time point in a large enough sample of Italian centers are stage II (potential over-treatment) and that an under-treatment of stage II and III rectal cancer patients (lack of radiotherapy) occurs too often in daily clinical practice in this country.

Background The availability of therapeutic regimens that effectively interfere with HIV-1 replication provides novel opportunities to investigate mechanisms of T-cell depletion as well as repopulation in infected individuals. Methods Nineteen HIV-1-infected individuals were investigated during one-year follow-up of highly active retroviral therapy (HAART). The frequencies of apoptotic T cells, as determined by propidium iodide, staining, TUNEL assay and analysis of annexin V, were assessed either in the absence or in the presence of anti-interleukin (IL)2 and anti-IL-4 neutralizing Ab. Spontaneous and lectin-induced cytokine production were assessed by ELISA. Results Increments of both naive and memory CD4 and CD8 T cells during HAART are accompanied by a decrease of T-cell apoptosis that, after 12 months of HAART, reaches normal levels. This is associated with increments of both spontaneous and activation-induced production of IL-2 and IL-4 by peripheral blood mononuclear cells (PBMCs), though only the latter was found defective at enrolment. During HAART, blocking of either IL-2 or IL-4 production by PBMCs using neutralizing Ab restores levels of T-cell apoptosis consistent with those determined at enrolment. These data suggest that both IL-2 and IL-4 produced by PBMCs during HAART provide anti-apoptotic signals that can contribute to an increased survival of T cells and may thus play a part in long-term immune reconstitution. Conclusions An effective viral suppression and, possibly, effects of PI on molecular targets other than viral components, can support a progressive normalization of T-cell survival that, at least in part, depends upon the restoration of proper soluble signals. These results provide evidence of a supporting role of endogenous cytokine production in peripheral T-cell repopulation during an effective and prolonged viral suppression. This may be relevant for the definition of immune-intervention targets aimed at immune reconstitution in HIV-1-infected patients.

Documenting successful remediation of polychlorinated biphenyl (PCB)-contaminated sediments is limited; potentially due to inadequate monitoring methods, complexities associated with the environment, and selected remedial techniques. At some sites, absence of appropriate baseline and postremoval monitoring limits proper evaluation of remedial efficacy. Accurate interpretation of interactions between media, space, time, species, lipid content, and remedial technique requires robust study design and data. This article presents baseline and postremoval data documenting reduced PCB concentrations in fish tissue, surface water, and sediment in response to the US Environmental Protection Agency (USEPA) time-critical removal action (TCRA) that was conducted at the former Bryant Mill Pond (BMP) on Portage Creek in Kalamazoo, Michigan. The BMP is part of an operable unit (OU) within the Allied Paper, Inc./Portage Creek/Kalamazoo River Superfund Site. PCBs discharged to the creek as a byproduct of carbonless copy paper recycling are the primary contaminant of concern. Paper waste residuals commonly appear as gray to light gray clays in river sediments and floodplain soils. The cleanup criterion was 10 mg/kg, with a residual PCB concentration goal of 1 mg/kg. Because the PCB-containing waste is (generally) associated with readily visible light gray clay, excavation of all visibly contaminated current or formerly impounded sediment served as a surrogate for the cleanup criteria and goal. Sediment was wet excavated and backfilled after diversion of the creek. After confirmation that PCB concentrations met cleanup criteria, the stream was diverted to the excavated side, and excavation and backfilling were completed. Overall, 146000 cubic yards of material including PCB-contaminated sediments were removed from the BMP. The long-term monitoring (LTM) program implemented by the Michigan Department of Environmental Quality (MDEQ), and historic data from a variety of sources (federal, state, and local agencies and responsible parties) provided data demonstrating TCRA effectiveness. Before TCRA, surface sediment PCB concentration in instream and formerly inundated sediment combined was 83 mg/kg (with a maximum of 700 mg/kg). Instream sediments that are more representative of fish exposures had a pre-TCRA surface weighted average concentration (SWAC) of 27 mg/kg. The post-TCRA SWAC for instream and floodplain sediments combined was 0.26 mg/kg. Average surface water concentrations at the downstream end of the BMP were reduced from 0.11 µg/L pre-TCRA to 0.0025 µg/L post-TCRA. Tissue samples for adult carp fillets decreased from 4 mg/kg pre-TCRA to 0.26 mg/kg post-TCRA; whole body white suckers from 3 mg/kg pre-TCRA to 0.1 mg/kg post-TCRA; whole body channel catfish from 39 mg/kg-L pre-TCRA to 2.6 mg/kg-L post-TCRA. Concentrations of PCBs in 2 species of resident fish (carp and white suckers), caged channel catfish, surface water, and sediment were reduced by over 1 order of magnitude within 1 year of completion, substantively accelerating natural recovery processes. A slight increase in PCB concentration was observed in both whole body suckers and adult carp fillets in the second monitoring period post-TCRA; however, these concentrations are still near an order of magnitude less than pre-TCRA concentrations and appear to be currently stable or on a slight downward trend.

To evaluate the changes occurring in the somatic innervation throughout the levator ani muscle in women with genitourinary prolapse and stress urinary incontinence (SUI).Thirty-four patients with genital prolapse entered the study and ten subjects with non-malignant pathologies acted as a control group. All patients were evaluated by urodynamic investigation and an electromyographic study of pelvic floor muscles to define the type of urinary incontinence. Biopsy samples were obtained from both groups of patients: the site of muscle biopsies were left and right part of perirectal pubococcygeus muscle. The evaluation of immunoreactivity was semiquantitative and based on staining intensity and distribution.In all cases, S-100 protein and NSE immunoreactivities were found in nerve fascicles running throughout the striated muscle. NPY and VIP positivities were more intense and diffuse, whereas SP immunoreactivity was quite scanty. The different patterns of NPY and VIP expression changed in relation to degree of genital prolapse and to the presence of SUI.Our immunohistochemical study shows the presence in the pelvic floor of neurons that are able to synthesize neuropeptides. The lower immunoreactivity score of same neuropeptides (VIP, NPY) observed among patients with third degree genital prolapse and with SUI could be related to biochemical damage of the neurons with subsequent lower production of chemical messengers.

In the United States, recent shale gas discoveries have generated renewed interest in using natural gas as a vehicular fuel, primarily in fleet applications, while outside the United States, natural gas vehicle use has expanded significantly in the past decade. In this report for the U.S. Department of Energy's Clean Cities Program-a public-private partnership that advances the energy, economic, and environmental security of the U.S. by supporting local decisions that reduce petroleum use in the transportation sector--the authors have examined the state of natural gas vehicle technology, current market status, energy and environmental benefits, implications regarding advancements in European natural gas vehicle technologies, research and development efforts, and current market barriers and opportunities for greater market penetration. The authors contend that commercial intracity trucks are a prime area for advancement of this fuel. Therefore, we examined an aggressive future market penetration of natural gas heavy-duty vehicles that could be seen as a long-term goal. Under this scenario using Energy Information Administration projections and the Greenhouse Gases, Regulated Emissions, and Energy Use in Transportation (GREET) life-cycle modeling of U.S. on-road heavy-duty use, natural gas vehicles would reduce petroleum consumption by approximately 1.2 million barrels of oil per day, while another 400,000 barrels of oil per day reduction could be achieved with significant use of natural gas off-road vehicles. This scenario would reduce daily oil consumption in the United States by about 8%.

Among the rare anomalies of the breast development, polythelia is the most common, between 1% and 5% of women and men present supernumerary nipples. Polymastia, usually presenting as ectopic breast tissue without areola-nipple complex, is seen mostly along the milk line, extending from the axilla to the pubic region. Ectopic breast tissue is functionally analogous to mammary gland and it is subjected to the same alterations and diseases, whether benign or malignant, that affect normal breast tissue. We report the case of a 21 years-old female evaluated by the medical staff after founding a solid nodular mass by suspect axillary lymphadenopathy. Differential diagnosis with lymphoma is the major problem in these cases. The mass was removed and the intraoperative histological examination showed fibroadenoma in axillary supernumerary breast. Presence of ectopic breast tissue is a rare condition; development of benign mass or malignant degeneration is possible, but it is very unusual. In case of polymastia diagnosis is simple; in case of isolated nodule, without local inflammation or infection, there are greater difficulties. Ultrasonography is diagnostic in case of breast fibroadenoma, but it might be inadequate in ectopic localizations owing to the shortage of mammary tissue around the mass. Preoperative diagnosis is important to plan an adequate surgical treatment; lumpectomy is indicated in case of benign tissue; in case of malignancy, therapy is based on the standard treatment used for breast cancer (surgery, chemotherapy and radiation therapy).

Responsiveness to hepatitis C virus (HCV) therapy depends on viral and host factors. Our aim was to assess sustained virologic response (SVR)-associated early gene expression in patients with HCV receiving pegylated interferon-alpha2a (PEG-IFN-α2a) or PEG-IFN-α2b and ribavirin with the duration based on genotypes. Blood samples were collected into PAXgene tubes prior to treatment as well as 1, 7, 28, and 56 days after treatment. From the peripheral blood cells, total RNA was extracted, quantified, and used for one-step reverse transcription polymerase chain reaction to profile 154 messenger RNAs. Expression levels of messenger RNAs were normalized with six “housekeeping” genes and a reference RNA. Multiple regression and stepwise selection were performed to assess differences in gene expression at different time points, and predictive performance was evaluated for each model. A total of 68 patients were enrolled in the study and treated with combination therapy. The results of gene expression showed that SVR could be predicted by the gene expression of signal transducer and activator of transcription-6 (STAT-6) and suppressor of cytokine signaling-1 in the pretreatment samples. After 24 hours, SVR was predicted by the expression of interferon-dependent genes, and this dependence continued to be prominent throughout the treatment. Conclusion: Early gene expression during anti-HCV therapy may elucidate important molecular pathways that may be influencing the probability of achieving virologic response. (HEPATOLOGY 2009.)