Surgical Intervention in Gastric Carcinoid is Associated With Improved Survival in Local and Regional Disease.

Introduction: Gastric carcinoid is a rare entity with complex management options. This study aims to determine if surgical intervention in patients with local, regional, and metastatic gastric carcinoid is associated with prolonged survival. Materials and Methods: The California Cancer Registry merged with the California Office of Statewide Health Planning and Development was queried for patients with a diagnosis of gastric carcinoid (2000 to 2011). Clinicopathologic characteristics, management, and outcomes were evaluated. Results: There were 1012 patients with a diagnosis of gastric carcinoid identified. The median age was 63 (range, 18 to 99) and the majority of patients were women (615, 60.7%). Most patients had localized disease (644, 64%), whereas 9.4% (95) had regional and 13.4% (133) had distant metastases at diagnosis. The majority of patients underwent gastric surgery (56.7%, n=574 vs. 43.2%, n=438). Prolonged survival was associated with gastric surgery in patients with both local (median survival not reached; P

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Efficacy of Modified Dose-dense Paclitaxel in Recurrent Cervical Cancer.

Objective: To examine survival outcomes of women with recurrent cervical cancer who received salvage chemotherapy with modified dose-dense paclitaxel (MDDP) monotherapy (paclitaxel 80 mg/m2, administered on day 1, 8, and 15 without day 22). Materials and Methods: A retrospective study was conducted to evaluate cause-specific survival after the first recurrence (SAR) of women with recurrent cervical cancer diagnosed between 2006 and 2014. Pooled analyses were performed to examine SAR in women who received MDDP monotherapy (n=17) for any treatment line, compared with those who received salvage chemotherapy with paclitaxel-doublet (n=18) and nonpaclitaxel regimens (n=52). Results: In the whole cohort, median SAR was 13.7 months including 63 (72.4%) events. MDDP monotherapy regimen was most commonly used in the second-line setting (35.3%) followed by the third/fourth lines (both, 23.5%). Among the women who received MDDP regimen, there were 6 (35.3%) women who received >=6 cycles; there was 1 (5.9%) women who discontinued the regimen due to adverse effects (grade 3 transaminitis); regimen postponement was seen in 2 (1.4%) of 140 total cycles; and the response rate after the sixth cycle of this regimen was 29.4% (1 complete and 4 partial responses). On univariate analysis, MDDP usage had the highest 2-year SAR rate (MDDP 54.1%, paclitaxel-doublet 43.6%, and nonpaclitaxel regimens 28.1%; Ptrend=0.044). On multivariate analysis, MDDP monotherapy remained an independent prognostic factor for improved SAR compared with the nonpaclitaxel regimen (adjusted-hazard ratio, 0.50; 95% confidence interval, 0.26-0.95; P=0.036). Conclusion: Our results suggested that MDDP monotherapy is a tolerable and relatively effective regimen for recurrent cervical cancer. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Advanced Age is Not a Contraindication for Treatment With Curative Intent in Esophageal Cancer.

Objectives: The objective of this study is to compare long-term outcomes between younger and older (70 y and above) esophageal cancer patients treated with curative intent. Materials and Methods: Overall survival (OS), disease-free survival (DFS), and locoregional recurrence-free interval were compared between older (70 y and above) and younger (below 70 y) esophageal cancer patients treated between 1998 and 2013. Treatment consisted of neoadjuvant chemoradiotherapy with surgery or definitive chemoradiotherapy: 36 to 50.4 Gy in 18 to 28 fractions combined with 5-fluorouracil/cisplatin or carboplatin/paclitaxel. Results: The study comprised 253 patients, of whom 76 were 70 years and older. Median age was 64 years (range, 41 to 83). Most patients had stage II-IIIA disease (83%). Planned treatment was neoadjuvant chemoradiotherapy with surgery for 169 patients (41 patients aged 70 y and older) and definitive chemoradiotherapy for 84 patients (31 patients aged 70 y and older). The compliance to radiotherapy was 92%, with no difference between older and younger patients. In 33 patients (13 patients aged 70 y and older) planned surgery was not performed. Median follow-up was 4.9 years. Three-year OS was 42%. The multivariable analysis showed no statistical difference in OS or in DFS comparing older and younger patients: OS (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.61-1.28), DFS (HR, 0.87; 95% CI, 0.60-1.25). Elderly showed a longer locoregional recurrence-free interval; HR, 0.53 (95% CI, 0.30-0.92; P=0.02) and a higher pathologic complete response rate (50% vs. 25%; P=0.02). Conclusions: Long-term outcomes of older esophageal cancer patients (70 y and above) selected for treatment with neoadjuvant chemoradiotherapy followed by surgery or definitive chemoradiotherapy were comparable with the outcomes of their younger counterparts. Advanced age alone should not be a contraindication for potentially curative chemoradiotherapy-based treatment in esophageal cancer patients. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Point-of-Care Ultrasonography Findings and Care Use Among Patients Undergoing Ultrasound-Guided Shoulder Injections.

Objective: The aims of the study were to assess the overall reduction of pain in patients undergoing ultrasound-guided shoulder injections and to characterize the preinjection point-of-care ultrasound findings and use of clinical services postinjection including the use of magnetic resonance imaging and surgeries. Design: Data of 172 patients who underwent ultrasound-guided subacromial subdeltoid injection or glenohumeral joint injection were reviewed for preinjection point-of-care ultrasound findings, change in pain intensity at 2 mos from baseline, and use of care at 6 mos' postinjection. Pain intensity was measured by the numeric rating scale and a dichotomous report of global impression of significant improvement in pain. Responders were defined as those with 50% or more reduction in numeric rating scale or those with global impression of 50% or more improvement. Results: There were 141 responders among the 172 patients analyzed. Full-thickness rotator cuff tears were higher in the ultrasound-guided subacromial subdeltoid injection group when compared with the glenohumeral joint injection group (P = 0.038) and abnormal bicipital tendon findings higher in the glenohumeral joint injection group (P = 0.016). There were no significant differences in specific abnormal U findings between responders versus nonresponders. Twelve patients had a shoulder magnetic resonance imaging and four patients underwent operative interventions after the injection. Conclusions: Overall pain reduction after ultrasound-guided shoulder injections was favorable in the short term. There was no specific preinjection point-of-care ultrasound findings associated with clinical pain reduction after injection. Additional imaging and operative intervention after ultrasound-guided shoulder injections seemed to be relatively low. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Could Activity Modifications Indicate Physical Decline Among Adults With Symptomatic Knee Osteoarthritis?.

Objectives: Mobility activity modifications indicate early functional losses that act as precursors to future declines among community-dwelling older adults. However, there is scarce evidence on whether activity modifications indicate poorer physical health among adults with symptomatic osteoarthritis, a major cause of disability. Our purpose was to investigate whether patient-reported mobility activity modifications indicated poorer physical health among adults with symptomatic knee osteoarthritis. Design: Secondary cross-sectional analysis of randomized trial data was performed. Preclinical Disability Questionnaire was used to group participants into the following three categories: difficulty, modified, and no difficulty walking/stair climbing. Kruskal Wallis and [chi]2 tests were used to compare clinical factors across groups. Results: Among 121 participants (median age = 60 yrs; 73% female; 60% white), less than 10% had modified walking/stair climbing. Compared with those with no walking difficulty, participants with modified walking had significantly less balance (P = 0.01) and global health (P = 0.01) as well as greater knee pain (P = 0.05) and physical disability (P = 0.04). Those with modified stair climbing had significantly smaller walking distances (P = 0.03) compared with those with no difficulty stair climbing. Conclusions: Activity modifications may signal early impairments in physical health among people with symptomatic knee osteoarthritis. If confirmed, patient-reported activity modifications may enhance symptom evaluation in osteoarthritis and enable a better understanding of the disablement process. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Inter-rater reliability of two paediatric early warning score tools.

Background: Paediatric early warning score (PEWS) assessment tools can assist healthcare providers in the timely detection and recognition of subtle patient condition changes signalling clinical deterioration. However, PEWS tools instrument data are only as reliable and accurate as the caregivers who obtain and document the parameters. Objective: The aim of this study is to evaluate inter-rater reliability among nurses using PEWS systems. Design: The study was carried out in five paediatrics departments in the Central Denmark Region. Inter-rater reliability was investigated through parallel observations. A total of 108 children and 69 nurses participated. Two nurses simultaneously performed a PEWS assessment on the same patient. Before the assessment, the two participating nurses drew lots to decide who would be the active observer. Intraclass correlation coefficient, Fleiss' [kappa] and Bland-Altman limits of agreement were used to determine inter-rater reliability. Results: The intraclass correlation coefficients for the aggregated PEWS score of the two PEWS models were 0.98 and 0.95, respectively. The [kappa] value on the individual PEWS measurements ranged from 0.70 to 1.0, indicating good to very good agreement. The nurses assigned the exact same aggregated score for both PEWS models in 76% of the cases. In 98% of the PEWS assessments, the aggregated PEWS scores assigned by the nurses were equal to or below 1 point in both models. Conclusion: The study showed good to very good inter-rater reliability in the two PEWS models used in the Central Denmark Region. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Southern Promises: A snapshot of the microbiology research landscape in South America based on bibliometric data

Abstract

Scientists have a single currency for productivity and impact: published articles. In an effort to map the global research landscape in microbiology, and to obviate the current lack of bibliometric analysis in the field, FEMS—the Federation of European Microbiological Societies generated a dataset encompassing an exhaustive, worldwide list of microbiology studies for 2013–4, which further includes information as author affiliation, funding agency and number of citation. The manually-curated database is useful in assessing impact and regional productivity of microbiology research at different levels. Here, the data for microbiology research in South America are presented and discussed in detail. Based on the analysis, it emerged that despite great degrees of variation between number of published articles among the countries, a more levelled research productivity was observed when considering further dimensions like population size or number of research Institutes. Normalized productivity and impact increase in countries with a 'central research hub,' i.e. an Institute or University producing a substantial portion of the national output (15% or more). From these observations, a possible strategy to increase impact and productivity in (microbiology) research for emerging countries is outlined.

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Characterization of a lactose-responsive promoter of ATP-binding cassette (ABC) transporter gene from Lactobacillus acidophilus 05–172

Abstract

A novel lactose-responsive promoter of the ATP binding cassette (ABC) transporter gene Lba1680 of Lactobacillus acidophilus strain 05–172 isolated from a traditionally fermented dairy product koumiss was characterized. In L. acidophilus 05–172, expression of Lba1680 was induced by lactose, with lactose-induced transcription of Lba1680 being 6.1-fold higher than that induced by glucose. This is in contrast to L. acidophilus NCFM, a strain isolated from human feces, in which expression of Lba1680 and Lba1679 is induced by glucose. Both gene expression and enzyme activity assays in Lactobacillus paracasei transformed with a vector containing the inducible Lba1680 promoter (PLba1680) of strain 05–172 and a heme-dependent catalase gene as reporter confirmed that PLba1680 is specifically induced by lactose. Its regulatory expression could not be repressed by glucose, and was independent of cAMP receptor protein. This lactose-responsive promoter might be used in the expression of functional genes in L. paracasei incorporated into a lactose-rich environment, such as dairy products.

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Investigation of triclosan contamination on microbial biomass and other soil health indicators

Abstract

Triclosan (TCS), is an antimicrobial compound found in personal care products, and consequently in greywater. After its release to the environment it continues its antimicrobial action on indigenous microbial communities. Little is known about the environmental impacts of high levels of TCS, which may occur due to accumulation following long term greywater application to soil. Soil microcosms were established using a silty clay loam and augmented with a range of triclosan concentrations ranging from 500 mg kg⁻¹ to 7500 mg kg⁻¹. Samples were analysed for substrate induced respiration, microbial biomass and sulphatase activity. The soil augmented with the the lowest concentration of TCS (500 mg kg⁻¹) significantly decreased microbial biomass, with a calculated EC₂₀ of 195 mg kg⁻¹. Substrate induced respiration indicated that the soil microbial community was impacted for all TCS concentrations, however the community showed potential to recover over time. Sulphatase activity was less sensitive to TCS and was significantly impacted at high concentrations of TCS (> 2500 mg kg⁻¹). It is likely that TCS has selective toxicity for more susceptible microbes when introduced into the soil environment. At high levels TCS could overwhelm TCS-degrading soil microbes.

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Carbon recycling by cyanobacteria: improving CO 2 -fixation through chemical production

Abstract

Atmospheric CO₂ levels have reached an alarming level due to industrialization and the burning of fossil fuels. In order to lower the level of atmospheric carbon, strategies to sequester excess carbon need to be implemented. The CO₂-fixing mechanism in photosynthetic organisms enables integration of atmospheric CO₂ into biomass. Additionally, through exogenous metabolic pathways in these photosynthetic organisms, fixed CO₂ can be routed to produce various commodity chemicals that are currently produced from petroleum. This review will highlight studies and modifications to different components of cyanobacterial CO₂-fixing systems, as well as the application of these systems towards CO₂-derived chemical production. 2,3-Butanediol is given particular focus as one of the most thoroughly studied systems for conversion of CO₂ to a bioproduct.

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Diversity and antimicrobial activity of bacteria isolated from different Brazilian coral species

Abstract

Corals harbor a wide diversity of bacteria associated with their mucus. These bacteria can play an important role in nutrient cycling, degradation of xenobiotics, and defense against pathogens by producing antimicrobial compounds. However, the diversity of the cultivable heterotrophic bacteria, especially in the Brazilian coral species, remains poorly understood. The present work compares the diversity of cultivable bacteria isolated from the mucus and surrounding environments of four coral species present along the Brazilian coast, and explores the antibacterial activity of these bacteria. Bacteria belonging to the phyla Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes were isolated. The mucus environment presented a significantly different bacteria composition, compared to the water and sediment environments, with high abundance of Alcanivorax, Acinetobacter, Aurantimonas, and Erythrobacter. No difference in the inhibition activity was found between the isolates from mucus and from the surrounding environment. Eighty three % of the bacteria isolated from the mucus presented antimicrobial activity against Serratia marcescens, an opportunistic coral pathogen, suggesting that they might play a role in maintaining the health of the host. Most of the bacteria isolates that presented positive antimicrobial activity belonged to the genus Bacillus.

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Patients with Huntington’s disease pioneered human stereotactic neurosurgery 70 years ago

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Measurement of the zygomatic region for the optimal placement of quad zygomatic implants

Abstract

Background

The zygomatic implant is suggested to be placed in zygomatic areas with the largest thickness, but regions to obtain the largest bone-to-implant contact (BIC) were unknown.

Purpose

To identify the zygomatic regions for placing quad zygomatic implants that obtain the largest BIC.

Materials and Methods

The zygomatic thicknesses of 300 zygomata were measured at total 12 points on the superior, middle, and inferior areas on the 3-dimensional reconstruction images. In 50 edentulous maxillae, the zygomatic BICs of virtually placed implants were measured and the incidence of the intrusion into the infratemporal fossa calculated at each point.

Results

The largest thickness in the superior, middle, and inferior regions were at Point A₁ (8.01 ± 2.10 mm), Point B₁ (7.02 ± 1.73 mm), and Point C₀ (6.65 ± 1.66 mm), respectively. The virtually placed implants at Point A₃ (16.70 ± 4.18 mm) and Point B₁ (12.07 ± 3.84 mm) had the highest BICs while retaining the minimum incidence of the intrusion complications.

Conclusion

To obtain the largest BICs and avoid the intrusion complications, results suggested that the postero-superior region (Point A₃) and the center of zygoma (Point B₁) were the optimal places for the placement of quad zygomatic implants.

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Clinical significance of farnesoid X receptor expression in thyroid neoplasia

Future Oncology, Ahead of Print.


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The phytological future of prostate cancer staging: prostate-specific membrane antigen positron emission tomography and the dandelion theory

Future Oncology, Ahead of Print.


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Metabolomics analysis reveals distinct profiles of nonmuscle-invasive and muscle-invasive bladder cancer

Abstract

Urothelial carcinoma is the most common form of bladder cancer, but pathway changes that occur with stage-wise progression have not been well defined. We used a metabolomics approach to identify potential metabolic pathways uniquely altered in normal urothelium, nonmuscle-invasive bladder cancer (NMIBC), and muscle-invasive bladder cancer (MIBC). We performed global metabolomic profiling using GC-mass spectrometry (MS) and LC-MS platforms to identify metabolite signatures between normal urothelium and high-grade urothelial carcinoma of different stages. Pathways globally dysregulated in cancer relative to normal urothelium included glucose, tricarboxylic acid (TCA) cycle, lipid, amino acid, and nucleotide pathways. Urothelial carcinoma showed elevated glucose utilization for glycolysis and increased sorbitol pathway intermediates, consistent with Warburg effect. Anaplerosis to sustain energy production suggested by increased late TCA cycle intermediates, amino acids, and dipeptides occurs in bladder cancer. Urothelial carcinoma also shows altered membrane lipid membrane metabolism and differential derivation of nucleic acid components pyrimidine and purine. In stage comparison, MIBC appears to preferentially enhance cyclooxygenase (COX) and lipoxygenase (LOX) signaling, increase heme catabolism, and alter nicotinamide adenine dinucleotide (NAD+) synthesis with a possible influence from associated inflammatory cells. We identify numerous metabolomic alterations in NMIBC and MIBC that likely reflect underlying pathway changes. Differential pathway activity may have value in designing stage-specific novel therapeutics in urothelial carcinoma.

Using a highly sensitive metabolomics approach, we identified multiple pathway changes between normal urothelium and high-grade urothelial carcinoma and between high-grade carcinomas of different stages. Several of these differential metabolite profiles suggest the potential for unique targeted therapy in NMIBC and MIBC populations.

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Small cell lung carcinoma cell line screen of etoposide/carboplatin plus a third agent

Abstract

The SCLC combination screen examined a 9-point concentration response of 180 third agents, alone and in combination with etoposide/carboplatin. The predominant effect of adding a third agent to etoposide/carboplatin was additivity. Less than additive effects occurred frequently in SCLC lines sensitive to etoposide/carboplatin. In SCLC lines with little or no response to etoposide/carboplatin, greater than additive SCLC killing occurred over the entire spectrum of SCLC lines but never occurred in all SCLC lines. Exposing SCLC lines to tubulin-targeted agents (paclitaxel or vinorelbine) simultaneously with etoposide/carboplatin resulted primarily in less than additive cell killing. As single agents, nuclear kinase inhibitors including Aurora kinase inhibitors, Kinesin Spindle Protein/EG5 inhibitors, and Polo-like kinase-1 inhibitors were potent cytotoxic agents in SCLC lines; however, simultaneous exposure of the SCLC lines to these agents along with etoposide/carboplatin, generally, resulted in less than additive cell killing. Several classes of agents enhanced the cytotoxicity of etoposide/carboplatin toward the SCLC lines. Exposure of the SCLC lines to the MDM2 inhibitor JNJ-27291199 produced enhanced killing in 80% of the SCLC lines. Chk-1 inhibitors such as rabusertib increased the cytotoxicity of etoposide/carboplatin to the SCLC lines in an additive to greater than additive manner. The combination of GSK-3β inhibitor LY-2090314 with etoposide/carboplatin increased killing in approximately 40% of the SCLC lines. Exposure to the BET bromodomain inhibitor MK-8628 increased the SCLC cell killing by etoposide/carboplatin in 20–25% of the SCLC lines. Only 10–15% of the SCLC lines had an increased response to etoposide/carboplatin when simultaneously exposed to the PARP inhibitor talazoparib.

Sixty-three human small cell lung cancer cell lines were screened to search for agents which may act synergistically with etoposide/carboplatin. Most third agents were additive or antagonistic with etoposide/carboplatin. Third agents which were synergistic are highlighted.

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Identification of sentinel lymph nodes by contrast-enhanced ultrasonography with Sonazoid in patients with breast cancer: a feasibility study in three hospitals

Abstract

The aim of this prospective study was to evaluate the feasibility of periareolar injection of the contrast agent Sonazoid (SNZ) followed by ultrasonography (US) for the identification of sentinel lymph node (SLN) in breast cancer patients with clinically negative node. Patients (n = 100) with T1-2N0M0 breast cancer received a periareolar injection of SNZ followed by US to identify contrast-enhanced SLN. Each contrast-enhanced SLN underwent fine needle aspiration cytology (FNAC) followed by SLN biopsy with a conventional method using blue dye and/or radiocolloid (B/R). In almost all cases, contrast-enhanced lymphatic vessels were clearly visualized by US soon after the periareolar injection of SNZ and the SLNs were easily identified with an identification rate of 98% (98/100) for SNZ and 100% (100/100) for B/R. The number of SLNs identified by SNZ (SNZ-SLN) (mean per patient, 1.52) was significantly lower than that identified by B/R (B/R-SLN) (2.19) (P < 0.0001). Twenty-five patients with positive SLNs had at least one positive SNZ-SLN. On a node-by-node basis, sensitivity, specificity, and accuracy of FNAC for SNZ-SLNs (n = 149) were 33.3%, 99.2%, and 85.9%, respectively. Identification of SLN by periareolar injection of SNZ is a technically simple method with an identification rate as high as 98%. SNZ-SLN thus seems to be a good target for FNAC, but sensitivity of FNAC for SNZ-SLNs needs to be improved.

Patients (n = 100) received periareolar injection of Sonazoid followed by ultrasonography of the axilla for identification of contrast-enhanced sentinel lymph node (SLN). This method is technically simple with a high success rate (98%) and comparable to the conventional method using blue dye and/or radiocolloid.

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Relationship between mammographic calcifications and the clinicopathologic characteristics of breast cancer in Western China: a retrospective multi-center study of 7317 female patients

Abstract

Background and purpose

Limited information is available regarding the correlations between mammographic calcifications and the epidemiological features of patients with breast cancer living different lifestyles in Western China. Thus, this study aimed to investigate the relationship between mammographic calcifications and the epidemiological characteristics of female patients with breast cancer in Western China.

Methods

This was a hospital-based, retrospective, multi-center epidemiological study of patients with breast cancer. Using the Western China Clinical Cooperation Group (WCCCG) database, we obtained the records of 7317 patients (with mammographic data) diagnosed with breast cancer between March 2011 and June 2016. These patients were divided into Groups I (mass alone) and II (mass combined with calcification), and their clinical and pathological data were compared.

Results

A total of 4211 patients were enrolled in Group I, and 3106 patients were enrolled in Group II. The tumors in Group II were more likely to be larger (P < 0.0001), higher grade (P = 0.0029), estrogen receptor (ER)+/progesterone receptor (PR)− (P = 0.0319), and human epidermal growth factor receptor 2 (HER-2)-positive (P < 0.0001), and to have axillary lymph node metastasis (P = 0.0033) than those in Group I. Regarding treatment, patients in Group II were more likely to have undergone chemotherapy (P = 0.0108) and anti-HER2 therapy (P = 0.0102), whereas patients in Group I were more likely to have undergone endocrine therapy (P < 0.0001).

Conclusions

In conclusion, mammographic calcifications in tumors were associated with distinct clinicopathologic characteristics and aggressive treatments.

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Grounding by Attention Simulation in Peripersonal Space: Pupils Dilate to Pinch Grip But Not Big Size Nominal Classifier

Abstract

Grammatical categories represent implicit knowledge, and it is not known if such abstract linguistic knowledge can be continuously grounded in real-life experiences, nor is it known what types of mental states can be simulated. A former study showed that attention bias in peripersonal space (PPS) affects reaction times in grammatical congruency judgments of nominal classifiers, suggesting that simulated semantics may include reenactment of attention. In this study, we contrasted a Chinese nominal classifier used with nouns denoting pinch grip objects with a classifier for nouns with big object referents in a pupil dilation experiment. Twenty Chinese native speakers read grammatical and ungrammatical classifier-noun combinations and made grammaticality judgment while their pupillary responses were measured. It was found that their pupils dilated significantly more to the pinch grip classifier than to the big object classifier, indicating attention simulation in PPS. Pupil dilations were also significantly larger with congruent trials on the whole than in incongruent trials, but crucially, congruency and classifier semantics were independent of each other. No such effects were found in controls.

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Evaluation of the budding and depth of invasion (BD) model in oral tongue cancer biopsies

Abstract

It is of great clinical importance to identify simple prognostic markers from preoperative biopsies that could guide treatment planning. Here, we compared tumor budding (B), depth of invasion (D), and the combined scores (i.e., budding and depth of invasion (BD) histopathologic model) in preoperative biopsies and the corresponding postoperative specimens of oral tongue squamous cell carcinoma (OTSCC). Tumor budding and depth of invasion were evaluated in the pre- and postoperative samples from 100 patients treated for OTSCC. Sensitivity and specificity statistics were used. Our results showed statistically significant (P < 0.001) relationship between pre- and postoperative BD scores. There was an agreement between the pre- and postoperative BD model scores in 83 cases (83%) with 57.1% sensitivity (95% CI 39.4 to 73.7%) and 96.9% specificity (95% CI 89.3 to 99.6%). Our findings suggest that the BD model, analyzed from representative biopsies, could be used for the treatment planning of OTSCC.

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Outcome of Azacitidine Therapy in Acute Myeloid Leukemia is not Improved by Concurrent Vorinostat Therapy but is Predicted by a Diagnostic Molecular Signature

Purpose: Azacitidine (AZA) is a novel therapeutic option in older patients with acute myeloid leukemia (AML) but its rational utilization is compromised by the fact that neither the determinants of clinical response nor its mechanism of action are defined. Co-administration of histone deacetylase inhibitors, such as vorinostat (VOR), is reported to improve the clinical activity of AZA but this has not been prospectively studied in AML. Experimental Design: We compared outcomes in 259 adults with AML (n=217) and MDS (n=42) randomized to receive either AZA monotherapy (75 mg/m²x seven days every 28 days) or AZA combined with VOR 300 mg bd on days 3-9 po. Next generation sequencing was performed in 250 patients on 41 genes commonly mutated in AML. Serial immunophenotyping of progenitor cells was performed in 47 patients. Results: Co-administration of VOR did not increase the overall response rate (P=0.84) or overall survival (OS) (P=0.32). Specifically, no benefit was identified in either de novo or relapsed AML. Mutations in the genes CDKN2A (P=0.0001), IDH1 (P=0.004) and TP53 (P=0.003) was associated with reduced OS. Lymphoid multi-potential progenitor populations were greatly expanded at diagnosis and although reduced in size in responding patients remained detectable throughout treatment. Conclusion: This study demonstrates no benefit of concurrent administration of VOR with AZA but identifies a mutational signature predictive of outcome after AZA based therapy. The correlation between heterozygous loss of function CDKN2A mutations and decreased OS implicates induction of cell cycle arrest as a mechanism by which AZA exerts its clinical activity.

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Phase 1 dose-escalation study of the anti-CD70 antibody ARGX-110 in Advanced Malignancies

Purpose: The purpose of this study was to evaluate safety, pharmacokinetics, pharmacodynamics and preliminary antitumor efficacy of ARGX-110, a glyco-engineered monoclonal antibody, targeting CD70, in patients with CD70 expressing advanced malignancies. <br /><br />Experimental Design: <p>Dose escalation with a sequential 3+3 design was performed in five steps at the 0.1, 1, 2, 5, and 10 mg/kg dose levels (N=26). ARGX-110 was administered intravenously every three weeks until progression or intolerable toxicity. Dose limiting toxicity was evaluated in the 21 days following the first ARGX-110 administration (Cycle 1). Samples for pharmacokinetics and pharmacodynamics were collected.</p> <br /><br />Results: <p>Dose limiting toxicity was not observed and the maximum tolerated dose was not reached. ARGX-110 was generally well tolerated, with no dose-related increase in treatment-emergent adverse events (TEAE). The most common TEAE were fatigue and drug related infusion-related reactions (IRRs). Of the 20 SAEs reported, 5 events, all IRRs, were considered related to ARGX-110.</p> <p>ARGX-110 demonstrates dose proportionality over the dose range 1-10 mg/kg, but not at 0.1 mg/kg and a terminal half-life of 10-13 days.</p> <p>The best overall response was stable disease (14/26) in all 26 evaluable patients with various malignancies and the mean duration of treatment was 15 weeks. No dose-response related anti-tumor activity was observed, but biomarker readouts provided signs of biological activity, particularly in patients with hematological malignancies.</p> <br /><br />Conclusions:This dose-escalation phase I trial provides evidence of good tolerability of ARGX-110, pharmacokinetics and preliminary anti-tumor activity at all dose levels in generally heavily pretreated patients with advanced CD70-positive malignancies.

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Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-Mediated Resistance to Type I MET Inhibitors in Nonclinical Models

Purpose: MET exon 14 deletion (METex14 del) mutations represent a novel class of non-small cell lung cancer (NSCLC) driver mutations.  We evaluated glesatinib, a spectrum-selective MET inhibitor exhibiting a type II binding mode, in METex14 del-positive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET Inhibitors.<br /><br />Experimental Design: As most MET inhibitors in clinical development bind the active site with a type I binding mode, we investigated mechanisms of acquired resistance to each MET inhibitor class utilizing in vitro and in vivo models and in glesatinib clinical trials.<br /><br />Results: Glesatinib inhibited MET signaling, demonstrated marked regression of METex14 del-driven patient-derived xenografts, and demonstrated a durable RECIST partial response in a METex14 del mutation-positive patient enrolled on a glesatinib clinical trial. Prolonged treatment of nonclinical models with selected MET inhibitors resulted in differences in resistance kinetics and mutations within the MET activation loop (i.e., D1228N, Y1230C/H) that conferred resistance to type I MET inhibitors, but remained sensitive to glesatinib. In vivo models exhibiting METex14 del/A-loop double mutations and resistance to type I inhibitors exhibited a marked response to glesatinib. Finally, a METex14 del mutation-positive NSCLC patient who responded to crizotinib but later relapsed, demonstrated a mixed response to glesatinib including reduction in size of a MET Y1230H mutation-positive liver metastasis and concurrent loss of detection of this mutation in plasma DNA. <br /><br />Conclusions: Together, these data demonstrate glesatinib exhibits a distinct mechanism of target inhibition and can overcome resistance to type I MET inhibitors.

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The KMT1A-GATA3-STAT3 circuit is a novel self-renewal signaling of human bladder cancer stem cells

Purpose: Bladder cancer (BC) is one of the most common urinary malignancies worldwide characterized by a high rate of recurrence and no targeted therapy method. Bladder cancer stem cells (BCSCs) play a crucial role in tumor initiation, metastasis and drug-resistance. However, the regulatory signaling and self-renewal mechanisms of BCSCs remain largely unknown. Here, we identified a novel signal, the KMT1A-GATA3-STAT3 circuit, which promoted the self-renewal and tumorigenicity of human BCSCs.<br />Experimental Design: In a discovery step, human BCSCs and bladder cancer non-stem cells (BCNSCs) isolated from primary BC samples #1 and #2, and the BC cell line EJ were analyzed by transcriptome microarray. In a validation step, 10 paired BC and normal tissues, different tumor cell lines, the public microarray datasets of human BC, and TCGA database were applied for the verification of gene expression.<br />Results: KMT1A was highly expressed and responsible for the increase of tri-methylating lysine 9 of histone H3 (H3K9me3) modification in BCSCs compared with either BCNSCs or normal bladder tissue. GATA3 bound to the -1710~-1530 region of STAT3 promoter and repressed its transcription. H3K9me3 modification on the -1351~-1172bp region of the GATA3 promoter mediated by KMT1A repressed the transcription of GATA3 and upregulated the expression of STAT3. Additionally, the activated STAT3 triggered self-renewal of BCSCs. Furthermore, depletion of KMT1A or STAT3 abrogated the formation of BCSC tumorspheres and xenograft tumors.<br />Conclusions:KMT1A positively regulated the self-renewal and tumorigenicity of human BCSCs via KMT1A-GATA3-STAT3 circuit, in which KMT1A could be a promising target for bladder cancer therapy.

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Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer

Purpose: Resistance to platinum-based chemotherapy or PARP inhibition in germline BRCA1 or BRCA2 mutation carriers may occur through somatic reversion mutations or intragenic deletions that restore BRCA1 or BRCA2 function. We assessed whether BRCA1/2 reversion mutations could be identified in circulating cell-free DNA (cfDNA) of ovarian or breast cancer patients previously treated with platinum and/or PARP inhibitors. <p>Experimental Design: cfDNA from 24 prospectively accrued BRCA1- or BRCA2-germline mutant patients, including 19 platinum-resistant/refractory ovarian cancer and five platinum and/or PARP inhibitor pre-treated metastatic breast cancer patients, was subjected to massively parallel sequencing targeting all exons of 141 genes and all exons and introns of BRCA1 and BRCA2. Functional studies were performed to assess the impact of the putative BRCA1/2 reversion mutations on BRCA1/2 function.</p> <p>Results: Diverse and often polyclonal putative BRCA1 or BRCA2 reversion mutations were identified in cfDNA from four ovarian cancer patients (21%) and from two breast cancer patients (40%). BRCA2 reversion mutations were detected in cfDNA prior to PARP inhibitor treatment in a breast cancer patient who did not respond to treatment, and were enriched in plasma samples after PARP inhibitor therapy. Foci formation and immunoprecipitation assays suggest that a subset of the putative reversion mutations restored BRCA1/2 function.</p> <p>Conclusions: Putative BRCA1/2 reversion mutations can be detected by cfDNA sequencing analysis in ovarian and breast cancer patients. Our findings warrant further investigation of cfDNA sequencing to identify putative BRCA1/2 reversion mutations and to aid the selection of patients for PARP inhibition therapy.

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Overcoming acquired resistance to AZD9291, a third generation EGFR inhibitor, through modulation of MEK/ERK-dependent Bim and Mcl-1 degradation

Purpose: <p>The mechanisms accounting for anticancer activity of AZD9291 (osimertinib or TAGRISSO™), an approved third generation EGFR inhibitor, in EGFR-mutant non-small cell lung cancer (NSCLC) cells and particularly for the subsequent development of acquired resistance are unclear and thus are the focus of this study.</p> <br /><br />Experimental Design: <p>AZD9219-resistant cell lines were established by exposing sensitive cell lines to AZD9291. Protein alterations were detected with Western blotting. Apoptosis was measured with annexin V/flow cytomentry. Growth-inhibitory effects of tested drugs were evaluated in vitro with cell number estimation and colony formation assay and in vivo with mouse xenogtaft models. Protein degradation was determined by comparing protein half-lives and inhibiting proteasome. Gene knockdown were achieved with siRNA or shRNA.</p> <br /><br />Results: <p>AZD9291 potently induced apoptosis in EGFR-mutant NSCLC cell lines, in which ERK phosphorylation was suppressed accompanied with Bim elevation and Mcl-1 reduction likely due to enhanced Mcl-1 degradation and increased Bim stability. Blocking Bim elevation by gene knockdown or enforcing Mcl-1 expression attenuated or abolished AZD9291-induced apoptosis. Moreover, AZD9291 lost its ability to modulate Bim and Mcl-1 levels in AZD9291-resistant cell lines. The combination of a MEK inhibitor with AZD9291 restores the sensitivity of AZD9291-resistant cells including those with C797S mutation to undergo apoptosis and growth regression in vitro and in vivo.</p> <br /><br />Conclusions: <p>Modulation of MEK/ERK-dependent Bim and Mcl-1 degradation critically mediates sensitivity and resistance of EGFR-mutant NSCLC cells to AZD9291 and hence is an effective strategy to overcome acquired resistance to AZD9291.

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Tumor Treating Fields: A Fourth Modality in Cancer Treatment

Despite major advances in therapy, cancer continues to be a leading cause of mortality. Additionally, toxicities of traditional therapies pose a significant challenge to tolerability and adherence. TTFields, a noninvasive anticancer treatment modality, utilizes alternating electric fields at specific frequencies and intensities to selectively disrupt mitosis in cancerous cells. TTFields target proteins crucial to the cell cycle, leading to mitotic arrest and apoptosis. TTFields also facilitate an antitumor immune response. Clinical trials of TTFields have proven safe and efficacious in patients with GBM, and are FDA-approved for use in newly-diagnosed and recurrent GBM. Trials in other localized solid tumors are ongoing.

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Association between MPO-463G > A polymorphism and cancer risk: evidence from 60 case-control studies

Abstract

Background

Though a number of studies have been conducted to explore the association between myeloperoxidase (MPO)-463G > A polymorphism and cancer risk, the results remain inconsistent. Therefore, we performed a meta-analysis to derive a more systematic estimation of this relationship.

Method

Relevant studies were searched by PubMed, EMBASE, CNKI, Google Scholar, Ovid, and Cochrane library prior to December 2015. The strength of the association between MPO-463G > A polymorphism and cancer risk was estimated by odds ratios (OR) with 95% confidence interval (95%CI). Cumulative analysis was used to evaluate the stability of results through time.

Results

The current analysis consisted of 16,858 cases and 21,756 controls from 60 studies. Pooled results showed that MPO-463G > A polymorphism were associated with the overall decreased cancer susceptibility in all the genetic models included in this study (additive model: OR = 0.84, 95%CI = 0.76–0.94; allele genetic model: OR = 0.90, 95%CI = 0.840–0.954; recessive genetic model: OR = 0.89, 95%CI = 0.83–0.95). However, in the stratified analysis of cancer type, the significant results were only found in lung cancer (dominant model: OR = 0.93, 95%CI = 0.87–0.99) and digestive system cancer groups (dominant model: OR = 0.67 0.53–0.84; allele frequency model = 0.71, 95%CI = 0.57–0.87), but not in the blood system cancer or breast cancer group. When we further stratified the digestive system cancer group into digestive tract and digestive gland cancer groups, results showed a significant association between allele A of MPO-463G > A and digestive gland cancer in all the genetic models (allele frequency model: OR = 0.63, 95%CI = 0.40–0.99; additive model: OR = 0.41, 95%CI = 0.23–0.73; recessive model: OR = 0.51, 95%CI = 0.29–0.89; dominant model: OR = 0.58, 95%CI = 0.35–0.96), digestive tract cancers in allele frequency model (OR = 0.75, 95%CI = 0.59–0.95), and dominant model (OR = 0.72, 95%CI = 0.56–0.92). When stratified by ethnicity, results demonstrated that the genotype A might be a protect factor for both Caucasians and Asians. In group analysis according to source of controls, significant results were found in population from hospital in all the genetic models. In cumulative analysis, result of allele contrast showed a declining trend and increasingly narrower 95% overall, while the inclination toward non-significant association with lung cancer risk.

Conclusions

This meta-analysis suggested that MPO-463G > A polymorphism was associated with the overall reduced cancer susceptibility significantly. It might be a more reliable predictor of digestive system cancer instead of lung cancer, blood system cancer, and breast cancer. In cumulative analysis, the stable trend indicated that evidence was sufficient to show the association between MPO-463G > A polymorphism and cancer risk.

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Comparison of marginal bone loss and implant success between axial and tilted implants in maxillary All-on-4 treatment concept rehabilitations after 5 years of follow-up

Abstract

Background

There is need for more scientific and clinical information on longer-term outcomes of tilted implants compared to implants inserted in an axial position.

Purpose

Comparison of marginal bone loss and implant success after a 5-year follow-up between axial and tilted implants inserted for full-arch maxillary rehabilitation.

Material and Methods

The retrospective clinical study included 891 patients with 3564 maxillary implants rehabilitated according to the All-on-4 treatment concept. The follow-up time was 5 years. Linear mixed-effect models were performed to analyze the influence of implant orientation (axial/tilted) on marginal bone loss and binary logistic regression to assess the effect of patient characteristics on occurrence of marginal bone loss >2.8 mm. Only those patients with measurements of at least one axial and one tilted implant available were analyzed. This resulted in a data set of 2379 implants (1201 axial, 1178 tilted) in 626 patients (=reduced data set).

Results

Axial and tilted implants showed comparable mean marginal bone losses of 1.14 ± 0.71 and 1.19 ± 0.82 mm, respectively. Mixed model analysis indicated that marginal bone loss levels at 5 years follow up was not significantly affected by the orientation (axial/tilted) of the implants in the maxillary bone. Smoking and female gender were associated with marginal bone loss >2.8 mm in a logistic regression analysis. Five-year implant success rates were 96%. The occurrence of implant failure showed to be statistically independent from orientation.

Conclusions

Within the limitations of this study and considering a follow-up time of 5 years, it can be concluded that tilted implants behave similarly with regards to marginal bone loss and implant success in comparison to axial implants in full-arch rehabilitation of the maxilla. Longer-term outcomes (10 years +) are needed to verify this result.

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Association of calcium sensing receptor polymorphisms at rs1801725 with circulating calcium in breast cancer patients

Abstract

Background

Breast cancer (BC) patients with late-stage and/or rapidly growing tumors are prone to develop high serum calcium levels which have been shown to be associated with larger and aggressive breast tumors in post and premenopausal women respectively. Given the pivotal role of the calcium sensing receptor (CaSR) in calcium homeostasis, we evaluated whether polymorphisms of the CASR gene at rs1801725 and rs1801726 SNPs in exon 7, are associated with circulating calcium levels in African American and Caucasian control subjects and BC cases.

Methods

In this retrospective case-control study, we assessed the mean circulating calcium levels, the distribution of two inactivating CaSR SNPs at rs1801725 and rs1801726 in 199 cases and 384 age-matched controls, and used multivariable regression analysis to determine whether these SNPs are associated with circulating calcium in control subjects and BC cases.

Results

We found that the mean circulating calcium levels in African American subjects were higher than those in Caucasian subjects (p < 0.001). As expected, the mean calcium levels were higher in BC cases compared to control subjects (p < 0.001), but the calcium levels in BC patients were independent of race. We also show that in BC cases and control subjects, the major alleles at rs1801725 (G/T, A986S) and at rs1801726 (C/G, Q1011E) were common among Caucasians and African Americans respectively. Compared to the wild type alleles, polymorphisms at the rs1801725 SNP were associated with higher calcium levels (p = 0.006) while those at rs1801726 were not. Using multivariable linear mixed-effects models and adjusting for age and race, we show that circulating calcium levels in BC cases were associated with tumor grade (p = 0.009), clinical stage (p = 0.003) and more importantly, with inactivating mutations of the CASR at the rs1801725 SNP (p = 0.038).

Conclusions

These data suggest that decreased sensitivity of the CaSR to calcium due to inactivating polymorphisms at rs1801725, may predispose up to 20% of BC cases to high circulating calcium-associated larger and/or aggressive breast tumors.

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Betamethasone gel compared with lidocaine jelly to reduce tracheal tube related postoperative airway symptoms: a randomized controlled trial

Post-operative airway symptoms can be troublesome to patients following an uneventful general anesthesia with endotracheal intubation. In this study, we compared the effectiveness of lubricating an endotrachea...

http://ift.tt/2uhVksA

Does weight lifting improve visual acuity? A replication of Gonzalo-Fonrodona and Porras (2013)

A physical effort such as lifting up a weight affects our perception and cognition. A previous study reported in two experiments that weight lifting improves visual acuity. In the previous study, participants'...

http://ift.tt/2u2tqFH

The in vitro effects of interferon-gamma, alone or in combination with amphotericin B, tested against the pathogenic fungi Candida albicans and Aspergillus fumigatus

Recent studies into the antifungal activity of NK-cells against the Aspergillus fumigatus have presented differing accounts on their mode of antifungal activity. One of these mechanisms proposed that NK-cells may...

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Magnitude and associated factors of anemia among pregnant women in Dera District: a cross-sectional study in northwest Ethiopia

Anemia is associated with adverse health and socio-economic consequences among pregnant women. Particularly, severe anemia increases the risk of maternal mortality by 20%. However, literatures are scarce in th...

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Effects of date palm pollen on fertility: research proposal for a systematic review

Over 10–15% of couples in different countries are infertile. Male infertility is a contributing factor and the only cause of infertility in respectively 50% and 20–30% of all cases of infertility. According to...

http://ift.tt/2uirMuH

Gemcitabine-induced TIMP1 attenuates therapy response and promotes tumor growth and liver metastasis in pancreatic cancer

Gemcitabine constitutes one of the backbones for chemotherapy treatment in pancreatic ductal adenocarcinoma (PDAC), but patients often respond poorly to this agent. Molecular markers downstream of gemcitabine treatment in pre-clinical models may provide an insight into resistance mechanisms. Using cytokine arrays, we identified potential secretory biomarkers of gemcitabine resistance (response) in the transgenic KRasG12D; Trp53R172H; Pdx-1 Cre (KPC) mouse model of PDAC. We verified the oncogenic role of the cytokine tissue inhibitor of matrix metalloproteinases 1 (TIMP1) in primary pancreatic tumors and metastases using both in vitro techniques and animal models. We identified potential pathways affected downstream of TIMP1 using the Illumina Human H12 array. Our findings were validated in both primary and metastatic models of pancreatic cancer. Gemcitabine increased inflammatory cytokines including TIMP1 in the KPC mouse model. TIMP1 was upregulated in patients with pancreatic intraepithelial neoplasias grade 3 and PDAC lesions relative to matched normal pancreatic tissue. Additionally, TIMP1 played a role in tumor clonogenic survival and vascular density, while TIMP1 inhibition resensitized tumors to gemcitabine and radiotherapy. We observed a linear relationship between TIMP-1 expression, liver metastatic burden, and infiltration by CD11b+Gr1+ myeloid cells and CD4+CD25+FOXP3+ Tregs, whereas the presence of tumor cells was required for immune cell infiltration. Overall, our results identify TIMP1 upregulation as a resistance mechanism to gemcitabine and provide a rationale for combining chemo/radiotherapy with TIMP1 inhibitors in PDAC.

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Mitochondrial superoxide increases age-associated susceptibility of human dermal fibroblasts to radiation and chemotherapy

Elderly cancer patients treated with ionizing radiation (IR) or chemotherapy experience more frequent and greater normal tissue toxicity relative to younger patients. The current study demonstrates that exponentially growing fibroblasts from elderly (old) male donor subjects (70, 72, 78 years) are significantly more sensitive to clonogenic killing mediated by platinum-based chemotherapy and IR, (~70-80% killing) relative to young fibroblasts (5 months and 1 year; ~10-20% killing) and adult fibroblasts (20 years old; ~10-30% killing). Old fibroblasts also displayed significantly increased (2-4 fold) steady-state levels of O2·-, O2 consumption, and mitochondrial membrane potential as well as significantly decreased (40-50%) electron transport chain (ETC) complex I, II, IV, V, and aconitase (70%) activities, decreased ATP levels, and significantly altered mitochondrial structure. Following adenoviral-mediated overexpression of SOD2 activity (5-7 fold), mitochondrial ETC activity and aconitase activity were restored, demonstrating a role for mitochondrial O2·- in these effects. Old fibroblasts also demonstrated elevated levels of endogenous DNA damage that were increased following treatment with IR and chemotherapy. Most importantly, treatment with the small-molecule, superoxide dismutase (SOD) mimetic (GC4419; 0.25 µM), significantly mitigated the increased sensitivity of old fibroblasts to IR and chemotherapy and partially restored mitochondrial function without affecting IR or chemotherapy-induced cancer cell killing. These results support the hypothesis that age-associated increased O2·- and resulting DNA damage mediate the increased susceptibility of old fibroblasts to IR and chemotherapy and can be mitigated by GC4419.

http://ift.tt/2vru0wK

Invasive anisakiasis by the parasite Anisakis pegreffii (Nematoda: Anisakidae): diagnosis by real-time PCR hydrolysis probe system and immunoblotting assay

Anisakiasis is a fish-borne zoonosis caused by Anisakis spp. larvae. One challenging issue in the diagnosis of anisakiasis is the molecular detection of the etiological agent even at very low quantity, such as in...

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A case report of co-infection of Melioidosis and cutaneous Leishmaniasis

Leishmaniasis and melioidosis are frequently reported from the North Central Province of Sri Lanka. However, only one case of co-infection of the two diseases has been reported to date over the world. This is ...

http://ift.tt/2vr3svG

Hepatic iron overload is associated with hepatocyte apoptosis during Clonorchis sinensis infection

Hepatic iron overload has been implicated in many liver diseases; however, whether it is involved in clonorchiasis remains unknown. The purpose of this study is to investigate whether Clonorchis sinensis (C. sine...

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A case report: primary amoebic meningoencephalitis in a young Zambian adult

Primary amoebic meningoencephalitis (PAM) is a fulminant disease of the brain caused by Naegleria fowleri. Although the disease is rare, the case fatality rate is very high. In this report, we describe the first ...

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HIV testing week 2015: lowering barriers for HIV testing among high-risk groups in Amsterdam

Evaluation of the HIV Testing Week (HTW) 2015 in Amsterdam: the number of (positive) tested persons, characteristics and testing history of the tested population, the differences in attendance per location and...

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Issue Information

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Clinical Outcomes in pT4 Tongue Carcinoma are Worse Than in pT3 Disease: How Extrinsic Muscle Invasion Should be Considered?

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Clinical Outcomes in pT4 Tongue Carcinoma are Worse than in pT3 Disease: How Extrinsic Muscle Invasion Should be Considered?

Abstract

Background

The identification of extrinsic tongue muscle invasion in oral cavity cancer remains challenging. Notably, the most recent American Joint Committee on Cancer (AJCC 2017, 8th edition) staging manual indicates that extrinsic muscle invasion does not lead to the diagnosis of a T4 tumor. Because this approach carries the risk of tumor downstaging, we compared the clinical outcomes of patients with oral tongue squamous cell carcinoma (SCC) staged as pT3 vs. pT4 according to the AJCC 2010, 7th edition criteria.

Methods

We retrospectively examined the records of consecutive patients with pT3 (n = 135) and pT4 (n = 68) tongue SCC who underwent radical surgery. Of the 68 pT4 tongue SCC, 63 (93%) had extrinsic muscle involvement alone. The 5-year locoregional control (LRC), distant metastasis (DM), and disease-free survival (DFS) rates served as outcome measures.

Results

Compared with pT3 tongue SCC, pT4 patients presented significantly more frequently with pN2 disease, extranodal extension, poor tumor differentiation, tumor depth >15 and >20 mm, margin status ≤4 mm, perineural invasion, vascular invasion, and were more frequently treated with surgery plus concurrent chemoradiotherapy. Less favorable 5-year outcomes were observed in patients with pT4 than pT3 tumors (LRC 50 vs. 75%, p < 0.001; DM 27 vs. 14%, p = 0.013; DFS 43 vs. 69%, respectively, p < 0.001). We identified pT4 disease (vs. pT3) as an independent adverse prognostic factor for LRC and DFS.

Conclusions

We suggest classifying patients with tongue SCC and extrinsic muscle invasion as having pT4 disease.

http://ift.tt/2vripOv

Impact of Bilateral Prophylactic Mastectomy and Immediate Reconstruction on Health-Related Quality of Life in Women at High Risk for Breast Carcinoma: Results of the Mastectomy Reconstruction Outcomes Consortium Study

Abstract

Background

Although bilateral prophylactic mastectomy (BPM) can reduce the risk of breast cancer, the decision to proceed surgically can have significant consequences and requires careful deliberation. To facilitate decision making for women at high risk for breast carcinoma, the risks and benefits of BPM should be well-elucidated. We sought to determine the effects of BPM and immediate reconstruction on health-related quality-of-life outcomes among a multisite cohort of women at high risk for breast carcinoma.

Methods

Patient-reported outcome data were prospectively collected as part of the Mastectomy Reconstruction Outcomes Consortium Study, and data on a subgroup of 204 high-risk women who elected to have BPM and immediate reconstruction were evaluated. Baseline scores were compared with scores at 1 or 2 years after reconstruction.

Results

Satisfaction with breasts and psychosocial well-being were significantly higher at both 1 and 2 years (p < 0.01); however, anxiety was significantly lower at 1 or 2 years (p < 0.01) and physical well-being of the chest and upper body was significantly worse at 1 year (p < 0.01).

Conclusion

Our results highlight the impact of BPM and immediate reconstruction on health-related quality-of-life outcomes in this setting. BPM and reconstruction can result in significant, positive, lasting changes in a woman's satisfaction with her breasts, as well as her psychosocial well-being. Furthermore, presurgery anxiety was significantly reduced by 1 year post-reconstruction and remained reduced at 2 years. With this knowledge, women at high risk for breast carcinoma, and their providers, will be better equipped to make the best individualized treatment decisions.

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Radical Lymph Node Dissection Along the Proximal Splenic Artery During Laparoscopic Gastrectomy for Gastric Cancer Using the Left Lateral Approach

Abstract

Background

Recent technical improvements allow safe laparoscopic lymph node dissection (LND) in gastric cancer.1 ^,2 In suprapancreatic LND, careful LND around the celiac artery (CA) is essential. From a patient's right side, deep LND is performed around the right side of the CA after dissecting around the common hepatic artery (CHA). For LND around the left side of the CA on the same operative axis as the right side, we developed a new procedure for LND along the proximal splenic artery (SA), performed from the patient's left side.

Methods

After LND around the CHA and right side of the CA from the patient's right side, the surgeon then moves to the patient's left side. The anterior pancreatic fascia is cut at the middle point of the SA to discern the dorsal layer of the LN along the SA, such as the splenic vein. LND is performed by preserving the posterior pancreatic fascia around the SA in a left-to-right direction. Finally, the LNs around the left side of the CA are deeply dissected.

Results

We performed this procedure on ten patients between April 2016 and January 2017; no operative complications were reported in grade II or higher cancer patients.3 After exposing the dorsal landmark, LNs around the proximal SA and left side of the CA were removed in all patients.

Conclusion

This procedure enables early identification of the dorsal layer and deep LND around the left side of the CA, keeping this layer. The left lateral approach is useful for radical LND along the proximal SA.

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Pertuzumab/Trastuzumab/CT Versus Trastuzumab/CT Therapy for HER2+ Breast Cancer: Results from the Prospective Neoadjuvant Breast Registry Symphony Trial (NBRST)

Abstract

Background

Pertuzumab became a standard part of neoadjuvant therapy for human epidermal growth factor receptor 2-positive (HER2+) breast cancers approximately halfway through Neoadjuvant Breast Registry Symphony Trial (NBRST) enrollment, providing a unique opportunity to determine biologically which clinical HER2+ patients benefit most from dual targeting. As a neoadjuvant phase 4 study, NBRST classifies patients by both conventional and molecular subtyping.

Methods

Of 308 clinical HER2+ patients enrolled in NBRST between 2011 and 2014 from 62 U.S. institutions, 297 received neoadjuvant chemotherapy (NCT) with HER2-targeted therapy and underwent surgery. This study compared the pathologic complete response (pCR) rate of BluePrint versus clinical subtypes with treatment, specifically differences between trastuzumab (T) treatment and trastuzumab and pertuzumab (T/P) treatment.

Results

In this study, 60% of the patients received NCT-T, and 40% received NCT-T/P. The overall pCR rate (ypT0/isN0) was 47%. BluePrint classified 161 tumors (54%) as HER2 type, with a pCR rate of 65%. This was significantly higher than the pCR rate for the 91 HER2+ tumors (31%) classified as luminal (18%) (p = 0.00001) and the 45 tumors (15%) classified as basal (44%) (p = 0.0166). The patients treated with T/P had higher pCR rates than those treated with trastuzumab alone. The difference was most pronounced in the BluePrint luminal patients (8 vs. 31%). The highest pCR was reached by the BluePrint HER2-type patients treated with T/P (76%).

Conclusions

The addition of pertuzumab leads to increased pCR rates for all HER2+ patient groups except for the BluePrint basal-type patients. This better response was most pronounced for the BluePrint luminal-type patients.

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Time to Initiation of Adjuvant Chemotherapy in Pancreas Cancer: A Multi-Institutional Experience

Abstract

Background

Despite randomized trials addressing adjuvant therapy (AT) for pancreas cancer, the ideal time to initiate therapy remains undefined. Retrospective analyses of the ESPAC-3 trial demonstrated that time to initiation of AT did not impact overall survival (OS). Given the absence of confirmatory data outside of a clinical trial, we sought to determine if AT timing in routine clinical practice is associated with OS differences.

Methods

Perioperative data of pancreatectomies for ductal adenocarcinoma from five institutions (2005–2015) were assessed. Delay in AT was defined as initiation >12 weeks after surgery. Multivariate analysis was performed to identify predictors of mortality.

Results

Of 867 patients, 172 (19.8%) experienced omission of AT. Improved OS was observed in patients who received AT compared with patients who did not (24.8 vs. 19.1 months, p < 0.01). Information on time to initiation of AT was available in 488 patients, of whom 407 (83.4%) and 81 (16.6%) received chemotherapy ≤12 and >12 weeks after surgery, respectively. There were no differences in recurrence-free survival or OS (all p > 0.05) between the timely and delayed AT groups. After controlling for perioperative characteristics and tumor pathology, patients who initiated AT ≤ 12 or > 12 weeks after surgery had a 50% lower odds of mortality than patients who only underwent resection (p < 0.01).

Conclusions

In a multi-institutional experience of resected pancreas cancer, delayed initiation of AT was not associated with poorer survival. Patients who do not receive AT within 12 weeks after surgery are still appropriate candidates for multimodal therapy and its associated survival benefit.

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Sentinel Lymph Node Biopsy for Recurrent Melanoma: A Multicenter Study

Abstract

Background

Sentinel lymph node biopsy (SLNB) is routinely performed for primary cutaneous melanomas; however, limited data exist for SLNB after locally recurrent (LR) or in-transit (IT) melanoma.

Methods

Data from three centers performing SLNB for LR/IT melanoma (1997 to the present) were reviewed, with the aim of assessing (1) success rate; (2) SLNB positivity; and (3) prognostic value of SLNB in this population.

Results

The study cohort included 107 patients. Management of the primary melanoma included prior SLNB for 56 patients (52%), of whom 10 (18%) were positive and 12 had complete lymph node dissections (CLNDs). In the present study, SLNB was performed for IT disease (48/107, 45%) or LR melanoma (59/107, 55%). A sentinel lymph node (SLN) was removed in 96% (103/107) of cases. Nodes were not removed for four patients due to lymphoscintigraphy failures (2) or nodes not found during surgery (2). SLNB was positive in 41 patients (40%, 95% confidence interval (CI) 31.5–50.5), of whom 35 (88%) had CLND, with 13 (37%) having positive nonsentinel nodes. Median time to disease progression after LR/IT metastasis was 1.4 years (95% CI 0.75–2.0) for patients with a positive SLNB, and 5.9 years (95% CI 1.7–10.2) in SLNB-negative patients (p = 0.18). There was a trend towards improved overall survival for patients with a negative SLNB (p = 0.06).

Conclusion

SLNB can be successful in patients with LR/IT melanoma, even if prior SLNB was performed. In this population, the rates of SLNB positivity and nonsentinel node metastases were 40% and 37%, respectively. SLNB may guide management and prognosis after LR/IT disease.

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Cosmetic Outcome and Chronic Breast Toxicity After Intraoperative Radiation Therapy (IORT) as a Single Modality or as a Boost Using the Intrabeam ® Device: A Prospective Study

Abstract

Purpose

We aim to report our results in terms of chronic toxicities and cosmetic outcomes after intraoperative radiotherapy (IORT) using kV X-rays in women treated for early breast cancer at our institution.

Methods

Patients with early breast carcinoma were recruited between April 2011 and November 2014. After breast-conserving surgery, patients were treated with IORT using the Intrabeam^® device. IORT was completed by whole-breast radiotherapy (WBRT) at a dose of 46–50.4 Gy in 23–28 fractions in case of adverse pathologic criteria on the final specimen examination. Skin toxicity was graded using the Late Effects in Normal Tissues—Subjective, Objective, Management and Analytic (LENT-SOMA) scale every 6 months, and cosmetic outcomes were evaluated at 36 months by patient self-evaluation and by two radiation oncologists, on a 1–10 scale.

Results

Forty-one women received IORT only and 30 patients received IORT followed by WBRT (IORT + WBRT group). After a median follow-up of 38.9 months, no locoregional or distant recurrence occurred. After IORT only, 2.4% of grade 2 or higher breast fibrosis, and no other grade 2 or higher disease, was observed. In the IORT + WBRT group, grade 2 or higher fibrosis and grade 2 or higher breast retraction were observed in 43.3 and 23.3% of patients, respectively. Objective cosmetic outcomes were very good and significantly better in the IORT-only group compared with the IORT + WBRT group (8.87 vs. 6.96) (p < 0.001).

Conclusion

IORT using the Intrabeam^® is well-tolerated, with very little chronic toxicity and good cosmetic outcome. However, a high rate of grade 2 or higher chronic breast toxicity was observed when IORT had to be completed by WBRT.

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The Impact of Residual Disease After Preoperative Systemic Therapy on Clinical Outcomes in Patients with Inflammatory Breast Cancer

Abstract

Background

Inflammatory breast cancer (IBC) is a rare and aggressive disease treated with multimodality therapy: preoperative systemic therapy (PST) followed by modified radical mastectomy (MRM), chest wall and regional nodal radiotherapy, and adjuvant biologic therapy and/or endocrine therapy when appropriate. In non-IBC, the degree of pathologic response to PST has been shown to correlate with time to recurrence (TTR) and overall survival (OS). We sought to determine if pathologic response correlates with oncologic outcomes of IBC patients.

Methods

Following review of IBC patients' records (1997–2014), we identified 258 stage III IBC patients; 181 received PST followed by MRM and radiotherapy and were subsequently analyzed. Pathologic complete response (pCR) to PST, hormone receptor and human epidermal growth factor receptor 2 (HER2) status, grade, and histology were evaluated as predictors of TTR and OS by Cox model.

Results

Overall, 95/181 (52%) patients experienced recurrence; 93/95 (98%) were distant metastases (median TTR 3.2 years). Seventy-three patients (40%) died (median OS 6.9 years). pCR was associated with improved TTR (hazard ratio [HR] 0.20, 95% confidence interval [CI] 0.09–0.46, p < 0.01, univariate; HR 0.17, 95% CI 0.07–0.41, p < 0.0001, multivariate) and improved OS (HR 0.26, 95% CI 0.11–0.65, p < 0.01, univariate). In patients with pCR, grade III (HR 1.91, 95% CI 1.16–3.13, p = 0.01), and triple-negative phenotype (HR 3.54, 95% CI 1.79–6.98, p = 0.0003) were associated with shorter TTR, while residual ductal carcinoma in situ was not (HR 0.85, 95% CI 0.53–1.35, p = 0.48, multivariate).

Conclusions

In stage III IBC, pCR was associated with prognosis, further influenced by grade, hormone receptor, and HER2 status. Investigating mechanisms that contribute to better response to PST could help improve oncologic outcomes in IBC.

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Analysis of Perioperative Chemotherapy in Resected Pancreatic Cancer: Identifying the Number and Sequence of Chemotherapy Cycles Needed to Optimize Survival

Abstract

Purpose

Receipt of 6 cycles of adjuvant chemotherapy (AC) is standard of care in pancreatic cancer (PC). Neoadjuvant chemotherapy (NAC) is increasingly utilized; however, optimal number of cycles needed alone or in combination with AC remains unknown. We sought to determine the optimal number and sequence of perioperative chemotherapy cycles in PC.

Methods

Single institutional review of all resected PCs from 2008 to 2015. The impact of cumulative number of chemotherapy cycles received (0, 1–5, and ≥6 cycles) and their sequence (NAC, AC, or NAC + AC) on overall survival was evaluated Cox-proportional hazard modeling, using 6 cycles of AC as reference.

Results

A total of 522 patients were analyzed. Based on sample size distribution, four combinations were evaluated: 0 cycles = 12.1%, 1–5 cycles of combined NAC + AC = 29%, 6 cycles of AC = 25%, and ≥6 cycles of combined NAC + AC = 34%, with corresponding survival. 13.1, 18.5, 37, and 36.8 months. On MVA (P < 0.0001), tumor stage [hazard ratio (HR) 1.35], LNR (HR 4.3), and R1 margins (HR 1.77) were associated with increased hazard of death. Compared with 6 cycles AC, receipt of 0 cycles [HR 3.57, confidence interval (CI) 2.47–5.18] or 1–5 cycles in any combination (HR 2.37, CI 1.73–3.23) was associated with increased hazard of death, whereas receipt of ≥6 cycles in any sequence was associated with optimal and comparable survival (HR 1.07, CI 0.78–1.47).

Conclusions

Receipt of 6 or more perioperative cycles of chemotherapy either as combined neoadjuvant and adjuvant or adjuvant alone may be associated with optimal and comparable survival in resected PC.

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Immaturity of Bile Canalicular–Ductule Networks in the Future Liver Remnant While Associating Liver Partition and Portal Vein Occlusion for Staged Hepatectomy (ALPPS)

Abstract

Background

We studied histologic changes of bile canalicular–ductule networks in the future liver remnant (FLR) while associating liver partition and portal vein occlusion for staged hepatectomy (ALPPS), since little is known about regeneration of these networks during the relatively short interval between procedures in ALPPS.

Methods

Bile canalicular–ductule networks were examined in specimens from eight patients treated with ALPPS and six patients undergoing hepatectomy following portal vein embolization (PVE). Expression of multidrug resistance-1 (MDR1), a membrane transporter in bile canaliculi (BC), was analyzed immunohistochemistcally. Morphologic changes of BC and tight junctions (TJs) adjoining BC were also assessed electron microscopically.

Results

Extrapolated kinetic growth of the FLR was greater during ALPPS (17.2 ± 6.8 mL/day) than after PVE (6.3 ± 3.4 mL/day; p = 0.005), and continuity of the MDR1-positive bile canalicular networks was less evident in ALPPS than PVE (p < 0.001). Electron microscopically, no significant difference was evident in numbers of BC or BC lumen size between the two groups; however, development of microvilli in BC was poorer in the ALPPS group than in the PVE group (p < 0.001). TJ/desmosome complexes were shorter in the ALPPS group (0.69 ± 0.52 μm) than in the PVE group (1.09 ± 0.50 μm; p < 0.001), and leaky TJs were seen more frequently in the ALPPS group (64.9 vs. 23.6%; p = 0.001).

Conclusions

Regeneration of bile canalicular–ductule networks in the FLR was poorer in ALPPS than PVE, which may be associated with prolonged cholestasis following final hepatectomy in ALPPS.

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Standard Pathologic Features Can Be Used to Identify a Subset of Estrogen Receptor-Positive, HER2 Negative Patients Likely to Benefit from Neoadjuvant Chemotherapy

Abstract

Background

The benefit of neoadjuvant chemotherapy (NAC) in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancers and in invasive lobular carcinoma (ILC) is uncertain due to the low rates of pathologic complete response (pCR).

Objective

The aim of this study was to determine if pathologic features can identify subsets likely to benefit from NAC.

Methods

Patients with stage I–III ER+, HER2− breast cancer receiving NAC were retrospectively reviewed. Endpoints were downstaging to breast-conserving surgery (BCS) and nodal pCR after NAC. Patients were grouped by progesterone receptor (PR) status and grade/differentiation (high grade or poor [HP] vs. non-HP).

Results

From 2007 to 2016, 402 ER+/HER2− cancers in patients receiving NAC were identified. Median age was 50 years, 98% were clinical stage II–III, and 75% were cN+. Overall pCR rate was 5%; breast pCR in 7% and nodal pCR in 15% of cN+ patients (p < 0.0001). Patients with ILC initially ineligible for BCS (n = 56) were less likely to downstage than those with invasive ductal carcinoma (IDC; n = 183, 16 vs. 48%, p ≤ 0.0001), with a similar trend in the axilla (p = 0.086). The rates of BCS eligibility after NAC were highest in PR−/HP patients (62%) and lowest in PR+/non-HP patients (29%) [p = 0.005]. In the axilla, nodal pCR among cN+ patients (n = 301) ranged from 0 to 35% (p < 0.0001) within these groups, and was most frequent in PR−/HP patients.

Conclusions

ER+/HER2− patients most likely to benefit from NAC are those with PR− and HP tumors. Patients with ILC are unlikely to downstage in the breast or axilla compared with IDC. The use of these criteria can assist in defining the initial treatment approach.

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Clinicopathological Determinants of an Elevated Systemic Inflammatory Response Following Elective Potentially Curative Resection for Colorectal Cancer

Abstract

Introduction

The postoperative systemic inflammatory response (SIR) is related to both long- and short-term outcomes following surgery for colorectal cancer. However, it is not clear which clinicopathological factors are associated with the magnitude of the postoperative SIR. The present study was designed to determine the clinicopathological determinants of the postoperative systemic inflammatory response following colorectal cancer resection.

Methods

Patients with a histologically proven diagnosis of colorectal cancer who underwent elective, potentially curative resection during a period from 1999 to 2013 were included in the study (n = 752). Clinicopathological data and the postoperative SIR, as evidenced by postoperative Glasgow Prognostic Score (poGPS), were recorded in a prospectively maintained database.

Results

The majority of patients were aged 65 years or older, male, were overweight or obese, and had an open resection. After adjustment for year of operation, a high day 3 poGPS was independently associated with American Society of Anesthesiologists (ASA) grade (hazard ratio [HR] 1.96; confidence interval [CI] 1.25–3.09; p = 0.003), body mass index (BMI) (HR 1.60; CI 1.07–2.38; p = 0.001), mGPS (HR 2.03; CI 1.35–3.03; p = 0.001), and tumour site (HR 2.99; CI 1.56–5.71; p < 0.001). After adjustment for year of operation, a high day 4 poGPS was independently associated with ASA grade (HR 1.65; CI 1.06–2.57; p = 0.028), mGPS (HR 1.81; CI 1.22–2.68; p = 0.003), NLR (HR 0.50; CI 0.26–0.95; p = 0.034), and tumour site (HR 2.90; CI 1.49–5.65; p = 0.002).

Conclusions

ASA grade, BMI, mGPS, and tumour site were consistently associated with the magnitude of the postoperative systemic inflammatory response, evidenced by a high poGPS on days 3 and 4, in patients undergoing elective potentially curative resection for colorectal cancer.

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Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Moderately and Poorly Differentiated Appendiceal Adenocarcinoma: Survival Outcomes and Patient Selection

Abstract

Background

Moderately and poorly differentiated adenocarcinoma of the appendix represents an aggressive histological variant with a high risk of recurrence and death.

Methods

Overall, 178 patients with moderately and poorly differentiated appendiceal adenocarcinoma were identified from a prospective database. Clinical, pathologic, and treatment factors were analyzed for outcomes.

Results

Diagnostic laparoscopy (DL) identified radiographic occult peritoneal metastasis in 25 (42%) patients. These patients had a significantly lower peritoneal carcinomatosis index (PCI) and improved overall survival (OS) compared with those with radiographic disease. Twenty-seven (41%) patients were excluded from cytoreductive surgery (CRS) because of findings on DL, while 116 (65%) patients underwent CRS and hyperthermic intraperitoneal chemotherapy (HIPEC), with a median disease-free survival (DFS) of 23 months. Mucinous histology (hazard ratio [HR] 0.52, p = 0.04) and PCI (HR 1.054, p = 0.02) were independent predictors of DFS. The median OS following CRS and HIPEC was 48 months. Mucinous histology (HR 0.352, p = 0.018), signet ring cells (HR 3.34, p = 0.02), positive peritoneal cytology (HR 0.081, p = 0.04), and PCI (HR 1.076, p = 0.004) were independently associated with OS. Eight-five (73.3%) patients received neoadjuvant chemotherapy, and 40 (47.1%) patients achieved a radiographic response; 36 (42.3%) had stable disease, while 9 (10.6%) had progressive disease. Stable or responsive disease was associated with improved median OS of 44 months, compared with 21 months for those with progressive disease (p = 0.011).

Conclusions

In selected patients, long-term survival can be obtained. Mucinous histology, absence of signet ring cells, negative peritoneal cytology, PCI ≤ 20, and response/stable disease after neoadjuvant chemotherapy are important selection criteria for CRS and HIPEC.

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Oncologic Outcome of Metastasectomy for Urothelial Carcinoma: Who Is the Best Candidate?

Abstract

Background

Resection of metastatic lesions (metastasectomy) is performed for highly selected patients with metastatic urothelial carcinoma (mUC). This study aimed to identify the clinicopathologic factors associated with oncologic outcome for patients who underwent metastasectomy for mUC.

Methods

This analysis included 37 UC patients who underwent metastasectomy with curative intent at nine Japanese hospitals. The primary end point was cancer-specific survival. The Kaplan–Meier method with the log-rank test and the multivariable Cox proportional hazards model addressed the relationship between clinical characteristics and survival.

Results

Metastasectomy was performed for pulmonary (n = 23), nodal (n = 7), and other (n = 7) metastases. The median survival time was 35.4 months (interquartile range [IQR] 15.5, not reached) from the detection of metastasis and 34.3 months (IQR 13.1, not reached) from metastasectomy. The 5-year cancer-specific survival rate after detection of metastasis was 39.7%. In the multivariate analysis, the time from primary surgery to detection of metastasis (time-to-recurrence [TTR]) of 15 months or longer (hazard ratio [HR] 0.23; p = 0.0063), no symptoms of recurrence (HR 0.23; p = 0.0126), and serum C-reactive protein (CRP) levels lower than than 0.5 mg/dl (HR 0.24; p = 0.0052) were significantly associated with better survival.

Conclusions

Long-term survival could be achieved for some patients with mUC who underwent metastasectomy. Lung and lymph nodes were predominant sites for metastasectomy. Symptoms, TTR, and CRP value were identified as associated with survival and should be taken into account when metastasectomy is considered.

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Patterns of Initial Recurrence in Gastric Adenocarcinoma in the Era of Preoperative Therapy

Abstract

Background

We sought to determine the sites of recurrence and identify predicting factors for recurrence and survival in patients who underwent gastrectomy for adenocarcinoma at an institution where preoperative therapy is commonly used for advanced gastric cancer.

Methods

We collected clinicopathologic data and sites of recurrence from a prospectively maintained database of patients who underwent potentially curative resection of gastric or gastroesophageal adenocarcinoma at our institution in 1995–2014, and we assessed associations between these characteristics and recurrence patterns and survival.

Results

We identified 488 patients who underwent R0 resection of localized gastric cancer. The median age was 63 years (interquartile range 53–71 years), and 60% were male. The most common T and N categories, per endoscopic ultrasonography, were T3 (58%) and N0 (61%). Preoperative treatment was used in 61% of patients. A total of 125 (26%) patients experienced recurrence during follow-up. Recurrences were locoregional in 19 patients (15%), peritoneal in 61 (49%), and nonperitoneal distant in 67 (54%). The peritoneum also was the most common organ of recurrence (49%), followed by the liver (21%). The median time from primary resection to recurrence was 2.7 years for locoregional, 1.3 years for peritoneal, and 0.6 years for nonperitoneal distant recurrence (p = 0.01). Median overall survival was markedly shorter after peritoneal and nonperitoneal distant recurrences than after locoregional recurrences.

Conclusions

The peritoneum was a common site of recurrence after curative resection of gastric cancer and was associated with poor survival. Prophylactic treatment targeting the peritoneal cavity might improve survival of advanced gastric cancer.

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Lack of Efficacy of Radioiodine Remnant Ablation for Papillary Thyroid Microcarcinoma: Verification Using Inverse Probability of Treatment Weighting

Abstract

Background

Most of the increase in thyroid cancer in recent decades has been due to papillary thyroid microcarcinoma (PTMC). We evaluated the efficacy of radioiodine remnant ablation (RRA) in patients with PTMC.

Methods

This historical cohort study included 1932 PTMC patients without lateral cervical lymph node (LN) or distant metastasis who underwent total thyroidectomy (TT) during the median 8.3 years of follow-up. The clinical outcomes of patients with or without RRA were compared using weighted logistic regression models with the inverse probability of treatment weighting (IPTW) method and considering risk factors, including age, sex, primary tumor size, extrathyroidal extension, multifocality, and central cervical LN metastasis.

Results

The median primary tumor size of the RRA group was significantly larger than that of the no-RRA group (0.7 vs. 0.5 cm, P < 0.001). There were significantly more patients with multifocality, extrathyroidal extension, and cervical LN metastasis in the RRA group compared with the no-RRA group. There was no significant difference in recurrence-free survival between the two groups (P = 0.11). Cox proportional–hazard analysis with IPTW by adjusting for clinicopathological risk factors demonstrated no significant difference in recurrence of PTMC according to RRA treatment (hazard ratio [HR] 2.02; 95% confidence interval [CI] 0.65–6.25; P = 0.2).

Conclusions

RRA had no therapeutic effect on the clinical outcomes of patients with PTMC who underwent TT. Surgical treatment without RRA could be applicable for patients with PTMC if there is no evidence of lateral cervical LN metastasis or distant metastasis.

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Expression of Programmed Cell Death Protein 1 by Tumor-Infiltrating Lymphocytes and Tumor Cells is Associated with Advanced Tumor Stage in Patients with Esophageal Adenocarcinoma

Abstract

Background

Despite recent advances in the therapy for adenocarcinoma of the esophagogastric junction (AEG), overall prognosis remains poor. Programmed cell death protein 1 (PD1) is a co-inhibitory receptor primarily expressed by T-cells. Tumor cells can escape anticancer immune responses by triggering the PD1 pathway. Moreover, PD1 receptor engagement on cancer cells may trigger tumor-intrinsic growth signals. This study aimed to evaluate the potential clinical relevance of PD1 expression by tumor-infiltrating lymphocytes (TILs) and cancer cells in the AEG.

Methods

Patients with AEG who underwent esophagectomy from 1992 to 2011 were included in the study. Expression of PD1was evaluated by immunohistochemistry and correlated with long-term overall survival (OS), disease-free survival (DFS), and various clinicopathologic parameters.

Results

Tumor biospecimens from 168 patients were analyzed. In the analysis, 81% of the patients showed high tumoral frequencies (>5%) of PD1-expressing TILs (TIL-PD1⁺), and 77% of patient tumors harbored high levels (>5%) of PD1⁺ cancer cells (cancer-PD1⁺). Expression of PD1 by TILs and cancer cells correlated significantly (p < 0.05) with patients' tumor stage and lymph node involvement. Compared with the patients who had low tumoral frequencies of PD1⁺ TILs or cancer cells, the TIL-PD1⁺ and cancer-PD1⁺ patients demonstrated significantly reduced DFS in the univariate analysis (5-year DFS: 73.3 vs. 41.9%, log-rank 0.008 and 71.3 vs. 41.6%, p = 0.008, respectively). Additionally, the cancer-PD1⁺ patients showed significantly decreased OS in the univariate analysis compared with the cancer-PD1⁻ patients (5-year OS: 68.8 vs. 43.5%; p = 0.047). However, these correlations did not reach significance in the multivariate analysis.

Conclusions

The PD1 receptor is expressed by both TILs and cancer cells in AEG. High expression of PD1 is associated with advanced tumor stage and lymph node involvement, but not with survival.

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Refining the Role of Lymph Node Biopsy in Survival for Patients with Nasopharyngeal Carcinoma: Population-Based Study from the Surveillance Epidemiology and End-Results Registry

Abstract

Background

The updated version of the National Comprehensive Cancer Network (NCCN) guidelines revised pretreatment workup for nasopharyngeal carcinoma (NPC) into "biopsy of the primary site or neck." Despite provision of important diagnostic information, concerns regarding tumor cell dissemination limit the application of lymph node biopsy. This study aimed to investigate whether biopsy of the neck is associated with impaired survival in NPC.

Methods

A propensity score-matched, population-based cohort identified from the Surveillance, Epidemiology, and End Results database was used to compare overall survival (OS) and disease-specific survival (DSS) of patients who underwent pretreatment cervical lymph node biopsy without subsequent neck dissection or removal of node compared with patients who did not undergo node biopsy.

Results

Of 2910 eligible patients, 416 (14.3%) underwent pretreatment lymph node biopsy. After use of control for patient, tumor, and demographic characteristics, biopsy was not associated with impaired OS (hazard ratio [HR], 1.15; 95% confidence interval [CI] 0.89–1.47; P = 0.29) or DSS (HR, 1.07; 95% CI 0.81–1.40; P = 0.63). Interestingly, in the subgroup analysis, the unfavorable effect of biopsy was observed for patients with differentiated non-keratinizing squamous cell carcinoma (but not other histologic types). Race did not positively alter the survival outcomes.

Conclusions

The findings provide reference for clinical practice, showing that pretreatment cervical lymph node biopsy is not associated with impaired survival in NPC, except for patients with differentiated non-keratinizing squamous cell carcinoma. The recommended NCCN guidelines would be more specific by adding details to the general recommendation that neck biopsy is safe for all patients. Future prospective studies are needed to verify the study findings.

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Bilateral Prophylactic Mastectomy and Immediate Breast Reconstruction in High-Risk Women: The Importance of Health-Related Quality of Life in Decision Making

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Standardized Kaempferia parviflora Extract Inhibits Intrinsic Aging Process in Human Dermal Fibroblasts and Hairless Mice by Inhibiting Cellular Senescence and Mitochondrial Dysfunction

Intrinsic skin aging is a complex biological phenomenon mainly caused by cellular senescence and mitochondrial dysfunction. This study evaluated the inhibitory effect of Kaempferia parviflora Wall ex. Baker ethanol extract (KPE) on H2O2-stimulated cellular senescence and mitochondrial dysfunction both in vitro and in vivo. KPE significantly increased cell growth and suppressed senescence-associated β-galactosidase activation. KPE inhibited the expression of cell-cycle inhibitors (p53, p21, p16, and pRb) and stimulated the expression of cell-cycle activators (E2F1 and E2F2). H2O2-induced hyperactivation of the phosphatidylinositol 3-kinase/protein kinase B (AKT) signaling pathway was suppressed by KPE through regulated expression of forkhead box O3a (FoxO3a) and mammalian target of rapamycin (mTOR). KPE attenuated inflammatory mediators (interleukin-6 (IL-6), IL-8, nuclear factor kappa B (NF-κB), and cyclooxygenase-2 (COX-2)) and increased the mRNA expression of PGC-1α, ERRα, NRF1, and Tfam, which modulate mitochondrial biogenesis and function. Consequently, reduced ATP levels and increased ROS level were also reversed by KPE treatment. In hairless mice, KPE inhibited wrinkle formation, skin atrophy, and loss of elasticity by increasing the collagen and elastic fibers. The results indicate that KPE prevents intrinsic aging process in hairless mice by inhibiting cellular senescence and mitochondrial dysfunction, suggesting its potential as a natural antiaging agent.

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Low prevalence of hepatitis B and hepatitis C virus serum markers in a cohort of pregnant women from Southern Italy

Mother-to-child transmission is still considered a major factor in the spread of hepatitis viruses. Nevertheless, epidemiological data on hepatitis B virus (HBV) and hepatitis C virus (HCV) in reproductive-age women are limited even in areas like the South of Italy where both viruses had been widespread.

http://ift.tt/2vlHQjG

A Consumer’s Guide for Probiotics: 10 Golden Rules for a Correct Use

Probiotics are used all over the world as their beneficial effects on the human organism have been widely demonstrated. Certain probiotics can down-regulate production of pro-inflammatory cytokines and promote intestinal epithelial barrier functions, increasing an anti-inflammatory response and contributing to the host's overall health. The main mechanisms by which probiotic microorganisms can interact with the host are by modulating the immune system and the epithelial cell functions and interacting with intestinal gut microbiota.

http://ift.tt/2tXmq97

Indicators of suboptimal tumor necrosis factor antagonist therapy in inflammatory bowel disease

Inflammatory bowel disease (IBD) is refractory to treatment in one-half of patients.

http://ift.tt/2vlNaUg

Arthroconidia in Lung Tissue: An Unusual Histopathological Finding in Pulmonary Coccidioidomycosis

Coccidioides immitis/posadsii presents in mycelial form with branching hyphae and arthroconidia when cultured in the laboratory. On histopathology, the presence of endospore-containing spherules is considered diagnostic of coccidioidomycosis. Here we report an unusual case of coccidioidomycosis with hyphae and arthroconidia in pulmonary tissue sections. A 49-year-old male patient with intermittently treated pulmonary coccidioidomycosis sought treatment for residual pulmonary complaints. A cavity in the left upper lobe was seen on CT scan.

http://ift.tt/2w4kM70

Effects of Vacuolar H + -ATPase Inhibition on Activation of Cathepsin B and Cathepsin L Secreted from MDA-MB231 Breast Cancer Cells

Abstract

Studies indicate secreted cathepsins are involved in metastasis. V-ATPases, which are necessary for activating intracellular cathepsins, also play a role in metastasis and are targeted to the plasma membrane of metastatic breast cancer cells. We are interested in a connection between cell surface V-ATPases, activation of secreted cathepsins and the metastatic phenotype of MDA-MB231 cells. We investigated whether V-ATPase inhibition would reduce the activity of secreted cathepsin B and cathepsin L. Using cell lysates and conditioned media, we measured cathepsin B and L activity within and outside of the cells. We found different forms of cathepsin B and L were secreted representing the pre-pro, pro and active forms of the proteases. Cathepsin B activity was higher than cathepsin L in conditioned media and in cell lysates. V-ATPase inhibition by concanamycin A decreased cathepsin B activity in conditioned media and significantly decreased cathepsin B activity in cell lysates. Cathepsin L activity showed a slight decrease in cell lysates. Changes in the activity of secreted and intracellular cathepsins following V-ATPase inhibition were supported by changes in the amounts of pro and active forms of cathepsin B in conditioned media and cathepsins B and L in cell lysates. Overall, our data shows that inactive forms of cathepsins B and L are secreted from the MB231 cells and V-ATPase activity is important for the activation of secreted cathepsin B. This indicates a connection between cell surface V-ATPases in metastatic breast cancer cells and the function of secreted cathepsin B.

http://ift.tt/2f6zKVS

Symptom cluster in men with castrate resistant prostate cancer

Men with metastatic castrate resistant prostate cancer (CRPC) experience significant physical and mental health morbidity along with impaired quality of life (QoL).1 Pain related to skeletal metastases is the predominant physical symptom, but patients also suffer fatigue and drowsiness. On average, each prostate cancer patient has a median of four clinically relevant symptoms (defined as ≥4/10 on the Edmonton Symptom Assessment Scale (ESAS)).2 Treatment related symptoms may also occur such as loss of libido, hot flashes, depression, osteoporosis, fatigue, weight gain, erectile dysfunction and cognitive impairment with hormone suppression.

http://ift.tt/2vfTrkM

The effect of communication skills training for generalist palliative care providers on patient-reported outcomes and clinician behaviours: a systematic review and meta-analysis

As most end of life care is provided by healthcare providers who are generalists rather than specialists in palliative care, effective communication skills training for generalists is essential.

http://ift.tt/2vgZaGH

Isolation and Suffering Related to Serious and Terminal Illness: Metaphors and Lessons from Albert Camus’ Novel, The Plague

Health care providers have much to learn from Albert Camus' great novel, The Plague . The Plague tells the story of a bubonic plague epidemic through the lens of doctor-narrator Rieux. In addition to Rieux, this essay also focuses on the perspective of Father Paneloux, a Jesuit priest who provides important religious commentary on the epidemic, before falling victim to it and dying. Camus' masterful engagement of the metaphor of isolation and its profound impact on suffering emphasizes the important role of community and spiritual perspectives of patients and providers in coping with serious illness, death, and dying.

http://ift.tt/2uWzlcI

Variation of stemness markers expression in tumor nodules from synchronous multi-focal hepatocellular carcinoma – an immunohistochemical study

Advancing knowledge in molecular pathogenesis of hepatocellular carcinoma (HCC) opens up new horizons in the diagnostic, prognostic and therapeutic perspectives. Assessing the expression of molecular targets p...

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Exploring the Histogenesis and Diagnostic Strategy Using Immunoassay and RT-PCR in Alveolar Soft Part Sarcoma

Abstract

Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma, but it's easily misdiagnosed in rare locations. The derivation of ASPS is still uncertain, therefore we conducted this study to explore the histogenesis of ASPS by analyzing stem cell markers (ALDH1, CD29, CD133 and Nestin). Protein TFE3 and fusion gene ASPS-TFE3 were tested in paraffin to explore diagnostic strategy and molecular pathological features. In this study, nine cases of ASPS were immunostained with stem cell surface markers (ALDH1, CD29, CD133 and Nestin) and protein TFE3. Seven cases of ASPS mRNA were successfully extracted from nine paraffin-embedded tissues. The expression of fusion gene ASPL-TFE3 was examined by reverse transcriptase-polymerase chain reaction. The immunohistochemical staining of nine patients showed that CD29 and Nestin were negative in all nine cases (0/9). CD133 was weakly positive in one cases (1/9) and ALDH1 was weakly positive in one cases (1/9). TFE3 was positive in nine cases (9/9). Seven paraffin tissues could be successfully extracted with mRNA in nine cases. The results of Reverse Transcription Polymerase Chain Reaction (RT-PCR) showed that ASPL-TFE3 fusion transcripts could be tested in the seven cases (four cases being type 2 and three cases being type 1). The positive rate of CD133 and ALDH1 were less than 1% and the expression of CD29 and Nestin were negative in ASPS. Immunohistochemistry results indicated that the histogenesis of ASPS maybe not derive from mesenchymal stem cells. Immunohistochemistry staining showed that TFE3 protein expression was highly sensitive in ASPS. Furthermore, RT-PCR results showed that fusion gene ASPL-TFE3 (ASPL-TFE3 type 1 and ASPL-TFE3 type 2) was expressed in ASPS, which could provide information for clinical molecular pathological diagnosis and improve the diagnosis rate of rare atypical ASPS.

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ABO genotype-phenotype discrepancy due to chimerism resolved by clonal separation

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Evidence for a pre-existing telomere deficit in non-clonal hematopoietic stem cells in patients with acute myeloid leukemia

Abstract

Telomere shortening represents an established mechanism connecting aging and cancer development. We sequentially analyzed telomere length (TL) of 49 acute myeloid leukemia (AML) patients at diagnosis (n = 24), once they achieved complete cytological remission (CCR) and/or during refractory disease or relapse and after 1-year follow-up, with all patients having at least two sequential samples. TL was analyzed by monochrome multiplex quantitative polymerase chain reaction. We have observed substantially shortened TL in the cells of patients at diagnosis compared to age-adjusted controls. In patients reaching CCR after chemotherapy, telomere shortening was less pronounced than in persistence or relapse but still significantly shortened compared to controls. We estimate patients harboring approximately 20 years of premature telomere loss compared to healthy aged-matched subjects at the time of AML onset. Our data indicate a pre-existing telomere deficit in non-clonal hematopoiesis of AML patients providing a link between age and AML development.

http://ift.tt/2u28Ftu