Hepatocellular carcinoma (HCC) is associated with inflammation, and roughly 30 % of the global population shows serological evidence of current or past infection with hepatitis B or hepatitis C virus. Resident...
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Παρασκευή 2 Σεπτεμβρίου 2016
Deletion of interleukin-6 in monocytes/macrophages suppresses the initiation of hepatocellular carcinoma in mice
Intestinal permeability to iohexol as an in vivo marker of chemotherapy-induced gastrointestinal toxicity in Sprague–Dawley rats
Abstract
Purpose
Gastrointestinal toxicity is the most common adverse effect of chemotherapy. Chemotherapeutic drugs damage the intestinal mucosa and increase intestinal permeability. Intestinal permeability is one of the key markers of gastrointestinal function and measuring intestinal permeability could serve as a useful tool for assessing the severity of chemotherapy-induced gastrointestinal toxicity.
Methods
Male Sprague–Dawley rats were injected intraperitoneally either with 5-fluorouracil (150 mg/kg), oxaliplatin (15 mg/kg) or irinotecan (200 mg/kg). Clinical signs of gastrointestinal toxicity were assessed daily by weighing the animals and by checking for diarrhea. After 48 h, intestinal permeability to iohexol was measured in vivo by giving the animals 1 ml of 647 mg/ml iohexol solution by oral gavage and collecting all the excreted urine for 24 h. All of the animals were euthanized 72 h after drug administration and tissue samples were harvested from the jejunum and colon.
Results
All chemotherapeutics caused significant body weight loss and diarrhea. Intestinal permeability to iohexol was also increased in all treatment groups and histological analysis revealed significant intestinal damage in both jejunum and colon. Iohexol permeability correlated with the severity of clinical signs of gastrointestinal toxicity and with acute colonic injury.
Conclusions
Chemotherapeutic drugs, such as 5-fluorouracil, oxaliplatin, and irinotecan, increase intestinal permeability to iohexol. Measuring intestinal permeability to iohexol could provide a simple marker for assessing chemotherapy-induced gastrointestinal toxicity.
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Irinotecan- and 5-fluorouracil-induced intestinal mucositis: insights into pathogenesis and therapeutic perspectives
Abstract
Purpose
Intestinal mucositis and diarrhea are common manifestations of anticancer regimens that include irinotecan, 5-fluorouracil (5-FU), and other cytotoxic drugs. These side effects negatively impact therapeutic outcomes and delay subsequent cycles of chemotherapy, resulting in dose reductions and treatment discontinuation. Here, we aimed to review the experimental evidence regarding possible new targets for the management of irinotecan- and 5-FU-related intestinal mucositis.
Methods
A literature search was performed using the PubMed and MEDLINE databases. No publication time limit was set for article inclusion.
Results
Here, we found that clinical management of intestinal mucositis and diarrhea is somewhat ineffective at reducing symptoms, possibly due to a lack of specific targets for modulation. We observed that IL-1β contributes to the apoptosis of enterocytes in mucositis induced by 5-FU. However, 5-FU-related mucositis is far less thoroughly investigated with regard to specific molecular targets when compared to irinotecan-related disease. Several studies have proposed that a correlation exists between the intestinal microbiota, the enterohepatic recirculation of active metabolites of irinotecan, and the establishment of mucositis. However, as reviewed here, this association seems to be controversial. In addition, the pathogenesis of irinotecan-induced mucositis appears to be orchestrated by interleukin-1/Toll-like receptor family members, leading to epithelial cell apoptosis.
Conclusions
IL-1β, IL-18, and IL-33 and the receptors IL-1R, IL-18R, ST2, and TLR-2 are potential therapeutic targets that can be modulated to minimize anticancer agent-associated toxicity, optimize cancer treatment dosing, and improve clinical outcomes. In this context, the pathogenesis of mucositis caused by other anticancer agents should be further investigated.
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Intestinal permeability to iohexol as an in vivo marker of chemotherapy-induced gastrointestinal toxicity in Sprague–Dawley rats
Abstract
Purpose
Gastrointestinal toxicity is the most common adverse effect of chemotherapy. Chemotherapeutic drugs damage the intestinal mucosa and increase intestinal permeability. Intestinal permeability is one of the key markers of gastrointestinal function and measuring intestinal permeability could serve as a useful tool for assessing the severity of chemotherapy-induced gastrointestinal toxicity.
Methods
Male Sprague–Dawley rats were injected intraperitoneally either with 5-fluorouracil (150 mg/kg), oxaliplatin (15 mg/kg) or irinotecan (200 mg/kg). Clinical signs of gastrointestinal toxicity were assessed daily by weighing the animals and by checking for diarrhea. After 48 h, intestinal permeability to iohexol was measured in vivo by giving the animals 1 ml of 647 mg/ml iohexol solution by oral gavage and collecting all the excreted urine for 24 h. All of the animals were euthanized 72 h after drug administration and tissue samples were harvested from the jejunum and colon.
Results
All chemotherapeutics caused significant body weight loss and diarrhea. Intestinal permeability to iohexol was also increased in all treatment groups and histological analysis revealed significant intestinal damage in both jejunum and colon. Iohexol permeability correlated with the severity of clinical signs of gastrointestinal toxicity and with acute colonic injury.
Conclusions
Chemotherapeutic drugs, such as 5-fluorouracil, oxaliplatin, and irinotecan, increase intestinal permeability to iohexol. Measuring intestinal permeability to iohexol could provide a simple marker for assessing chemotherapy-induced gastrointestinal toxicity.
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Potential influence of being overweight on the development of hepatic dysfunction in Japanese patients with EGFR-mutated non-small cell lung cancer undergoing gefitinib monotherapy: the Okayama Lung Cancer Study Group experience
Abstract
Background
Being overweight has been reported to induce hepatic dysfunction during cytotoxic chemotherapy. Severe hepatic dysfunction can also be observed during gefitinib monotherapy, leading to interrupted or discontinued treatment. However, whether being overweight is a risk factor during gefitinib therapy is unknown.
Methods
We retrospectively reviewed 183 Japanese patients with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor-naïve non-small cell lung cancer (NSCLC) harboring EGFR mutations, who received gefitinib monotherapy between July 2007 and February 2014. We defined being overweight as having a body mass index (BMI) ≥ 25 kg/m2 and assessed its potential relationship with ≥grade 2 hepatic dysfunction.
Results
The patient demographics were as follows: 114 women; median age 72 years (range 42–95 years); BMI ≥ 25 kg/m2, n = 32; performance status 0–1, n = 136; stage IIIB/IV, n = 141; and major EGFR mutations, n = 171. Hepatic dysfunction ≥grade 2 during the gefitinib therapy was observed in 44 (24.0 %) patients, 22 (50.0 %) of whom interrupted or discontinued treatment. The median duration from gefitinib administration to the development of hepatic dysfunction was 56 days (range 6–1,352 days). Overweight patients were more likely to develop hepatic dysfunction ≥grade 2 compared to non-overweight patients according to a multivariate analysis adjusted for several confounding factors (hazard ratio 2.24; 95 % confidence interval 1.01–4.95; p = 0.046).
Conclusion
These results suggest that being overweight may induce hepatic dysfunction during gefitinib monotherapy in Japanese patients with EGFR-mutated NSCLC.
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Development of three-dimensional transperineal ultrasound for image-guided radiation therapy of the prostate: Early evaluations of feasibility and use for inter- and intrafractional prostate localization
Publication date: Available online 2 September 2016
Source:Practical Radiation Oncology
Author(s): Apoorva Trivedi, Takamura Ashikaga, Daphne Hard, Jessica Archambault, Martin Lachaine, David T. Cooper, Harold James Wallace
Transperineal ultrasound (TPUS) allows for continuous imaging of the prostate gland, but the accuracy of TPUS has not been rigorously studied. We determined the feasibility of prostate imaging with TPUS and subsequently compared prostate localization with TPUS and Computed Tomography (CT).Methods and MaterialsWe completed two sequential evaluations of TPUS. The feasibility study included 15 men with localized prostate cancer and tested if TPUS adequately imaged the prostate. Image qualities of the prostate and adjacent normal structures were measured. The subsequent study included 17 men who at the time of initial radiation treatment planning and in three subsequent sessions had CT and TPUS imaging performed and compared.ResultsFeasibility of TPUS was confirmed in the first trial. After expected hardware and software modifications were completed, TPUS provided near complete edge definition of the prostate in the final 5 patients in the feasibility trial. The second study allowed for the comparison of 30 image sets. The differences between TPUS and CT in each direction (mean+standard deviation) were found to be 0.06±2.86mm (A/P), 0.49±3.49mm (S/I), and 0.63±3.27mm (L/R), with no significant difference between the two modalities (all p's>0.32). The Euclidean distance variance using the two techniques was 5.25±1.79mm, which was significantly different.ConclusionsTPUS provides good imaging of the prostate gland. We noted excellent correlation in gland localization when TPUS is compared to CT when comparing routine three-dimensional positional data. Euclidean distance variation suggests the potential that summation of small errors may in fact lead to significant differences in actual gland positional certainty. The reported difference is within the range of standard planning target volume (PTV) expansion however requires additional evaluation.
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Regarding “The dosimetric impact of image guided radiation therapy by intratumoral fiducial markers” by Yu et al. (Vol 6, Issue 4, p276–283)
Publication date: Available online 2 September 2016
Source:Practical Radiation Oncology
Author(s): Jeffrey V. Siebers, J. James Gordon
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Management of Independent Motion between Multiple Targets in Lung Cancer Radiotherapy
Publication date: Available online 2 September 2016
Source:Practical Radiation Oncology
Author(s): Feng Liu, An Tai, Ergun Ahunbay, Elizabeth Gore, Candice Johnstone, X. Allen Li
To quantify interfractional independent motions between multiple primary targets in radiotherapy (RT) of lung cancer and to study the dosimetric benefits of an online adaptive replanning method to account for these variations.MethodsNinety five on-treatment diagnostic-quality CTs acquired for nine lung cancer patients treated with image-guided radiation therapy (IGRT) using a CT-on rail (CTVision, Siemens) were analyzed. On each on-treatment CT set, contours of the targets (GTV, CTV, or involved nodes) and organs at risk were generated by populating the planning contours using an auto-segmentation tool (ABAS, Elekta) with manual editing. For each patient, an intensity modulated radiation therapy (IMRT) plan was generated based on the planning CT with a prescription dose of 60Gy in 2Gy per fraction. Three plans were generated and compared for each on-treatment CT set: an IGRT (repositioning) plan by copying the original plan with the required shifts, an online adaptive plan by rapidly modifying the aperture shapes and segment weights of the original plan to conform to the on-treatment anatomy and a new fully re-optimized plan based on the on-treatment CT.ResultsThe interfractional deviations of the distance between centers of masses of the targets from the planning CTs varied from −1.0 to 0.8cm with an average−0.09±0.41cm (one standard deviation). The average combined CTV V100 were 99.0±0.7%, 97.8±2.8%, 99.0±0.6%, and 99.1±0.6%, and the lung V20 Gy 928±332cm3, 944±315cm3, 917±300cm3, and 891±295cm3 for the original, repositioning, adaptive and re-optimized plans, respectively. Wilcoxon signed-rank tests showed that the adaptive plans were statistically significantly better than the repositioning plans and comparable with the re-optimized plans.ConclusionInterfractional, relative volume changes and independent motions between multiple primary targets during lung cancer RT which cannot be accounted for by the current IGRT repositioning exist, but can be corrected by the online adaptive replanning method.
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Editorial Board
Publication date: September–October 2016
Source:Practical Radiation Oncology, Volume 6, Issue 5
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Response to Letter to the Editor: Regarding “The Dosimetric Impact of Image Guided Radiotherapy by Intra-tumoral Fiducial Markers”
Publication date: Available online 2 September 2016
Source:Practical Radiation Oncology
Author(s): Suhong Yu, Varun Sehgal, Muthana Al-Ghazi, Lesley Lawrenson, Randy Wei, Jeffrey Kuo, Parima Daroui, Nilam Ramsinghani
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Table of Contents
Publication date: September–October 2016
Source:Practical Radiation Oncology, Volume 6, Issue 5
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Deletion of interleukin-6 in monocytes/macrophages suppresses the initiation of hepatocellular carcinoma in mice
Abstract
Background
Hepatocellular carcinoma (HCC) is associated with inflammation, and roughly 30 % of the global population shows serological evidence of current or past infection with hepatitis B or hepatitis C virus. Resident hepatic macrophages, known as Kupffer cells (KCs), are considered as the specific tumor-associated macrophages (TAMs) of HCC, and can produce various cytokines—most importantly interleukin (IL)-6—to promote tumorigenesis of HCC. However, the roles of KCs and IL-6 in carcinogenesis in the liver are still unclear.
Methods
We analyzed leukocyte-related peripheral blood data of 192 patients and constructed a mouse model in which the bone marrow was cleared out by irradiation and reconstructed using bone marrow donated from IL-6-deficient mice to further elucidate the hepatic pathological changes in response to toxic challenge and oncogenic gene mutation.
Results
Peripheral monocyte counts and serum IL-6 levels were significantly higher in patients with HCC than in those without HCC. In addition, there was a significant difference in the levels of IL-6 among individuals with different histopathological grades. In mice with selective IL-6 ablation in monocytes/KCs, we observed decreased toxic liver injury, inflammatory infiltration, and systemic inflammation. In Mdr2-deficient mice, which spontaneously developed HCC, the loss of IL-6 in monocytes/KCs resulted in inhibition of IL-6/signal transducer and activator of transcription 3 signaling, decreased serum IL-6 levels, and delayed tumorigenesis.
Conclusions
Our findings demonstrate that increased TAM-derived IL-6 had an amplifying effect on the inflammation response, thereby promoting the occurrence and development of HCC.
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Breast Lumps That Do Not Arise from the Breast
Abstract
An elderly lady presented to the surgical outpatient with a lump in her breast. On examination, there was a well-defined large lump measuring about 12 × 10 cm, hard in consistency and fixed to the chest wall, the skin appeared to be free, and the nipple–areola complex was normal. A provisional diagnosis of phylloides tumor was made, but digital rectal examination revealed a circumferential rectal growth. To our surprise, biopsy of the rectal growth and the chest wall mass revealed similar adenocarcinoma cells. This image illustrates the possibility that a common clinical entity such as a breast lump can sometimes surprise even the most seasoned clinicians.
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NAB-paclitaxel and gemcitabine in metastatic pancreatic ductal adenocarcinoma (PDAC): from clinical trials to clinical practice
Abstract
Background
Pancreatic adenocarcinoma is an aggressive disease with poor prognosis. In a randomized phase III trial, combination of Nab-paclitaxel (Nab-P) plus gemcitabine showed superior activity and efficacy in first-line treatment compared with gemcitabine alone.
Methods
Nab-P is not dispensed in Italy; however, we obtained this drug from our Ethics Committee for compassionate use. The aim of this study was to evaluate the efficacy and safety profile of this Nab-P and gemcitabine combination in a cohort of patients treated outside clinical trials. From January 2012 to May 2014, we included 41 patients with advanced pancreatic adenocarcinoma receiving combination of 125 mg/m2 Nab-P and 1 g/m2 gemcitabine on days 1, 8 and 15 of a 28-day cycle, as first-line treatment. Median age of patients was 67 (range 41–77) years, and 11 patients were aged ≥70 years.
Results
Eastern Co-operative Oncology Group performance status was 0 or 1 in 32 patients (78 %) and 2 in nine patients (22 %). Primary tumor was located in the pancreatic head or body/tail in 24 (58.5 %) and 17 (41.5 %) patients, respectively, and nine patients had received biliary stent implantation before starting chemotherapy. Median carbohydrate antigen 19–9 level was 469 U/l (range 17.4–61546 U/l) and 29 patients (70.7 %) had referred pain at the time of diagnosis. Patients received a median six cycles (range 1–14) of treatment. Overall response rate was 36.6 %; median progression-free survival was 6.7 months [(95 % confidence interval (CI) 5.966–8.034), and median overall survival was 10 months (95 % CI 7.864–12.136). Treatment was well tolerated. No grade 4 toxicity was reported. Grade 3 toxicity included neutropenia in 10 patients (24.3 %), thrombocytopenia in five (12 %), anemia in three (7.3 %), diarrhea in four (9.7 %), nausea and vomiting in two (4.9 %), and fatigue in six (14.6 %). Finally, pain control was achieved in 24 of 29 patients (82.3 %) with a performance status improvement of 10 % according to the Karnofsky scale.
Conclusions
Our results confirm that combination of gemcitabine plus Nab-P is effective both in terms of overall response rate, progression-free survival and overall survival, with a good safety profile.
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The effect of neoadjuvant chemotherapy and chemoradiotherapy on exercise capacity and outcome following upper gastrointestinal cancer surgery: an observational cohort study
Abstract
Background
In 2014 approximately 21,200 patients were diagnosed with oesophageal and gastric cancer in England and Wales, of whom 37 % underwent planned curative treatments. Potentially curative surgical resection is associated with significant morbidity and mortality. For operable locally advanced disease, neoadjuvant chemotherapy (NAC) improves survival over surgery alone. However, NAC carries the risk of toxicity and is associated with a decrease in physical fitness, which may in turn influence subsequent clinical outcome. Lower levels of physical fitness are associated with worse outcome following major surgery in general and Upper Gastrointestinal Surgery (UGI) surgery in particular. Cardiopulmonary exercise testing (CPET) provides an objective assessment of physical fitness. The aim of this study is to test the hypothesis that NAC prior to upper gastrointestinal cancer surgery is associated with a decrease in physical fitness and that the magnitude of the change in physical fitness will predict mortality 1 year following surgery.
Methods
This study is a multi-centre, prospective, blinded, observational cohort study of participants with oesophageal and gastric cancer scheduled for neoadjuvant cancer treatment (chemo- and chemoradiotherapy) and surgery. The primary endpoints are physical fitness (oxygen uptake at lactate threshold measured using CPET) and 1-year mortality following surgery; secondary endpoints include post-operative morbidity (Post-Operative Morbidity Survey (POMS)) 5 days after surgery and patient related quality of life (EQ-5D-5 L).
Discussion
The principal benefits of this study, if the underlying hypothesis is correct, will be to facilitate better selection of treatments (e.g. NAC, Surgery) in patients with oesophageal or gastric cancer. It may also be possible to develop new treatments to reduce the effects of neoadjuvant cancer treatment on physical fitness. These results will contribute to the design of a large, multi-centre trial to determine whether an in-hospital exercise-training programme that increases physical fitness leads to improved overall survival.
Trial registration
ClinicalTrials.gov NCT01325883 - 29th March 2011.
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Piloting a generic cancer consumer quality index in six European countries
Abstract
Background
Accounting for patients' perspective has become increasingly important. Based on the Consumer Quality Index method (founded on Consumer Assessment of Healthcare Providers and Systems) a questionnaire was recently developed for Dutch cancer patients. As a next step, this study aimed to adapt and pilot this questionnaire for international comparison of cancer patients experience and satisfaction with care in six European countries.
Method
The Consumer Quality Index was translated into the local language at the participating pilot sites using cross-translation. A minimum of 100 patients per site were surveyed through convenience sampling. Data from seven pilot sites in six countries was collected through an online and paper-based survey. Internal consistency was tested by calculating Cronbach's alpha and validity by means of cognitive interviews. Demographic factors were compared as possible influencing factors.
Results
A total of 698 patients from six European countries filled the questionnaire. Cronbach's alpha was good or satisfactory in 8 out of 10 categories. Patient satisfaction significantly differed between the countries. We observed no difference in patient satisfaction for age, gender, education, and tumor type, but satisfaction was significantly higher in patients with a higher level of activation.
Conclusion
This European Cancer Consumer Quality Index(ECCQI) showed promising scores on internal consistency (reliability) and a good internal validity. The ECCQI is to our knowledge the first to measure and compare experiences and satisfaction of cancer patients on an international level, it may enable healthcare providers to improve the quality of cancer care.
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Associations of genetic polymorphisms of the transporters organic cation transporter 2 ( OCT2 ), multidrug and toxin extrusion 1 ( MATE1 ), and ATP-binding cassette subfamily C member 2 ( ABCC2 ) with platinum-based chemotherapy response and toxicity in non-small cell lung cancer patients
Abstract
Background
Platinum-based chemotherapy is the first-line treatment of non-small cell lung cancer (NSCLC); it is therefore important to discover biomarkers that can be used to predict the efficacy and toxicity of this treatment. Four important transporter genes are expressed in the kidney, including organic cation transporter 2 (OCT2), multidrug and toxin extrusion 1 (MATE1), ATP-binding cassette subfamily B member 1 (ABCB1), and ATP-binding cassette subfamily C member 2 (ABCC2), and genetic polymorphisms in these genes may alter the efficacy and adverse effects of platinum drugs. This study aimed to evaluate the association of genetic polymorphisms of these transporters with platinum-based chemotherapy response and toxicity in NSCLC patients.
Methods
A total of 403 Chinese NSCLC patients were recruited for this study. All patients were newly diagnosed with NSCLC and received at least two cycles of platinum-based chemotherapy. The tumor response and toxicity were evaluated after two cycles of treatment, and the patients' genomic DNA was extracted. Seven single-nucleotide polymorphisms in four transporter genes were selected to investigate their associations with platinum-based chemotherapy toxicity and response.
Results
OCT2 rs316019 was associated with hepatotoxicity (P = 0.026) and hematological toxicity (P = 0.039), and MATE1 rs2289669 was associated with hematological toxicity induced by platinum (P = 0.016). In addition, ABCC2 rs717620 was significantly associated with the platinum-based chemotherapy response (P = 0.031). ABCB1 polymorphisms were associated with neither response nor toxicity.
Conclusion
OCT2 rs316019, MATE1 rs2289669, and ABCC2 rs717620 might be potential clinical markers for predicting chemotherapy toxicity and response induced by platinum-based treatment in NSCLC patients.
Trial registration Chinese Clinical Trial Registry ChiCTR-RNC-12002892
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Associations of genetic polymorphisms of the transporters organic cation transporter 2 (OCT2), multidrug and toxin extrusion 1 (MATE1), and ATP-binding cassette subfamily C member 2 (ABCC2) with platinum-based chemotherapy response and toxicity in non-small cell lung cancer patients
Platinum-based chemotherapy is the first-line treatment of non-small cell lung cancer (NSCLC); it is therefore important to discover biomarkers that can be used to predict the efficacy and toxicity of this tre...
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The effect of time on racial differences in epithelial ovarian cancer (OVCA) diagnosis stage, overall and by histologic subtypes: a study of the National Cancer Database
Abstract
Purpose
Previous studies assessing racial and ethnic differences in ovarian cancer (OVCA) diagnosis stage fail to present subtype-specific results and provide historic data on cases diagnosed between 10 and 20 years ago. The purpose of this analysis is to assess non-Hispanic Black (NHB) and non-Hispanic White (NHW) differences in late-stage diagnosis including; (1) factors associated with late-stage diagnosis of invasive epithelial OVCA overall and by histologic subtypes, (2) potential changes across time and (3) current patterns of trends in a national cancer registry in the USA and Puerto Rico between 1998 and 2011.
Methods
NHB and NHW OVCA cases were derived from the National Cancer Database (NCDB). Diagnosis stage was analyzed as a dichotomous and a four level-category variable, respectively; early (stages I and II; localized) versus late (stages III and IV; regional and distant) and stages I, II, III and IV. Diagnosis period was trichotomized (1998–2002, 2003–2007, 2008–2011). Racial differences in stage were tested using Chi-square statistics. Odds ratios (OR) and 95 % confidence intervals (95 % CI) were estimated using multivariable binomial and generalized ordered logistic regressions. Interactions between race and diagnosis period were evaluated.
Results
Between 1998 and 2011, 11,562 (7.8 %) NHB and 137,106 (92.2 %) NHW were diagnosed with OVCA. In adjusted models, NHB were significantly more likely diagnosed with late-stage OVCA than NHW (ORadj 1.26, 95 % CI 1.19–1.33). Interaction between race and diagnosis period was marginally significant (p value = 0.09), with racial differences in stage decreasing over time (1998–2002: ORadj 1.36, 95 % CI 1.23–1.49; 2003–2007: ORadj 1.27, 95 % CI 1.15–1.39; 2008–2011; ORadj 1.15, 95 % CI 1.05–1.27). NHB were also more likely to be diagnosed with stage 4 high-grade serous (ORadj 1.46, 95 % CI 1.22–1.74), clear cell (ORadj 2.71, 95 % CI 1.94–3.79) and mucinous (ORadj 2.78, 95 % CI 2.24–3.46) carcinomas than NHW.
Conclusions
Racial differences in late-stage OVCA diagnosis exist; however, these differences are decreasing with time. Within NCDB, NHB are significantly more likely diagnosed with late-stage OVCA and more specifically high-grade serous, clear cell and mucinous carcinomas than NHW.
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Cost-effectiveness analysis in melanoma detection: A transition model applied to dermoscopy
Source:European Journal of Cancer, Volume 67
Author(s): Isabelle Tromme, Catherine Legrand, Brecht Devleesschauwer, Ulrike Leiter, Stefan Suciu, Alexander Eggermont, Laurine Sacré, Jean-François Baurain, Luc Thomas, Philippe Beutels, Niko Speybroeck
AimThe main aim of this study is to demonstrate how our melanoma disease model (MDM) can be used for cost-effectiveness analyses (CEAs) in the melanoma detection field. In particular, we used the data of two cohorts of Belgian melanoma patients to investigate the cost-effectiveness of dermoscopy.MethodsA MDM, previously constructed to calculate the melanoma burden, was slightly modified to be suitable for CEAs. Two cohorts of patients entered into the model to calculate morbidity, mortality and costs. These cohorts were constituted by melanoma patients diagnosed by dermatologists adequately, or not adequately, trained in dermoscopy. Effectiveness and costs were calculated for each cohort and compared. Effectiveness was expressed in quality-adjusted life years (QALYs), a composite measure depending on melanoma-related morbidity and mortality. Costs included costs of treatment and follow-up as well as costs of detection in non-melanoma patients and costs of excision and pathology of benign lesions excised to rule out melanoma.ResultsThe result of our analysis concluded that melanoma diagnosis by dermatologists adequately trained in dermoscopy resulted in both a gain of QALYs (less morbidity and/or mortality) and a reduction in costs.ConclusionThis study demonstrates how our MDM can be used in CEAs in the melanoma detection field. The model and the methodology suggested in this paper were applied to two cohorts of Belgian melanoma patients. Their analysis concluded that adequate dermoscopy training is cost-effective. The results should be confirmed by a large-scale randomised study.
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Infection risk with immunomodulatory and proteasome inhibitor–based therapies across treatment phases for multiple myeloma: A systematic review and meta-analysis
Source:European Journal of Cancer, Volume 67
Author(s): Benjamin W. Teh, Simon J. Harrison, Leon J. Worth, Karin A. Thursky, Monica A. Slavin
BackgroundThe objective of this review was to determine the impact of immunomodulatory drugs (IMiDs) and proteasome inhibitor (PI)–based therapy on infection risk in patients with myeloma across three treatment periods: induction, maintenance therapy and relapse/refractory disease (RRMM).MethodsA systematic review and meta-analysis of randomised controlled trials (RCT) of IMiD and PI-based therapy versus conventional therapy from 1990 to 2015 using MEDLINE, EMBASE and CENTRAL was conducted. Study methods, characteristics, interventions, outcomes and rate of infection were extracted using a standardised tool.FindingsThirty RCTs of 13,105 patients fulfilled inclusion criteria. The rate of severe infection with the use of IMiD-based therapy was 13.4%, 22.4%, 10.5% and 16.6% for induction therapy for non-transplant- and transplant-eligible patients, maintenance therapy and therapy for RRMM, respectively. Rate of severe infection with PI-based induction in transplant-eligible patients was 19.7%. Compared to conventional therapy, use of IMiD-based induction therapy was associated with reduced risk for transplant patients (RR 0.76, p < 0.01). There was no significant difference with PI-based therapy. For maintenance therapy and RRMM, use of IMiD-based therapy was significantly associated with 74% and 51% increased risk of severe infection, respectively. Compared to thalidomide, bortezomib-based induction therapy and lenalidomide maintenance therapy were associated with increased risk of severe infection (RR 2.03, p < 0.01; RR 1.95, p = 0.03).InterpretationThe differential impact of myeloma therapies on risk for infection and the effect of treatment phases upon risk have now been established. Thalidomide is associated with the lowest risk of severe infection when used for induction and maintenance therapy.FundingFight Cancer Foundation.
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A study-level meta-analysis of efficacy data from head-to-head first-line trials of epidermal growth factor receptor inhibitors versus bevacizumab in patients with RAS wild-type metastatic colorectal cancer
Publication date: November 2016
Source:European Journal of Cancer, Volume 67
Author(s): Volker Heinemann, Fernando Rivera, Bert H. O'Neil, Sebastian Stintzing, Reija Koukakis, Jan-Henrik Terwey, Jean-Yves Douillard
BackgroundHead-to-head trials comparing first-line epidermal growth factor receptor inhibitor (EGFRI) versus vascular endothelial growth factor inhibitor (bevacizumab) therapy yielded differing results, and debate remains over optimal first-line therapy for patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC).MethodsA PubMed search identified first-line mCRC trials comparing EGFRI plus chemotherapy versus bevacizumab plus chemotherapy; data were subsequently updated using recent congress presentations. This study-level meta-analysis estimated the overall survival (OS) treatment effect of first-line chemotherapy plus EGFRIs or bevacizumab in patients with RAS WT mCRC. Secondary end-points were progression-free survival (PFS), objective response rate (ORR), resection rate and safety. Early tumour shrinkage (ETS) of ≥20% at week 8 was an exploratory end-point.ResultsThree trials comprising data from 1096 patients with RAS WT mCRC were included. OS (hazard ratio [HR]: 0.80 [95% confidence interval: 0.68–0.93]), ORR (odds ratio [OR]: 0.57) and ETS (OR: 0.48) favoured EGFRIs plus chemotherapy versus bevacizumab plus chemotherapy. PFS (HR: 0.98) and resections (OR: 0.93) were similar between treatments. For patients with KRAS exon 2 WT/'other' RAS mutant mCRC the OS HR was 0.70. A safety meta-analysis was not possible due to a lack of data; in the individual studies, skin toxicities and hypomagnesaemia were more common with EGFRIs, nausea and hypertension were more common with bevacizumab.ConclusionsThis meta-analysis supports a potential benefit for first-line EGFRI plus chemotherapy versus bevacizumab plus chemotherapy with respect to OS, ORR and ETS in patients with RAS WT mCRC. A patient-level meta-analysis is awaited.
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A rapid method for quantifying free and bound acetate based on alkylation and GC-MS analysis
Abstract
Background
Acetyl-CoA is a key metabolic intermediate with roles in the production of energy and biomass, as well as in metabolic regulation. It was recently found that acetate is crucial for maintaining acetyl-CoA production in hypoxic cancer cells. However, the availability of free acetate in the tumor environment and how much tumor cells consume remains unknown. Similarly, much is still to be learned about changes in the dynamics and distribution of acetylation in response to tumor-relevant conditions. The analysis of acetate is non-trivial, and to help address these topics, we developed a rapid and robust method for the analysis of both free and bound acetate in biological samples.
Results
We developed a sensitive and high-throughput method for the analysis of acetate based on alkylation to its propyl derivative and gas chromatography-mass spectrometry. The method facilitates simultaneous quantification of both 12C- and 13C-acetate, shows high reproducibility (< 10 % RSD), and has a wide linear range of quantification (2–2000 μM). We demonstrate the method's utility by measuring free acetate uptake by cultured cancer cells and by quantifying total acetylation (using hydrolysis) in separate cellular compartments. Additionally, we measure free acetate in tissues and bio-fluids and show that there are considerable differences in acetate concentrations between organs in vivo, providing insights into its complex systemic metabolism and availability for various types of tumors.
Conclusions
Our approach for the quantification of acetate is straightforward to implement using widely available equipment and reagents, and will aid in in-depth investigation of various aspects of acetate metabolism. It is also readily adaptable to the analysis of formate and short-chain fatty acids, making it highly relevant to the cancer metabolism community.
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Prognostic value of angiopoietin-2 in non-small cell lung cancer patients: a meta-analysis
Abstract
Background
Non-small cell lung cancer (NSCLC) is the most frequent cause of cancer deaths worldwide. The targeted therapy had made important progress in recent years, but few potential predictive biomarkers for prognosis of NSCLC patients were identified. Angiopoietin-2 (Ang-2), a cytokine upregulated in tumor endothelial cells and some tumor cells including NSCLC, is a partial agonist and antagonist of angiopoietin-1 (Ang-1). Ang-1 is another ligand for the tyrosine kinase receptor Tie2; it promotes recruitment of pericytes and smooth muscle cells, stabilizing vascular networks by binding to Tie2. Although many studies mainly considered that Ang-2 correlated with progression and prognosis of NSCLC significantly, there are much conflicting and controversial data. Therefore, we conducted a meta-analysis to assess the relationship between Ang-2 and prognosis, a clinical outcome of NSCLC.
Methods
The search was based on major databases from PubMed, Cochrane Library, EMBASE, and CNKI, and 20 eligible publications (range from 2002 to 2015) are included in our meta-analysis with 2011 NSCLC patients in total. These studies illuminated the correlation between the expression of Ang-2 and NSCLC, based on either prognostic factors or clinicopathological features. Pooled calculations were carried out on the odds ratio (OR) and the corresponding 95 % confidence interval (CI) to perform this meta-analysis, and all statistical analyses were carried out by STATA 12.0 and Review Manager 5.3.
Results
According to our results, the expression of Ang-2 in NSCLC tissues was significantly higher than that in normal lung tissues, indicating that Ang-2 over-expression may be a predictive marker (pooled OR = 5.09, corresponding 95 % confidence interval (95 % CI) 3.10–8.36, p = 0.000). In addition, our pooled data showed that Ang-2 expression was positively correlated with tumor stages (pooled OR = 3.58, 95 % CI 2.40–5.35, p = 0.000), differentiation (pooled OR = 0.65, 95 % CI 0.45–0.94, p = 0.02), lymphatic invasion (pooled OR = 3.15, 95 % CI 1.97–5.03, p = 0.000), and poor survival (pooled OR = 1.93, 95 % CI 1.47–2.52, p = 0.000) of NSCLC, but seems to have no significant impact on tumor size (pooled OR = 1.09, 95 % CI 0.59–2.00, p = 0.78).
Conclusions
These results demonstrate that Ang-2 expression significantly correlated with poor prognosis for patients with NSCLC.
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Germline PMS2 mutation screened by mismatch repair protein immunohistochemistry of colorectal cancer in Japan
Summary
Germline PMS2 gene mutations were detected by RT-PCR/direct sequencing of total RNA extracted from puromycin-treated peripheral blood lymphocytes (PBL) and multiplex ligation-dependent probe amplification (MLPA) analyses of Japanese patients with colorectal cancer (CRC) fulfilling either the revised Bethesda guidelines or an age at disease onset of younger than 70 years, and screened by mismatch repair protein immunohistochemistry of formalin-fixed paraffin embedded sections. Of the 501 subjects examined, 7 (1.40%) showed the down-regulated expression of the PMS2 protein alone and were referred to the genetic counseling clinic. Germline PMS2 mutations were detected in 6 (85.7%), including 3 nonsense and 1 frameshift mutations by RT-PCR/direct sequencing and 2 genomic deletions by MLPA. No mutations were identified in the other MMR genes, i.e. MSH2, MLH1, and MSH6. The prevalence of the down-regulated expression of the PMS2 protein alone was 1.40% among the subjects examined and IHC results predicted the presence of PMS2 germline mutations. RT-PCR from puromycin-treated PBL and MLPA may be employed as the first screening step to detect PMS2 mutations without pseudogene interference, followed by the long-range PCR/nested PCR validation using genomic DNA.
This article is protected by copyright. All rights reserved.
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The impact of Sulfatase-2 on cancer progression and prognosis in patients with renal cell carcinoma
Abstract
Heparan sulfate-specific endosulfatase-2, SULF-2, can modulate the signaling of HSPG-binding proteins. The involvement of SULF-2 in cancer growth varies by cancer type. The roles of SULF-2 expression in the progression and prognosis of renal cell carcinomas (RCCs) have not yet been fully clarified. In the present study, the expression levels of SULF-2 mRNA and protein in 49 clinical RCC samples were determined by RT-PCR and immunostaining. The existence of RCCs with higher SULF-2 expression and lower SULF-2 expression compared to the adjacent normal kidney tissues was suggested. High SULF-2 expression was correlated with an early clinical stage and less invasive pathological factors. Low SULF-2 expression was correlated with an advanced stage and higher invasive factors. Three-year cancer-specific survival (CSS) for high SULF-2 RCCs and low SULF-2 RCCs were 100% and 71.4%, respectively (log-rank p = 0.0019), with a significantly shorter CSS observed in low SULF-2 RCC patients. The influence of SULF-2 expression level on Wnt/VEGF/FGF signaling, cell viability and invasive properties was examined in three RCC cell lines, Caki-2, ACHN and 786-O, using a SULF-2 suppression model involving siRNA or a SULF-2 overexpression model involving a plasmid vector. High SULF-2 expression enhanced Wnt signaling and Wnt-induced cell viability, but not cell invasion. In contrast, low levels of SULF-2 expression significantly enhanced both cell invasion and viability through the activation of VEGF/FGF pathways. RCCs with lower SULF-2 expression might have a higher potential for cell invasion and proliferation, leading to a poorer prognosis via the activation of VEGF and/or FGF signaling.
This article is protected by copyright. All rights reserved.
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High expression of the Notch ligand Jagged-1 is associated with poor prognosis after surgery for colorectal cancer
Abstract
The importance of Notch signaling in colorectal cancer (CRC) carcinogenesis and progression has previously been presented. Increased expression of Jagged-1 (JAG1), a Notch ligand, in CRC has been revealed, but the detailed prognostic significance of JAG1 in CRC has not been determined. Protein expression of JAG1 was examined using immunohistochemistry in 158 CRC specimens. Expression of JAG1 and E-cadherin and their associations with clinicopathologic characteristics, overall survival (OS), and relapse-free survival (RFS) were evaluated. In vitro studies using compounds to regulate intracellular signaling and small interfering RNA to silence JAG1 were performed in a colon cancer cell line. JAG1 expression in cancerous tissues was weak, moderate, or strong in 32, 36, and 32% of specimens, respectively, and correlated with histologic type and T stage. In multivariate analysis, JAG1 expression, histologic type, and lymphatic invasion independently correlated with OS and RFS. Combination of high JAG1 expression and low E-cadherin expression had an additive effect toward poorer OS and RFS compared with the low JAG1/high E-cadherin expression subtype. A significant correlation between JAG1 expression and KRAS status was detected in groups stratified as high E-cadherin expression. In vitro studies suggested that RAS-MEK-MAP kinase and the Wnt pathways positively regulated JAG1 expression. Gene silencing with siJAG1 indicated that JAG1 promotes the transition from epithelial to mesenchymal characteristics and cell growth. Conclusions: High expression of JAG1 is regulated by various pathways and associated with poor prognosis through promoting the epithelial to mesenchymal transition and cell proliferation or maintaining of cell survival in CRC.
This article is protected by copyright. All rights reserved.
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The experience of canakinumab in renal amyloidosis secondary to Familial Mediterranean fever
Abstract
Introduction
Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by self-limited recurrent attacks of fever and serositis. Patients may develop renal amyloidosis. Colchicine prevents attacks and renal amyloidosis. Five to 10 % of the patients with FMF are resistant or intolerant to colchicine.
Case description
Herein, we reported our experience with clinical-laboratory features and treatment responses of a pediatric FMF patient with amyloidosis treated with canakinumab. We observed a significant decrease in proteinuria and increase growth in the patient.
Discussion and evaluation
The most serious complication of FMF is the development of AA type amyloidosis which is characterized by proteinuria. Colchicine is the prototype drug that decreases production of amyloidogenic precursor protein. Occasionally, colchicine inadequate patient is observed, as in our case. Canakinumab is a human anti-IL-1β monoclonal antibody. Previously, canakinumab efficacy were shown in a limited number of studies.
Conclusions
Our data, though limited to only one patient, emphasize that therapeutic intervention with canakinumab seems to be improve kidney function in colchicine-resistant FMF with renal amyloidosis.
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Quantitative Information on Oncology Prescription Drug Websites
Abstract
Our objective was to determine whether and how quantitative information about drug benefits and risks is presented to consumers and healthcare professionals on cancer-related prescription drug websites. We analyzed the content of 65 active cancer-related prescription drug websites. We assessed the inclusion and presentation of quantitative information for two audiences (consumers and healthcare professionals) and two types of information (drug benefits and risks). Websites were equally likely to present quantitative information for benefits (96.9 %) and risks (95.4 %). However, the amount of the information differed significantly: Both consumer-directed and healthcare-professional-directed webpages were more likely to have quantitative information for every benefit (consumer 38.5 %; healthcare professional 86.1 %) compared with every risk (consumer 3.1 %; healthcare professional 6.2 %). The numeric and graphic presentations also differed by audience and information type. Consumers have access to quantitative information about oncology drugs and, in particular, about the benefits of these drugs. Research has shown that using quantitative information to communicate treatment benefits and risks can increase patients' and physicians' understanding and can aid in treatment decision-making, although some numeric and graphic formats are more useful than others.
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Helicobacter pylori infection, H19 and LINC00152 expression in serum and risk of gastric cancer in a Chinese population
Source:Cancer Epidemiology, Volume 44
Author(s): Tian Yang, Hongmei Zeng, Wanqing Chen, Rongshou Zheng, Yang Zhang, Zhexuan Li, Jun Qi, Minjie Wang, Tianhui Chen, Jianlin Lou, Lingeng Lu, Tong Zhou, Shuyang Dai, Meng Cai, Weicheng You, Kaifeng Pan
Gastric cancer (GC) is a consequence of multifactorial and multistep processes. Helicobacter pylori (H. pylori) infection plays a crucial role in gastric carcinogenesis. Long non-coding RNAs (lncRNAs) have shown great potential as powerful cancer biomarkers. To investigate the possible roles of lncRNAs and H. pylori infection in GC development, we measured expression levels of three lncRNAs (H19, LINC00152, uc001lsz) in serum from a total of 285 Chinese participants using reverse transcription-quantitative polymerase chain reaction. We found significant associations between high expression of both H19 and LINC00152 in serum and increased risk of GC; the adjusted OR for H19 was 2.17 (95% CI: 1.21-3.88), and for LINC00152 was 2.09 (95% CI: 1.18-3.70). Further analyses indicated an elevated risk of GC in subjects with both high H19 expression and H. pylori infection (OR: 13.75, 95% CI: 4.75-39.84). Significant joint effect between LINC00152 and H. pylori infection on risk of GC was also found (OR: 17.49, 95% CI: 4.78-63.92). Serum H19 and LINC00152 may serve as potential biomarkers for diagnosis of GC, particularly for those with H. pylori infection.
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Fertility preservation in pediatric and adolescent cancer patients in Switzerland: A qualitative cross-sectional survey
Source:Cancer Epidemiology, Volume 44
Author(s): Tamara Diesch, Nicolas Xavier von der Weid, Gabor Szinnai, Sabine Schaedelin, Christian De Geyter, Alicia Rovó
Fertility preservation (FP) is an important topic of discussion in the field of oncology, particularly in pediatric oncology. Despite the awareness of severe impact of infertility on quality of life and different guidelines available in this area, the options in FP are not routinely discussed with the pediatric cancer patients and their parents. To the best of our knowledge, this is the first survey report concerned to FP counseling and procedures in pediatric and adolescent cancer patients in Switzerland. This survey was conducted from June 2014 to October 2014 on the counseling and procedures performed between 2009 and 2013; the questionnaire was completed by one of the professional from hematology/oncology centers in Switzerland. Currently, only four out of nine centers have a program for FP. In 2013, 45/301 (15%) patients received FP counseling and 36/301 (12%) underwent an FP procedure. The most commonly performed procedures from 2009 to 2013 were administration of gonadotropin releasing hormone agonist (3%) and cryopreservation of ovarian tissue in females (3%) and cryopreservation of sperms in males (6%); the most frequently cited reason for the absence of FP counseling was lack of time (55%). Therefore, this survey should help to develop and harmonize practices with respect to FP counseling and procedures in Switzerland, and to establish FP as a standard of care during cancer treatment.
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Hypermethylation of the CaSR and VDR genes in the parathyroid glands in chronic kidney disease rats with high-phosphate diet
Abstract
Chronic kidney disease (CKD) disrupts mineral homeostasis and its representative pathosis is defined as secondary hyperparathyroidism (SHPT). SHPT occurs during the early course of progressive renal insufficiency, and is associated with mortality and cardiovascular events. SHPT results in reduction of calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) in the parathyroid glands during CKD. However, the precise mechanism of CaSR and VDR reduction is largely unknown. CKD was induced through two-step 5/6 nephrectomy, and then CKD rats and sham-operated rats were maintained for 8 weeks on diets containing 0.7 % phosphorus (normal phosphate) or 1.2 % phosphorus (high phosphate). In gene expression analysis, TaqMan probes were used for quantitative real-time polymerase chain reaction. Finally, CaSR and VDR protein expressions were analyzed using immunohistochemistry. DNA methylation analysis was performed using a restriction digestion and quantitative PCR. CaSR and VDR mRNA were reduced only in CKD rats fed the high-phosphorus diets (CKD HP), then CaSR and VDR immunohistochemical expressions were compatible with gene expression assay. SHPT was then confirmed only in CKD HP rats. Furthermore, sole CKD HP rats showed the hypermethylation in CaSR and VDR genes; however, the percentage methylation of both genes was low. Although CaSR and VDR hypermethylation was demonstrated in PTGs of CKD HP rats, the extent of hypermethylation was insufficient to support the relevance between hypermethylation and down-regulation of gene expression because of the low percentage of methylation. Consequently, our data suggest that mechanisms, other than DNA hypermethylation, were responsible for the reduction in mRNA and protein levels of CaSR and VDR in PTGs of CKD HP rats.
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Quantitative Information on Oncology Prescription Drug Websites
Abstract
Our objective was to determine whether and how quantitative information about drug benefits and risks is presented to consumers and healthcare professionals on cancer-related prescription drug websites. We analyzed the content of 65 active cancer-related prescription drug websites. We assessed the inclusion and presentation of quantitative information for two audiences (consumers and healthcare professionals) and two types of information (drug benefits and risks). Websites were equally likely to present quantitative information for benefits (96.9 %) and risks (95.4 %). However, the amount of the information differed significantly: Both consumer-directed and healthcare-professional-directed webpages were more likely to have quantitative information for every benefit (consumer 38.5 %; healthcare professional 86.1 %) compared with every risk (consumer 3.1 %; healthcare professional 6.2 %). The numeric and graphic presentations also differed by audience and information type. Consumers have access to quantitative information about oncology drugs and, in particular, about the benefits of these drugs. Research has shown that using quantitative information to communicate treatment benefits and risks can increase patients' and physicians' understanding and can aid in treatment decision-making, although some numeric and graphic formats are more useful than others.
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Oroxylin a could be a Promising Radiosensitizer for Esophageal Squamous Cell Carcinoma by Inducing G2/M Arrest and Activating Apoptosis
Abstract
To evaluate the radiosensitization of Oroxylin A on esophageal carcinoma cell as well as the optimal scheduling of Oroxylin A and radiotherapy (RT). Cell proliferation was estimated by a CCK8 assay. Radiosensitization was evaluated by a clonogenic survival assay. The progressions of Cell apoptosis and Cell cycle were investigated by flow cytometry. Expressions of survivin and cell cycle regulators were evaluated by Western blot analysis. A dose-dependent cell survival reduction was found in response to radiation with or without Oroxylin A. The apoptosis rates were remarkably dose-dependent higher in combination groups than in either Oroxylin A or radiation alone group. Besides, Oroxylin A could obviously radiosensitize ESCC cells by arresting tumor cells in G2/M phase and regulating cyclin B1 and Cdc 2 protein expression. Oroxylin A could be a promising radiosensitizer for esophageal squamous cell carcinoma by inducing G2/M phase blocking and activating cell apoptosis.
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MicroRNA-Mediated Post-Transcriptional Regulation of Epithelial to Mesenchymal Transition in Cancer
Abstract
Epithelial to mesenchymal transition (EMT) program participates in tissue repair, embryogenesis and numerous pathological conditions, particularly cancer progression and tumor metastasis. A highly complex and strongly controlled post-transcriptionally regulated network of microRNAs (miRNAs) regulates the EMT process. miRNAs are critical parts of the post-transcriptional regulation of gene expression. A set of miRNAs target multiple components of major signaling pathways and downstream effectors of EMT. miRNAs associated with this process are involved in controlling tumor progression and invasiveness either as oncogenes or as tumor suppressors. Since several miRNAs directly affect EMT-related master regulators, they have been discovered to have the potential to be used as biomarkers or targets in EMT-based pathological conditions such as cancer. Therefore, comprehensive understanding of miRNA-EMT correlation with tumor metastatic spread may provide improvements to diagnostic tools or therapeutics for cancer. This review summarizes our current knowledge about some of these important miRNAs and focuses on their specific roles in regulation of the EMT process in cancer.
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Panax notoginseng saponins administration modulates pro- /anti-inflammatory factor expression and improves neurologic outcome following permanent MCAO in rats
Abstract
Ischemic stroke, particularly permanent occlusion, accounts for the overwhelming majority of all strokes. In addition to the occlusion of arteries, the inflammatory response plays a pivotal role in the severity of the cerebral injury and its clinical prognosis. Here, panax notoginseng saponins (PNS) extracted from a traditional Chinese herbal medicine was administered following permanent middle cerebral artery occlusion (MCAO) in rats to explore the neuroprotective mechanisms against ischemic injury. The results showed that MCAO surgery was successful in producing an infarct and that PNS and nimodipine could ameliorate the neurological deficits. The expression levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) were increased, while the level of interleukin-10 (IL-10) was reduced in the infarct cortex 7 days after MCAO, as assessed by immunohistochemistry, western blotting and quantitative real-time PCR (qRT-PCR). PNS was able to markedly reduce the overexpression of IL-1β and TNF-α while significantly promoting the expression of IL-10, but did not affect the elevated expression of TGF-β1. Meanwhile, nimodipine was able to significantly reduce the expression of IL-1β and TNF-α, but had no obvious effect on IL-10 or TGF-β1. In addition, the serum levels of TNF-α, IL-10 and TGF-β1 were basically consistent with cerebral tissue results; however, the IL-1β levels did not differ. We conclude that PNS can directly down-regulate the overexpression of proinflammatory factors IL-1β and TNF-α while up-regulating the expression of anti-inflammatory factor IL-10 in the core region of the cerebral infarct, thereby preventing neurological damage in rats after permanent MCAO.
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Measurement error in CT assessment of appendix diameter
Abstract
Background
Appendiceal diameter continues to be cited as an important criterion for diagnosis of appendicitis by computed tomography (CT).
Objective
To assess sources of error and variability in appendiceal diameter measurements by CT.
Materials and methods
In this institutional review board-approved review of imaging and medical records, we reviewed CTs performed in children <18 years of age between Jan. 1 and Dec. 31, 2010. Appendiceal diameter was measured in the axial and coronal planes by two reviewers (R1, R2). One year later, 10% of cases were remeasured. For patients who had multiple CTs, serial measurements were made to assess within patient variability. Measurement differences between planes, within and between reviewers, within patients and between CT and pathological measurements were assessed using correlation coefficients and paired t-tests.
Results
Six hundred thirty-one CTs performed in 519 patients (mean age: 10.9 ± 4.9 years, 50.8% female) were reviewed. Axial and coronal measurements were strongly correlated (r = 0.92-0.94, P < 0.0001) with coronal plane measurements significantly larger (P < 0.0001). Measurements were strongly correlated between reviewers (r = 0.89-0.9, P < 0.0001) but differed significantly in both planes (axial: +0.2 mm, P=0.003; coronal: +0.1 mm, P=0.007). Repeat measurements were significantly different for one reviewer only in the axial plane (0.3 mm difference, P<0.05). Within patients imaged multiple times, measured appendix diameters differed significantly in the axial plane for both reviewers (R1: 0.5 mm, P = 0.031; R2: 0.7 mm, P = 0.022).
Conclusion
Multiple potential sources of measurement error raise concern about the use of rigid diameter cutoffs for the diagnosis of acute appendicitis by CT.
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What did Sun Yat-sen really die of? A re-assessment of his illness and the cause of his death
Abstract
This year is the 150th anniversary of the birth of Sun Yat-sen (November 12, 1866) and the 91st year following his death (March 12, 1925). It generally has been believed that the cause of his death was "liver cancer." However, as indicated in the official autopsy report, dated March 13, 1925, of the Peking Union Medical College Hospital (PUMCH) in Beijing, the cause of his death in reality was an adenocarcinoma of the gallbladder with direct extension to the liver and diaphragm as well as widespread metastases to the peritoneal cavity. This important piece of information seems to have never been reported in the English language literature, and it was only in 2013 that the true cause of his death was stated in a one-line sentence in a non-medical Chinese online source. It had been mistakenly believed that the cause of Dr. Sun's death was liver cancer, based on the observations made following an exploratory laparotomy, which had been performed at PUMCH on January 26, 1925. The purpose of this short report is to provide more details relating to his terminal illness and to correct the historical record for a medical audience as to the cause of the death of Sun Yat-sen, a very important figure in the history of 20th century China.
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Eco-Friendly Synthesis of Silver Nanoparticles Through Economical Methods and Assessment of Toxicity Through Oxidative Stress Analysis in the Labeo Rohita
Abstract
The physicochemical and biological properties of metals change as the particles are reduced to nanoscale. This ability increases the application of nanoparticles in commercial and medical industry. Keeping in view this importance, Silver nanoparticles (Ag-NPs) were synthesized by reduction methods using formaldehyde as reducing agent in the chemical route and lemon extracts in the biological route. The scanning electron microscope (SEM) images of nanoparticles suggested that the particles were either agglomerated or spherical in shape with mean diameter of 16.59 nm in the chemical route and 42.93 nm in the biological route. The particles were between 5 and 80 nm with maximum frequency between 5 and 20 nm in the chemical route and between 5 and 100 nm with maximum frequency between 15 and 50 nm in the biological method. In the second phase of the study, the effect of Ag-NPs on the oxidative stress was studied. For this purpose, Labeo rohita (20 ± 2.5 g in weight and 12 ± 1.4 cm in length) were involved. Six treatments were applied in three replicates having five fishes in each replicate. The first treatment was used as control group, and the other five treatments were exposed to either 10 or 20 or 30 or 45 or 55 mg L−1 of Ag-NPs for 28 days. The treatment of Ag-NPs caused oxidative stress in the liver and gill tissues, which induced alterations in the activities of antioxidant enzymes. The level of catalase (CAT) was decreased in response to Ag-NPs concentration in dose-dependent manner. Ag-NPs treatment stimulated the liver and gill tissues to significantly increase the level of superoxide dismutase (SOD), which might be due to synthesis of SOD and addition in the pre-existing SOD level. The level decreases again due to depletion of SOD level. There was a sharp decline in the activities of glutathione S-transferase (GST) in both gills and liver tissues even at lower concentration, and this decrease in the GST activity was significantly different at each treatment after 28 days of treatment except 20 mg L−1. The malondialdehyde (MDA) levels of gills and liver tissues were increased with the increase in the concentration. The elevated levels of glutathione (GSH) showed that the liver started defensive mechanism against the oxyradicals. This study finds out the cheap eco-friendly and economical method of Ag-NP synthesis. It is further revealed that Ag-NPs caused oxidative stress in the aquatic animals if exposure occurs at high concentrations.
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Cancers, Vol. 8, Pages 83: Prospects in the Application of Photodynamic Therapy in Oral Cancer and Premalignant Lesions
Oral cancer is a global health burden with significantly poor survival, especially when the diagnosis is at its late stage. Despite advances in current treatment modalities, there has been minimal improvement in survival rates over the last five decades. The development of local recurrence, regional failure, and the formation of second primary tumors accounts for this poor outcome. For survivors, cosmetic and functional compromises resulting from treatment are often devastating. These statistics underscore the need for novel approaches in the management of this deadly disease. Photodynamic therapy (PDT) is a treatment modality that involves administration of a light-sensitive drug, known as a photosensitizer, followed by light irradiation of an appropriate wavelength that corresponds to an absorbance band of the sensitizer. In the presence of tissue oxygen, cytotoxic free radicals that are produced cause direct tumor cell death, damage to the microvasculature, and induction of inflammatory reactions at the target sites. PDT offers a prospective new approach in controlling this disease at its various stages either as a stand-alone therapy for early lesions or as an adjuvant therapy for advanced cases. In this review, we aim to explore the applications of PDT in oral cancer therapy and to present an overview of the recent advances in PDT that can potentially reposition its utility for oral cancer treatment.
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Treatment Interval between Neoadjuvant Chemoradiotherapy and Surgery in Rectal Cancer Patients: A Population-Based Study
Abstract
Background
Neoadjuvant chemoradiation therapy (CRT) has been widely implemented in the treatment of rectal cancer patients, but optimal timing of surgery after neoadjuvant therapy is unclear. The purpose of this study was to evaluate the effects of prolonged intervals between long-course CRT and surgery in rectal cancer patients.
Methods
Data on all rectal cancer patients diagnosed between 2006 and 2011 were retrieved from the population-based Netherlands Cancer Registry; the main outcome parameters were pathologic complete response (pCR) and overall survival (OS). Outcomes were reported separately for patients with early tumors (ETs; N = 217) and locally advanced rectal cancer (LARC; N = 1073). Patients were divided into 2-week interval groups according to treatment interval, ranging from 5–6 to 13–14 weeks. Kaplan–Meier curves, and logistic regression and Cox regression models were used for data analysis.
Results
No significant difference in pCR rate was observed for ET patients according to treatment interval. Compared with a treatment interval of 7–8 weeks, pCR rates in LARC patients were higher after 9–10 weeks (18.4 %; odds ratio [OR] 1.56, 95 % CI 1.03–2.37) and 11–12 weeks of treatment interval (20.8 %; OR 1.94, 95 % CI 1.15–3.26). Treatment interval did not influence OS in ET or LARC patients.
Conclusions
Treatment intervals of 9–12 weeks between surgery and CRT seem to improve the chances of pCR in LARC patients, without an effect on OS. The length of treatment interval did not affect outcomes in patients with ET. The ongoing search for minimally invasive surgery drives the need for exploration of factors that improve pathologic response.
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Low Preoperative Prognostic Nutritional Index Predicts Poor Survival Post-gastrectomy in Elderly Patients with Gastric Cancer
Abstract
Background
Preoperative nutritional status may predict short- and long-term outcomes of patients with cancer.
Objective
The aim of this study was to clarify the impact of preoperative nutritional status on outcomes of elderly patients who have undergone gastrectomy for gastric cancer (GC).
Methods
A review examining 147 patients treated for GC by gastrectomy at our institution between January 2004 and December 2011 was conducted. Onodera's prognostic nutritional index (PNI) was invoked, using an optimal cutpoint to stratify patients by high (PNI > 43.8; n = 84) or low (PNI ≤ 43.8; n = 63) nutritional status. Clinicopathologic features and short- and long-term outcomes, including the cause of death, were compared.
Results
In multivariate analysis, low PNI was identified as an independent correlate of poor 5-year overall survival (OS). In subgroup analysis, 5-year OS rates for patients with stage 1 GC were significantly worse in the low PNI (vs. high PNI) patient subset, which also posed a significantly higher risk of death from other disease; however, 5-year cancer-specific survival and PNI were unrelated. Deaths from recurrence in both groups were statistically similar, and morbidity rates did not differ significantly by group.
Conclusions
PNI is useful in predicting long-term outcomes of elderly patients surgically treated for GC, helping to identify those at high risk of death from other disease. In an effort to improve patient outcomes, nutritional status and oncologic staging merit attention.
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LYMPHA Technique to Prevent Secondary Lower Limb Lymphedema
Abstract
Background
Inguinofemoral lymphadenectomy carries a high risk of lower limb lymphedema. This report describes the feasibility of performing multiple lymphatic-venous anastomoses (MLVA) after inguinofemoral lymph node completion (LYMPHA technique) and the possible benefit of LYMPHA for preventing lymphedema.
Methods
Between February, 2011 and October, 2014, 11 patients with vulvar cancer and 16 patients with melanoma of the trunk requiring inguinofemoral lymphadenectomy underwent lymph node dissection and the LYMPHA technique. Blue dye was injected into the thigh 10 min before surgery. Lymphatics afferent to the blue nodes were used to perform MLVA using a collateral branch of the great saphenous vein.
Results
The mean age of patients in the vulvar cancer group was 52 years (range, 48–75 years). The melanoma group comprised seven men and nine women with a mean age of 41 years (range, 37–56 years). Of the 16 patients, 5 with vulvar cancer underwent bilateral inguinofemoral lymphadenectomy, whereas the remaining 6 patients with vulvar cancer and all 16 patients with melanoma of the trunk had unilateral node dissection. All the patients were treated by the LYMPHA technique. No lymphocele or infectious complications occurred. Transient lower-extremity edema occurred for one melanoma patient (6.25 %), which resolved after 2 months, and permanent lower-extremity edema occurred for one patient (9 %) with vulvar cancer.
Conclusions
The LYMPHA technique appears to be feasible, safe, and effective for the prevention of lower limb lymphedema, thereby improving the patient's quality of life and decreasing health care costs.
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Clinical Impact of Intraoperative Cytological Assessment of Bone Resection Margins in Patients with Head and Neck Carcinoma
Abstract
Background
Surgical treatment of head and neck squamous cell carcinoma (HNSCC) patients often results in complex defects, affecting functional structures. Frozen sections are valuable to guide resections and control for adequate margins; however, intraoperative assessment of bone remains challenging.
Objective
The objective of this study was to evaluate the clinical impact of an intraoperative cytological assessment of bone margins (ICAB) on resection status and patient outcome.
Methods
ICAB analysis (n = 267) was implemented in 102 patients during resection of HNSCC for a guided resection of affected bone. The cytological findings were compared with the final histological results of the corresponding bone margins, and the surgical consequences, R1 rates, and patient outcome of the ICAB intervention group were compared with an equal control group of 100 patients.
Results
ICAB revealed a sensitivity of 94.4 % [95 % confidence interval (CI) 81.3–99.3], specificity of 97.4 % (95 % CI 94.4–99.0), positive predictive value of 85.0 % (95 % CI 70.2–94.3), and negative predictive value of 99.1 % (95 % CI 96.9–99.9). Osseous R1 resections were reduced from 8 to 2.9 % (∆R1 = 5.1 %; p = 0.113), rendering a relative risk reduction (RRR) of 63.2 % with a number needed to treat (NNT) of 19.57. ICAB influenced final resection status, with a reduction of R1 resections from 17 to 7.8 % (∆R1 = 9.2 %; p = 0.026), with an RRR of 59.65 % and an NNT of 9.66. The ICAB intervention group revealed a higher disease-free survival [p(log-rank) = 0.045] and overall survival [p(log-rank) = 0.014] according to multivariable analysis.
Conclusion
ICAB, applied as a routine diagnostic tool to supplement frozen sections, can help to reduce R1 resections in order to improve patient outcome.
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A Randomized Clinical Trial of Preoperative Administration of Branched-Chain Amino Acids to Prevent Postoperative Ascites in Patients with Liver Resection for Hepatocellular Carcinoma
Abstract
Background
Massive postoperative ascites remains a major threat that can lead to liver failure and other fatal complications, especially in patients with poor liver function. Branched-chain amino acid (BCAA) administration increases biosynthesis and secretion of albumin by hepatocytes and increases oncotic pressure by elevating blood albumin concentration, thereby decreasing peripheral edema, ascites, and pleural effusion.
Method
We randomly allocated consecutive patients undergoing major liver resection for hepatocellular carcinoma to either a group where oral BCAA administration was initiated 3 weeks before liver resection, or a non-BCAA group. The primary study endpoint was development of postoperative ascites.
Results
Overall, 39 patients were allocated to the BCAA group, while 38 were assigned to the non-BCAA group. No significant difference in the rate of refractory ascites, considered alone, was evident between the BCAA (5.1 %) and non-BCAA groups (13.2 %; p = 0.263). However, the occurrence of refractory ascites and/or pleural effusion was significantly less frequent in the BCAA group (5.1 %) than in the non-BCAA group (21.1 %; p = 0.047). Furthermore, the postoperative serum concentration of reduced-state albumin was greater immediately after liver resection in the BCAA group than in the non-BCAA group.
Conclusion
Preoperative administration of BCAA did not significantly improve prevention of refractory ascites, but significant effectiveness in preventing ascites, pleural effusion, or both, as well as improving metabolism of albumin, was demonstrated [University Hospital Medical Information Network (UMIN) reference number 000004244].
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Sentinel Node Mapping in Cervical and Endometrial Cancer: Indocyanine Green Versus Other Conventional Dyes—A Meta-Analysis
Abstract
Background
Historically, blue dyes, 99Tc or a combination of the two tracers have been used for sentinel lymph node (SLN) mapping in cervical and endometrial cancer patients. Indocyanine green (ICG), as a tracer, has been recently introduced in this setting. Our goal was to assess the differences in overall and bilateral detection rates as well as in false-negative rates among the different tracers.
Methods
The electronic databases PubMed, MEDLINE, and Scopus were searched in January 2016 by searching the terms "sentinel lymph node" and "dye" and "indocyanine green," and "cervical cancer" or "endometrial cancer." Series comparing different tracers injected intracervically and reporting the detection rate and/or SLN false-negative rate were selected.
Results
Forty-five studies were retrieved. Six studies including 538 patients met selection criteria. Compared with blue dyes, ICG SLN mapping had higher overall (odds ratio [OR] 0.27; 95 % confidence interval [CI] 0.15–0.50; p < 0.0001) and bilateral detection rates (OR 0.27; 95 % CI 0.19–0.40; p < 0.00001). No differences were found between ICG and 99TC, although these results are based on data of a single series. No differences in overall and bilateral detection rates were found between ICG and the combination of blue dyes and 99TC. The pooled analysis of false-negative rates data showed no difference in false-negative rates between tracers.
Conclusions
In cervical and endometrial cancer, ICG SLN mapping seems to be equivalent to the combination of blue dyes and 99TC in terms of overall and bilateral detection rates. Its safety profile and ease of use may favor its employment respect to conventional tracers.
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Do LORIS Trial Eligibility Criteria Identify a Ductal Carcinoma In Situ Patient Population at Low Risk of Upgrade to Invasive Carcinoma?
Abstract
Background
The Surgery Versus Active Monitoring for Low-Risk DCIS (LORIS) trial is studying the safety of monitoring core-biopsy diagnosed low-risk ductal carcinoma in situ (DCIS) without excision. We sought to determine the incidence and characteristics of synchronous invasive carcinoma found in LORIS-eligible women who underwent excision, as this knowledge is essential in assessing the safety of observation alone.
Methods
Women meeting LORIS eligibility criteria (age ≥46 years, screen-detected calcifications, non-high-grade DCIS diagnosed by core biopsy, absence of nipple discharge, or strong family history of breast cancer) who underwent surgical excision from 2009 to 2012 were identified. Histologic findings of excision specimens were reviewed.
Results
Overall, 296 LORIS-eligible cases were identified; 58 (20 %) had invasive carcinoma on final pathology (90 % invasive ductal, 78 % >1 mm in size, 21 % high grade, 3 % triple negative, 9 % HER2 amplified). Of these, 18 (31 %) were pT1b or larger and 3 (5 %) were pN1. Among eligible upgraded cases, 90 % received radiation, 89 % received endocrine therapy, and 18 % were recommended chemotherapy. Women upgraded to invasive carcinoma were more likely to have intermediate-grade DCIS on core biopsy and to have undergone mastectomy.
Conclusions
Among LORIS-eligible women, 20 % had invasive carcinoma at surgical excision that was heterogeneous in grade, size, and receptor status. Information gained from surgical excision influenced receipt of adjuvant radiation and endocrine therapy in most patients, and indicated benefit from chemotherapy in 18 % of patients. Surgical excision is warranted until additional risk stratification is available to identify a cohort of DCIS patients at lower risk for clinically significant synchronous invasive carcinoma.
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Neoadjuvant Systemic Therapy for Breast Cancer: Factors Influencing Surgeons’ Referrals
Abstract
Background
This study aimed to assess the influence of disease- and patient-related factors on surgeons' decisions to refer patients with early-stage breast cancer (EBC) for neoadjuvant systemic therapy (NST).
Methods
An online survey of United States surgeons evaluated the influence of selected disease- and patient-related factors on surgeons' decisions, rated their influence (individually and in combination), and provided a relative ranking of jointly considered factors using best–worst scaling.
Results
The participants in this study were 100 licensed surgeons. The surgeons referred approximately 25 % of EBC patients for NST to improve surgical management. Approximately 75 % of the surgeons agreed that NST is important for EBC, if only to improve surgical management. More than half were "very likely" to refer EBC patients for NST based on anatomicopathologic factors. Less than 50 % were "very likely" to do so when considering tumor phenotype factors. Tumor size and lymph node status were ranked highest in hypothetical patient scenarios. Regarding combinations of factors, the importance of any single factor varied according to the combinations presented. Less than half of the respondents were "very familiar," and half were "somewhat familiar" with NST guidelines for breast cancer. More than half of the respondents were unaware that findings have shown achievement of pathologic complete response (pCR) after NST to be associated with improved survival.
Conclusions
Surgeons' decision to refer for NST is strongly driven by surgical management goals. Anatomicopathologic factors are more influential than tumor phenotype. However, no single disease or patient factor consistently drives the decision to refer for NST. Surgeons' awareness of the association between pCR achievement and longer survival could be improved.
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