Local relapse of nasopharyngeal cancer and Voxel-based analysis of FMISO uptake using PET with semiconductor detectors

Abstract

Background

Hypoxic cancer cells are thought to be radioresistant and could impact local recurrence after radiotherapy (RT). One of the major hypoxic imaging modalities is [¹⁸F]fluoromisonidazole positron emission tomography (FMISO-PET). High FMISO uptake before RT could indicate radioresistant sites and might be associated with future local recurrence. The predictive value of FMISO-PET for intra-tumoral recurrence regions was evaluated using high-resolution semiconductor detectors in patients with nasopharyngeal carcinoma after intensity-modulated radiotherapy (IMRT).

Methods

Nine patients with local recurrence and 12 patients without local recurrence for more than 3 years were included in this study. These patients received homogeneous and standard doses of radiation to the primary tumor irrespective of FMISO uptake. The FMISO-PET image before RT was examined via a voxel-based analysis, which focused on the relationship between the degree of FMISO uptake and recurrence region.

Results

In the pretreatment FMISO-PET images, the tumor-to-muscle ratio (TMR) of FMISO in the voxels of the tumor recurrence region was significantly higher than that of the non-recurrence region (p < 0.0001). In the recurrent patient group, a TMR value of 1.37 (95% CI: 1.36–1.39) corresponded to a recurrence rate of 30%, the odds ratio was 5.18 (4.87–5.51), and the area under the curve (AUC) of the receiver operating characteristic curve was 0.613. In all 21 patients, a TMR value of 2.42 (2.36–2.49) corresponded to an estimated recurrence rate of 30%, and the AUC was only 0.591.

Conclusions

The uptake of FMISO in the recurrent region was significantly higher than that in the non-recurrent region. However, the predictive value of FMISO-PET before IMRT is not sufficient for up-front dose escalation for the intra-tumoral high-uptake region of FMISO. Because of the higher mean TMR of the recurrence region, a new hypoxic imaging method is needed to improve the sensitivity and specificity for hypoxia.

http://ift.tt/2wENuO2

A case of pure red cell aplasia during nivolumab therapy for cardiac metastatic melanoma.

Nivolumab is an antibody against programmed cell death 1 and functions as an immune checkpoint inhibitor for various malignancies, including unresectable melanomas. Nivolumab causes several immune-related adverse events, which typically include skin rash, pneumonitis, thyroid dysfunction, hepatitis, and colitis; in rare cases, anemia may be present. There are several reports of autoimmune hemolytic anemia that has developed in response to nivolumab; however, there are few reports of pure red cell aplasia (PRCA). We describe a patient who developed PRCA during nivolumab administration. A 70-year-old Japanese woman received nivolumab for cardiac metastasis from malignant melanoma from an unknown site. Twenty-one months after nivolumab administration (31 courses), treatment was discontinued because she developed severe anemia. Blood test results indicated normocytic, normochromic anemia, and reticulocytopenia, but all other components were normal. Bone marrow aspiration showed increased megakaryocytes and decreased erythroblasts; these findings were consistent with PRCA. Anemia improved without recurrence after treatment with corticosteroids and blood transfusions. The steroid dosage was reduced gradually, and to date, the patient has not experienced recurrence of anemia. The tumor decreased in size and the patient has shown a continued response to treatment with decrease in disease for 3 years. Although it is unclear how nivolumab causes PRCA, hematological toxicities have been reported in patients treated with immunotherapy drugs. PRCA might be an unrecognized immune-mediated adverse event that did not manifest during the clinical trial phase. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2w5I8Yx

Acute motor and sensory axonal neuropathy related to treatment with MEK inhibitors in a patient with advanced melanoma.

Approximately one-half of advanced cutaneous melanomas have a V600 mutation in the BRAF gene that activates the mitogen-activated protein kinase pathway. The combination of BRAF plus MEK inhibitors is one of the most effective treatments for these patients. Severe neurological toxicities have been reported in the literature. However, these toxicities are very rare. Here, we present one patient with acute motor and sensory axonal neuropathy, which is a subtype of Guillain-Barre syndrome, secondary to treatment with MEK inhibitors. This side effect had never been described as related to these agents. However, the mitogen-activated protein kinase pathway can be involved in Guillain-Barre syndrome, and awareness of early neurological injury signs is important in patients treated with MEK inhibitors. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2wEMdqe

Clinical grade manufacturing of genetically modified, CAR-expressing NK-92 cells for the treatment of ErbB2-positive malignancies

Abstract

Background

The NK-92/5.28.z cell line (also referred to as HER2.taNK) represents a stable, lentiviral-transduced clone of ErbB2 (HER2)-specific, second-generation CAR-expressing derivative of clinically applicable NK-92 cells. This study addresses manufacturing-related issues and aimed to develop a GMP-compliant protocol for the generation of NK-92/5.28.z therapeutic doses starting from a well-characterized GMP-compliant master cell bank.

Materials and methods

Commercially available GMP-grade culture media and supplements (fresh frozen plasma, platelet lysate) were evaluated for their ability to support expansion of NK-92/5.28.z. Irradiation sensitivity and cytokine release were also investigated.

Results

NK-92/5.28.z cells can be grown to clinically applicable cell doses of 5 × 10⁸ cells/L in a 5-day batch culture without loss of viability and potency. X-Vivo 10 containing recombinant transferrin supplemented with 5% FFP and 500 IU/mL IL-2 in VueLife 750-C1 bags showed the best results. Platelet lysate was less suited to support NK-92/5.28.z proliferation. Irradiation with 10 Gy completely abrogated NK-92/5.28.z proliferation and preserved viability and potency for at least 24 h. NK-92/5.28.z showed higher baseline cytokine release compared to NK-92, which was significantly increased upon encountering ErbB2(+) targets [GZMB (twofold), IFN-γ (fourfold), IL-8 (24-fold) and IL-10 (fivefold)]. IL-6 was not released by NK cells, but was observed in some stimulated targets. Irradiation resulted in upregulation of IL-8 and downregulation of sFasL, while other cytokines were not impacted.

Conclusion

Our concept suggests NK-92/5.28.z maintenance culture from which therapeutic doses up to 5 × 10⁹ cells can be expanded in 10 L within 5 days. This established process is feasible to analyze NK-92/5.28.z in phase I/II trials.

http://ift.tt/2xNNgmi

High mobility group box 1 enhances hyperthermia-induced seizures and secondary epilepsy associated with prolonged hyperthermia-induced seizures in developing rats

Abstract

Levels of high mobility group box 1 (HMGB1), an important inflammatory mediator, are high in the serum of febrile seizure (FS) patients. However, its roles in FS and secondary epilepsy after prolonged FS are poorly understood. We demonstrate HMGB1's role in the pathogenesis of hyperthermia-induced seizures (HS) and secondary epilepsy after prolonged hyperthermia-induced seizures (pHS). In the first experiment, 14–15-day-old male rats were divided into four groups: high-dose HMGB1 (100 μg), moderate-dose (10 μg), low-dose (1 μg), and control. Each rat was administered HMGB1 intranasally 1 h before inducing HS. Temperature was measured at seizure onset with electroencephalography (EEG). In the second experiment, 10–11-day-old rats were divided into four groups: pHS + HMGB1 (10 μg), pHS, HMGB1, and control. HMGB1 was administered 24 h after pHS. Video-EEGs were recorded for 24 h at 90 and 120 days old; histological analysis was performed at 150 days old. In the first experiment, the temperature at seizure onset was significantly lower in the high- and moderate-dose HMGB1 groups than in the control group. In the second experiment, the incidence of spontaneous epileptic seizure was significantly higher in the pHS + HMGB1 group than in the other groups. Comparison between pHS + HMGB1 groups with and without epilepsy revealed that epileptic rats had significantly enhanced astrocytosis in the hippocampus and corpus callosum. In developing rats, HMGB1 enhanced HS and secondary epilepsy after pHS. Our findings suggest that HMGB1 contributes to FS pathogenesis and plays an important role in the acquired epileptogenesis of secondary epilepsy associated with prolonged FS.

http://ift.tt/2x9XOPu

Second opinion strategies in breast pathology: a decision analysis addressing over-treatment, under-treatment, and care costs

Abstract

Purpose

To estimate the potential near-term population impact of alternative second opinion breast biopsy pathology interpretation strategies.

Methods

Decision analysis examining 12-month outcomes of breast biopsy for nine breast pathology interpretation strategies in the U.S. health system. Diagnoses of 115 practicing pathologists in the Breast Pathology Study were compared to reference-standard-consensus diagnoses with and without second opinions. Interpretation strategies were defined by whether a second opinion was sought universally or selectively (e.g., 2nd opinion if invasive). Main outcomes were the expected proportion of concordant breast biopsy diagnoses, the proportion involving over- or under-interpretation, and cost of care in U.S. dollars within one-year of biopsy.

Results

Without a second opinion, 92.2% of biopsies received a concordant diagnosis. Concordance rates increased under all second opinion strategies, and the rate was highest (95.1%) and under-treatment lowest (2.6%) when all biopsies had second opinions. However, over-treatment was lowest when second opinions were sought selectively for initial diagnoses of invasive cancer, DCIS, or atypia (1.8 vs. 4.7% with no 2nd opinions). This strategy also had the lowest projected 12-month care costs ($5.907 billion vs. $6.049 billion with no 2nd opinions).

Conclusions

Second opinion strategies could lower overall care costs while reducing both over- and under-treatment. The most accurate cost-saving strategy required second opinions for initial diagnoses of invasive cancer, DCIS, or atypia.

http://ift.tt/2wESzpB

Disease-stabilizing treatment based on all-trans retinoic acid and valproic acid in acute myeloid leukemia – identification of responders by gene expression profiling of pretreatment leukemic cells

Abstract

Background

Acute myeloid leukemia (AML) is an aggressive malignancy only cured by intensive therapy. However, many elderly and unfit patients cannot receive such treatment due to an unacceptable risk of treatment-related morbidity and mortality. Disease-stabilizing therapy is then the only possible strategy, one alternative being treatment based on all-trans retinoic acid (ATRA) combined with the histone deacetylase inhibitor valproic acid and possibly low-toxicity conventional chemotherapy.

Methods

Primary AML cells were derived from 43 patients included in two clinical studies of treatment based on ATRA, valproic acid and theophyllamine; low toxicity chemotherapy (low-dose cytarabine, hydroxyurea, 6-mercaptopurin) was also allowed. Pretreatment leukemic cells were analyzed by mutation profiling of 54 genes frequently mutated in myeloid malignancies and by global gene expression profiling before and during in vivo treatment.

Results

Patients were classified as responders and non-responders to the treatment, however response to treatment showed no significant associations with karyotype or mutational profiles. Significance analysis of microarray (SAM) showed that responders and non-responders significantly differed with regard to the expression of 179 different genes. The differentially expressed genes encoding proteins with a known function were further classified based on the PANTHER (protein annotation through evolutionary relationship) classification system. The identified genes encoded proteins that are involved in several important biological functions, but a main subset of the genes were important for transcriptional regulation. These pretherapy differences in gene expression were largely maintained during treatment. Our analyses of primary AML cells during in vivo treatment suggest that ATRA modulates HOX activity (i.e. decreased expression of HOXA3, HOXA4 and HOXA5 and their regulator PBX3), but altered function of DNA methyl transferase 3A (DNMT3A) and G-protein coupled receptor signaling may also contribute to the effect of the overall treatment.

Conclusions

Responders and non-responders to AML stabilizing treatment based on ATRA and valproic acid differ in the pretreatment transcriptional regulation of their leukemic cells, and these differences may be important for the clinical effect of this treatment.

Trial registrations

ClinicalTrials.gov no. NCT00175812; EudraCT no. 2004–001663-22, registered September 9, 2005 and ClinicalTrials.gov no. NCT00995332; EudraCT no. 2007–2007–001995-36, registered October 14, 2009.

http://ift.tt/2eJPxtQ

Target volume delineation of anal cancer based on magnetic resonance imaging or positron emission tomography

Abstract

Purpose

To compare target volume delineation of anal cancer using positron emission tomography (PET) and magnetic resonance imaging (MRI) with respect to inter-observer and inter-modality variability.

Methods

Nineteen patients with anal cancer undergoing chemoradiotherapy were prospectively included. Planning computed tomography (CT) images were co-registered with 18F–fluorodexocyglucose (FDG) PET/CT images and T2 and diffusion weighted (DW) MR images. Three oncologists delineated the Gross Tumor Volume (GTV) according to national guidelines and the visible tumor tissue (GTV_T). MRI and PET based delineations were evaluated by absolute volumes and Dice similarity coefficients.

Results

The median volume of the GTVs was 27 and 31 cm³ for PET and MRI, respectively, while it was 6 and 11 cm³ for GTV_T. Both GTV and GTV_T volumes were highly correlated between delineators (r = 0.90 and r = 0.96, respectively). The median Dice similarity coefficient was 0.75 when comparing the GTVs based on PET/CT (GTV_PET) with the GTVs based on MRI and CT (GTV_MRI). The median Dice coefficient was 0.56 when comparing the visible tumor volume evaluated by PET (GTV_{T_PET}) with the same volume evaluated by MRI (GTV_{T_MRI}). Margins of 1–2 mm in the axial plane and 7–8 mm in superoinferior direction were required for coverage of the individual observer's GTVs.

Conclusions

The rather good agreement between PET- and MRI-based GTVs indicates that either modality may be used for standard target delineation of anal cancer. However, larger deviations were found for GTV_T, which may impact future tumor boost strategies.

http://ift.tt/2wG7sWZ

Ternary cocktail nanoparticles for sequential chemo-photodynamic therapy

Abstract

Background

Previous clinical trials have already demonstrated that combinations of two or more drugs were more effective in the cancer treatment, especially sequential photodynamic design combing with sequential chemotherapy. In our study, we propose a ternary cocktail NP delivery system based on self-decomposable NPs, which could realize synergistic chemo-photodynamic therapy through double loading chemo-drugs and multi-level programmable PDT treatment.

Methods

PS drug methylene blue (MB) was encapsulated into the center of the NP_small, NP_big&thin, and NP_big&thick carriers through "grown-in" loading mechanism, which was released based on the drug concentration difference of the drug release environment. NP_small, NP_big&thin, and NP_big&thick carriers have three different drug release profiles, which could realize multi-level programmable PDT treatment. At the same time, antitumor drug gemcitabine hydrochloride (GM) and Docetaxel (DTX), were chosen as the double loading chemo-drugs that absorbed onto the NP_big&thin and NP_big&thick surface, respectively. In specific, various particle configurations were used for modulating the inner MB sequential release with three pulse T_max. Also, by adjusting the NP_big&thin and NP_big&thick configuration, the release interval lag time between absorbed GM and DTX can be successfully modulated to achieve maximized chemotherapeutic efficacy.

Results

In vitro and in vivo results demonstrated that these three pulses T_max and the sustained release of MB could maximize the multi-level programmable PDT treatment. And the absorbed GM and DTX also have a release time lag of 12 h, which has been proved as the most effectiveness synergistic interval lag time in the cancer treatment.

Conclusion

Such a precise sequential release manner ternary cocktail NPs provided a promising platform for efficient and safe chemo-photodynamic therapy, which serves as a promising drug delivery system to cure cancer in the future.

http://ift.tt/2wDQHgD

Expanded access to cancer treatments from conversion to neutropenia prophylaxis with biosimilar filgrastim-sndz

Future Oncology, Ahead of Print.


http://ift.tt/2j1NtPl

ERp29 controls invasion and metastasis of gastric carcinoma by inhibition of epithelial-mesenchymal transition via PI3K/Aktsignaling pathway

Abstract

Background

Gastric cancer (GC) accounts for the fourth most occurring malignancy and the third major cause of cancer death. Identifying novel molecular signaling pathways participating in gastric tumorigenesis and progression is pivotal for rational design of targeted therapies to improve advanced GC outcome. Recently, the endoplasmic reticulum (ER) protein 29 (ERp29) has been shown to inversely associate with primary tumor development and function as a tumor suppressor in breast cancer. However, the role of ERp29 in GC patients' prognosis and its function in GC progression is unknown.

Methods

Clinical importance of ERp29 in the prognosis of GC patients was assessed by examining its expression in 148 GC tumor samples and correlation with clinicopathological characteristics and survival of the patients. The function and underlying mechanisms of ERp29 in GC growth, invasion and metastasis were explored both in vitro and in vivo.

Results

Downregulation of ERp29 was commonly found in GC tissues and highly correlated with more aggressive phenotypes and poorer prognosis. Functional assays demonstrated that knockdown of ERp29 increased GC cell migration and invasion and promoted metastasis. Conversely, ectopic overexpression of ERp29 produced opposite effects. Mechanistic studies revealed that loss of ERp29 induced an epithelial-to-mesenchymal transition (EMT) in the GC cells through activation of PI3K/Akt pathway signaling.

Conclusion

These findings suggest that downregulation of ERp29 is probably one of the key molecular mechanisms responsible for the development and progression of GC.

http://ift.tt/2xNBf0a

The association between smoking and breast cancer characteristics and outcome

Abstract

Background

Smoking is associated with an increased incidence of hormone receptor positive breast cancer. Data regarding worse breast cancer outcome in smokers are accumulating. Current literature regarding the impact of smoking on breast cancer characteristics is limited. We evaluated the impact of smoking on breast cancer characteristics and outcome.

Methods

This was a retrospective single center study. All women diagnosed from 4/2005 through 3/2012 and treated in our institute for early, estrogen receptor positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer, whose tumors were sent for Oncotype DX analysis were included. Medical records were reviewed for demographics, clinico-pathological parameters, treatment and outcome. Data regarding smoking were retrieved according to patients' history at the first visit in the oncology clinic. Patients were grouped and compared according to smoking history (ever smokers vs. never smokers), smoking status (current vs. former and never smokers) and smoking intensity (pack years ≥30 vs. the rest of the cohort). Outcomes were adjusted in multivariate analyses and included age, menopausal status, ethnicity, tumor size, nodal status and grade.

Results

A total of 662 women were included. 28.2% had a history of smoking, 16.6% were current smokers and 11.3% were heavy smokers. Smoking had no impact on tumor size, nodal involvement and Oncotype DX recurrence score. Angiolymphatic and perineural invasion rates were higher in current smokers than in the rest of the cohort (10.4% vs. 5.1%, p = 0.045, 8.3% vs. 3.5%, p = 0.031, respectively). Smoking had no other impact on histological characteristics. Five-year disease free survival and overall survival rates were 95.7% and 98.5%, respectively. Smoking had no impact on outcomes. Adjusted disease free survival and overall survival did not influence the results.

Conclusions

Smoking had no clinically significant influence on tumor characteristics and outcome among women with estrogen receptor positive, HER2 negative, early breast cancer. As the study was limited to a specific subgroup of the breast cancer population in this heterogeneous disease and since smoking is a modifiable risk factor for the disease, further research is required to clarify the possible impact of smoking on breast cancer.

http://ift.tt/2eJDywm

Development and external validation of nomograms to predict the risk of skeletal metastasis at the time of diagnosis and skeletal metastasis-free survival in nasopharyngeal carcinoma

Abstract

Background

The skeletal system is the most common site of distant metastasis in nasopharyngeal carcinoma (NPC); various prognostic factors have been reported for skeletal metastasis, though most studies have focused on a single factor. We aimed to establish nomograms to effectively predict skeletal metastasis at initial diagnosis (SMAD) and skeletal metastasis-free survival (SMFS) in NPC.

Methods

A total of 2685 patients with NPC who received bone scintigraphy (BS) and/or 18F–deoxyglucose positron emission tomography/computed tomography (18F–FDG PET/CT) and 2496 patients without skeletal metastasis were retrospectively assessed to develop individual nomograms for SMAD and SMFS. The models were validated externally using separate cohorts of 1329 and 1231 patients treated at two other institutions.

Results

Five independent prognostic factors were included in each nomogram. The SMAD nomogram had a significantly higher c-index than the TNM staging system (training cohort, P = 0.005; validation cohort, P < 0.001). The SMFS nomogram had significantly higher c-index values in the training and validation sets than the TNM staging system (P < 0.001 and P = 0.005, respectively). Three proposed risk stratification groups were created using the nomograms, and enabled significant discrimination of SMFS for each risk group.

Conclusion

The prognostic nomograms established in this study enable accurate stratification of distinct risk groups for skeletal metastasis, which may improve counseling and facilitate individualized management of patients with NPC.

http://ift.tt/2xNBacS

Circadian disruption promotes tumor growth by anabolic host metabolism; experimental evidence in a rat model

Abstract

Background

Light at night creates a conflicting signal to the biological clock and disrupts circadian physiology. In rodents, light at night increases the risk to develop mood disorders, overweight, disrupted energy metabolism, immune dysfunction and cancer. We hypothesized that constant light (LL) in rats may facilitate tumor growth via disrupted metabolism and increased inflammatory response in the host, inducing a propitious microenvironment for tumor cells.

Methods

Male Wistar rats were exposed to LL or a regular light-dark cycle (LD) for 5 weeks. Body weight gain, food consumption, triglycerides and glucose blood levels were evaluated; a glucose tolerance test was also performed. Inflammation and sickness behavior were evaluated after the administration of intravenous lipopolysaccharide. Tumors were induced by subcutaneous inoculation of glioma cells (C6). In tumor-bearing rats, the metabolic state and immune cells infiltration to the tumor was investigated by using immunohistochemistry and flow cytometry. The mRNA expression of genes involved metabolic, growth, angiogenes and inflammatory pathways was measured in the tumor microenvironment by qPCR. Tumor growth was also evaluated in animals fed with a high sugar diet.

Results

We found that LL induced overweight, high plasma triglycerides and glucose levels as well as reduced glucose clearance. In response to an LPS challenge, LL rats responded with higher pro-inflammatory cytokines and exacerbated sickness behavior. Tumor cell inoculation resulted in increased tumor volume in LL as compared with LD rats, associated with high blood glucose levels and decreased triglycerides levels in the host. More macrophages were recruited in the LL tumor and the microenvironment was characterized by upregulation of genes involved in lipogenesis (Acaca, Fasn, and Pparγ), glucose uptake (Glut-1), and tumor growth (Vegfα, Myc, Ir) suggesting that LL tumors rely on these processes in order to support their enhanced growth. Genes related with the inflammatory state in the tumor microenvironment were not different between LL and LD conditions. In rats fed a high caloric diet tumor growth was similar to LL conditions.

Conclusions

Data indicates that circadian disruption by LL provides a favorable condition for tumor growth by promoting an anabolic metabolism in the host.

http://ift.tt/2eJDpJk

Prognostic consequences of implementing cancer patient pathways in Denmark: a comparative cohort study of symptomatic cancer patients in primary care

Abstract

Background

Cancer Patient Pathways (CPPs) were introduced in 2000–2015 in several European countries, including Denmark, to reduce the time to diagnosis and treatment initiation and ultimately improve patient survival. Yet, the prognostic consequences of implementing CPPs remain unknown for symptomatic cancer patients diagnosed through primary care.

We aimed to compare survival and mortality among symptomatic patients diagnosed through a primary care route before, during and after the CPP implementation in Denmark.

Methods

Based on data from the Danish Cancer in Primary Care (CaP) Cohort, we compared one- and three-year standardised relative survival (RS) and excess hazard ratios (EHRs) before, during and after CPP implementation for seven types of cancer and all combined (n = 7725) by using life-table estimation and Poisson regression. RS estimates were standardised according to the International Cancer Survival Standard (ICSS) weights. In addition, we compared RS and EHRs for CPP and non-CPP referred patients to consider potential issues of confounding by indication.

Results

In total, 7725 cases were analysed: 1202 before, 4187 during and 2336 after CPP implementation. For all cancers combined, the RS_3years rose from 45% (95% confidence interval (CI): 42;47) before to 54% (95% CI: 52;56) after CPP implementation. The excess mortality was higher before than after CPP implementation (EHR_3years before vs. after CPP = 1.35 (95% CI: 1.21;1.51)). When comparing CPP against non-CPP referred patients, we found no statistically significant differences in RS, but we found lower excess mortality among the CPP referred (EHR_1year CPP vs. non-CPP = 0.86 (95% CI: 0.73;1.01)).

Conclusion

We found higher relative survival and lower mortality among symptomatic cancer patients diagnosed through primary care after the implementation of CPPs in Denmark. The observed changes in cancer prognosis could be the intended consequences of finding and treating cancer at an early stage, but they may also reflect lead-time bias and selection bias. The finding of a lower excess mortality among CPP referred compared to non-CPP referred patients indicates that CPPs may have improved the cancer prognosis independently.

http://ift.tt/2xN4ksp

The values of neutrophil-lymphocyte ratio and/or prostate-specific antigen in discriminating real Gleason score ≥ 7 prostate cancer from group of biopsy-based Gleason score ≤ 6

Abstract

Background

The discrepant concordance between biopsy and radical prostatectomy (RP) specimen are well reported. To validate the clinical usefulness of neutrophil-lymphocyte ratio (NLR) in discriminating real GS ≥ 7 PCa from biopsy-based GS ≤ 6 PCa in comparison with serum total prostate-specific antigen (tPSA) and value of their combination.

Methods

One hundred one patients who underwent physical examinations incidentally found elevated tPSA and subsequently received biopsy with a conclusion of GS ≤ 6 and RP with an interval of 4-6 weeks after biopsy were enrolled. NLR and tPSA were obtained within 15 days prior to biopsy. Logistic regression model was applied appropriately; McNemar tests and AUC model were performed to evaluate differences among tPSA, NLR and their combination and corresponding diagnostic power respectively.

Results

The pathological results from RP specimen comprised 61 patients with GS ≤ 6 and 100 patients with GS ≥ 7. Higher tPSA and NLR were significantly associated with patients with actual GS ≥ 7 (All P < 0.05) concurrently. Multivariate logistic regression indicated that tPSA (OR = 1.088, 95% C.I. = 1.029-1.151, P = 0.003) and NLR (OR = 1.807, 95% C.I. = 1.021-3.200, P = 0.042) could be independent predictors for GS groupings. Under cutoff value of 14.09 ng/ml for tPSA and 2.25 for NLR, the sensitivity, specificity and accuracy were 60.0%, 80.3% and 67.7% for tPSA, 42%, 88.5% and 59.6% for NLR, and 71.0%, 75.4% and 72.7% for combination of tPSA and NLR (tPSA + NLR) respectively. The sensitivity of tPSA + NLR was significantly higher in comparison with tPSA (P = 0.001) and NLR (P < 0.001). Except for sensitivity, no significant difference was found between tPSA and NLR in specificity (P = 0.227) and accuracy (P = 0.132). tPSA got the largest AUC with 0.732 (p < 0.001, 95% C.I.: 0.651-0.813).

Conclusions

Serum tPSA and NLR were significantly elevated among GS ≥ 7 PCa concurrently. The combination of tPSA and NLR might have additional benefit to biopsy on discriminating real GS ≥ 7 Pca from biopsy-based GS ≤ 6 PCa. More stratification models and prospectively multicenter studies are necessary.

http://ift.tt/2eJDbBY

Bile-stained amniotic fluid: a case report

Green-stained amniotic fluid does not always indicate that meconium was passed in utero.

http://ift.tt/2wEgEwQ

Ureter metastatic castration-resistant prostate cancer: a case report

In most cases, prostate cancer metastasizes to the lymph nodes, bone, and liver. In very rare cases, it metastasizes to the ureter. Due to the difficulty in making a preoperative diagnosis, ureteral metastasis...

http://ift.tt/2w53OEf

Columnar metaplasia in the remnant esophagus is a long-term indicator for pneumonia after radical esophagectomy

Abstract

Background

This study investigated the long-term risk factors for pneumonia after esophageal reconstruction using a gastric tube via the posterior mediastinal route following esophagectomy for esophageal cancer. The influence of columnar metaplasia in the remnant esophagus was specifically assessed.

Methods

Among 225 patients who underwent esophagectomy between January 2004 and December 2010, the subjects were 54 patients who could be followed up for more than 5 years. Routine oncologic follow-up consisted of CT scanning of the abdomen and chest every 4–6 months and annual endoscopy. Data on the occurrence of pneumonia were collected by retrospective review of chest CT scans. Risk factors for pneumonia investigated by univariate and multivariate analyses included the age, gender, diameter of the stapler, length of the intrathoracic remnant esophagus, anastomotic stricture, and presence of columnar metaplasia in the remnant esophagus.

Results

The median age was 62.4 years (interquartile range: 55.8–68.0 years). Forty-three patients were men. Pneumonia was detected in 39 patients (72.2%). The incidence of columnar metaplasia in the remnant esophagus increases with time. Anastomotic stricture was significantly related to the absence of columnar metaplasia on endoscopy in the first year after esophagectomy (p = 0.013). Univariate analysis showed that the frequency of pneumonia was significantly related to the intrathoracic remnant esophagus length ≥4.4 cm (p = 0.014), age over 65 years (p = 0.014), and the presence of columnar metaplasia in the remnant esophagus in the fifth year after esophagectomy (p = 0.005). Among them, age over 65 years and the presence of columnar metaplasia in the remnant esophagus in the fifth year after esophagectomy were found to be independent indicators of the postoperative pneumonia by multivariate analysis.

Conclusion

Pneumonia occurred in 72.2% (39/54) of patients after esophagectomy for esophageal cancer. The presence of columnar metaplasia after esophagectomy is an indicator for pneumonia over the long term.

http://ift.tt/2x9uU1V

Descriptive Rules for Achalasia of the Esophagus, June 2012: 4th Edition

http://ift.tt/2xN3g85

Alcohol consumption and bladder cancer risk with or without the flushing response: The Japan Public Health Center-based Prospective Study

ABSTRACT

The association between alcohol consumption and bladder cancer risk has been insufficiently investigated in East Asian populations, who frequently have the inactive enzyme for metabolizing acetaldehyde. Given that acetaldehyde associated with alcohol consumption is assessed as a carcinogen, consideration of differences in acetaldehyde exposure would aid accuracy in assessing the bladder cancer risk associated with alcohol consumption. Here, we conducted a population-based cohort study in Japan to examine this association, including information on the flushing response as a surrogate marker of the capacity of acetaldehyde metabolism. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariate Cox proportional hazard models. During follow up from 1990 through 2012 for the 95915 subjects (45649 men and 50266 women, aged 40-69 years), 354 men and 110 women were newly diagnosed with bladder cancer. No significant association between alcohol consumption and bladder cancer risk was observed in the overall analysis. Among male flushers, HRs were 1.04 (95% CI 0.70-1.54), 1.67 (1.16-2.42), 1.02 (0.62-1.67) and 0.63 (0.33-1.20) for alcohol consumption of 1-150, 151-300, 301-450, >450 g/week of pure ethanol compared with non- and occasional drinkers, respectively, indicating an inverted U-shaped association between alcohol consumption and bladder cancer risk. In contrast, no significant association was identified among male non-flushers. The marginally significant interaction between alcohol consumption and the flushing response (P for interaction = 0.083) may support our hypothesis that acetaldehyde derived from alcohol consumption is associated with bladder cancer risk. A prospective study considering polymorphisms of genes involved in acetaldehyde metabolism is warranted. This article is protected by copyright. All rights reserved.

http://ift.tt/2x9dWkq

G protein-coupled receptor GPR55 promotes colorectal cancer and has opposing effects to cannabinoid receptor 1

Abstract

The putative cannabinoid receptor GPR55 has been shown to play a tumor-promoting role in various cancers, and is involved in many physiological and pathological processes of the gastrointestinal (GI) tract. While the cannabinoid receptor 1 (CB₁) has been reported to suppress intestinal tumor growth, the role of GPR55 in the development of GI cancers is unclear. We, therefore, aimed at elucidating the role of GPR55 in colorectal cancer (CRC), the third most common cancer worldwide.

Using azoxymethane (AOM)- and dextran sulfate sodium (DSS)-driven CRC mouse models, we found that GPR55 plays a tumor-promoting role that involves alterations of leukocyte populations, i.e. myeloid-derived suppressor cells and T lymphocytes, within the tumor tissues. Concomitantly, expression levels of COX-2 and STAT3 were reduced in tumor tissue of GPR55 knockout mice, indicating reduced presence of tumor-promoting factors. By employing the experimental CRC models to CB₁ knockout and CB₁/GPR55 double knockout mice, we can further show that GPR55 plays an opposing role to CB₁. We report that GPR55 and CB₁ mRNA expression are differentially regulated in the experimental models and in a cohort of 86 CRC patients. Epigenetic methylation of CNR1 and GPR55 was also differentially regulated in human CRC tissue compared to control samples.

Collectively, our data suggest that GPR55 and CB₁ play differential roles in colon carcinogenesis where the former seems to act as oncogene and the latter as tumor suppressor. This article is protected by copyright. All rights reserved.

http://ift.tt/2xNDr7S

The Contribution of Toll-Like Receptor Signaling to the Development of Liver Fibrosis and Cancer in Hepatocyte-Specific TAK1-Deleted Mice

Abstract

Hepatocyte death is associated with liver inflammation, fibrosis, and hepatocellular carcinoma (HCC). Damaged cells trigger inflammation through activation of Toll-like receptor (TLR). Although the role of TLR4 in HCC development has been reported, the role of TLR9 in the development of HCC remains elusive. To investigate the role of TLR4 and TLR9 signaling in liver inflammation-fibrosis-cancer axis, we took advantage of mice with hepatic deletion of transforming growth factor-β-activated kinase 1 (Tak1ΔHep) that develop spontaneous liver injury, inflammation, fibrosis, and HCC, recapitulating the pathology of human HCC. We generated double knockout mice lacking genes of our interest with hepatic Tak1. Tak1ΔHep mice and Tlr4-deficient Tak1ΔHep mice had similar serum ALT levels, but Tlr4-deficient Tak1ΔHep mice exhibited significantly reduced macrophage infiltration, myofibroblast activation, and tumor formation. Ablation of TLR9 reduced spontaneous liver injury, inflammation, fibrosis, and cancer development in Tak1ΔHep mice. In addition, the common adaptor, myeloid differentiation factor 88 (MyD88)-deficient Tak1ΔHep mice also attenuated liver injury, macrophage recruitment, collagen deposition, and tumor growth compared with control Tak1ΔHep mice. Genetic ablation of TNF receptor type I (TNFR) in Tak1ΔHep mice remarkably reduced liver inflammation-fibrosis-cancer axis. Surprisingly, disruption of interleukin-1 receptor (IL-1R) had no effect on liver injury and tumor formation, although Il1r-deficient Tak1ΔHep showed attenuated macrophage infiltration and collagen deposition. In conclusion, TLR4- and TLR9-MyD88 are driving forces of progression to HCC accompanied by liver inflammation and fibrosis in Tak1ΔHep mice. Importantly, TLR4 and TLR9 downstream TNFR, but not IL-1R signaling is crucial for the development of HCC in Tak1ΔHep mice. This article is protected by copyright. All rights reserved.

http://ift.tt/2x8RbwX

Epileptic seizures in nonalcoholic Wernicke’s encephalopathy: a case report and literature review

Abstract

Wernicke encephalopathy (WE) is characterized by eye signs, cerebellar dysfunction, and confusion. Epileptic seizures are rare in nonalcoholic WE. We reviewed the clinical, laboratory, radiological, and prognostic characteristics of nonalcoholic WE accompanied by epileptic seizures. We reported 1 case and searched similar cases using PubMed, WoK, Ovid, and Embase. WE was diagnosed according to dietary deficiencies, clinical symptoms and brain magnetic resonance imaging (MRI). We reviewed 13 patients (median age, 27 years; 5 men) with clear histories of thiamine deficiency and symptoms of typical WE. The type of epileptic seizures reported in the 13 cases reviewed was generically reported as seizures or convulsions in 4 patients; 7 patients had generalized tonic-clonic seizures, 1 partial seizure, and 1 generalized convulsive status epileptics. Two patients had epileptic seizures as the first symptom of WE. Laboratory tests mainly indicated metabolic acidosis and electrolyte disturbances. Electroencephalography may present as normal patterns, increased slow waves or epileptic discharge. Six patients had cortical lesions on brain MRI. These lesions were usually diffuse and band-like, and sometimes involved all lobes either symmetrically or asymmetrically, with the frontal lobe as the most susceptible area. All cortical lesions were accompanied by non-cortical lesions typical of WE. Brain MRI abnormalities, after thiamine treatment, mostly disappeared on follow-up MRIs. The patients had good prognoses. Only 1 patient had repeated seizures, and there were no comas or deaths. Patients with nonalcoholic WE accompanied by seizures are young and generally have good prognoses. Most patients experienced generalized convulsive seizures, which may have been related to abnormal cerebral cortical metabolism due to subacute thiamine deficiency.

http://ift.tt/2w4yoxB

A case of cisplatin-refractory advanced pure seminoma showing complete remission after treatment with high-dose carboplatin plus etoposide as fourth-line salvage chemotherapy

Abstract

We report the case of a patient who achieved complete remission (CR) of cisplatin-refractory metastatic pure seminoma after treatment with high-dose carboplatin and etoposide (CE) with peripheral blood stem cell transplantation as fourth-line chemotherapy. A 38-year-old man was diagnosed with advanced pure seminoma (pT3N3M1aS3). In the international germ cell consensus classification, his prognosis was classified as intermediate. He was treated with high-dose CE as fourth-line chemotherapy after treatment with BEP, VeIP, and TIN. After two cycles of high-dose CE, the concentrations of T-HCG and other tumor markers showed normal levels. A CT scan and PET–CT showed that the lymph node swelling had disappeared and there was no uptake. The CR has continued for 27 months after the treatment. High-dose CE might be less toxic and have a better prognostic outcome than other treatments as salvage chemotherapy for patients with cisplatin-refractory advanced testicular cancer.

http://ift.tt/2eImIhy

Liver stereotactic radiotherapy (SRT) with functional treatment planning for patients with intermediate stage hepatocellular carcinoma (HCC)

Abstract

Objective

The objective of this study was to analyze hepatic failure progression and survival in patients with Barcelona Clinic Liver Cancer (BCLC) A3-B hepatocellular carcinoma (HCC) after stereotactic radiotherapy (SRT) with functional treatment planning.

Methods

Liver SPECT was co-registered to 4DCT for avoidance of functional liver during SRT planning. Liver dose constraints/fractionation was based on functional liver volume. Concurrent capecitabine was administered for fraction size ≤ 4 Gy. Hepatic function, toxicity, and radiographic response were documented q4–6 months following radiotherapy.

Results

Twenty-two patients (14 Child-Pugh A, 8 Child-Pugh B Cirrhosis) with 39 lesions were analyzed. Fourteen patients received SBRT (mean dose 44.7 Gy, 5–6 fractions). Eight patients received SRT and concurrent capecitabine (mean dose 40.7 Gy, 14–18 fractions). Mean follow-up was 20 months. Nine patients developed grade ≤ 2 transient elevation of liver enzymes. At 24 months, Child-Pugh class was stable in 59% patients and MELD progression free survival was 76%. No RILD or accelerated hepatic failure was observed. In-field local control was 97.4% and overall survival was 59% at 2 years.

Conclusions

Liver SRT with functional treatment planning is safe in intermediate hepatocellular carcinoma. Liver failure is not hastened despite the inclusion of 36% Child-Pugh B patients.

http://ift.tt/2gDUfX9

A Survey on Breast Cancer Awareness Among Medical, Paramedical, and General Population in North India Using Self-Designed Questionnaire: a Prospective Study

Abstract

Breast cancer (BC) has become the most common cancer in urban women. Unfortunately, most women are not aware of BC symptoms/signs, prevention, and management. In resource-limited countries like India where we do not have structured screening/awareness programs, a majority of women present with locally advanced BC. The aim of our study is to identify the present status of awareness about BC prevention, early detection, symptoms, and management in urban and rural Indian women (medical, paramedical, and nonmedical) and to assess whether education and socioeconomic strata have any role in better awareness about BC or not. We did a prospective cross-sectional observation study among the medical, paramedical, and nonmedical women in the northern part of India. We designed a questionnaire keeping in mind the three domains about BC—knowledge (questions 1–25 include risk factors, genetics, lifestyle changes, hormones, associated cancers, and modes of presentation like lump, nipple/skin changes), breast self-examination (questions 25–37), and attitude to prevention and early detection (questions 38–44). We also asked how many do breast self-examination (BSE) and what they think are the three main factors responsible for late presentation and the three main ways to increase BC awareness. The Likert scale was used for objective assessment. We analyzed the whole data using SPSS software version 15. A total of 220 women out of 270 completed the questionnaire. Out of 220 women, 26.4% were medical, 20.9% paramedical, and 52.7% nonmedical. Most women were educated (82.7%) and married (65%). 59.5% women resided in urban areas and the rest (40.5%) were from rural areas. We found that there was relatively more knowledge in the medical group; however, the skills of BSE and attitude to prevention and early detection in all the three subgroups and among rural and urban women were suboptimal and not different significantly. The three main factors responsible for delayed presentation were shyness and not knowing BSE, ignorance about BC symptoms, and social stigma of cancer along with financial constraints. The three main ways to improve BC awareness suggested were to have more advertisements on television and social media, roadside campaigns and in colleges along with group discussions and debates, and at grassroots level to involve Anganwadi workers and nurses to create more awareness in villages. There was less breast cancer knowledge and awareness among the nonmedical women compared to those among the medical and paramedical, the skills of BSE and attitude to prevention and early detection were suboptimal in all the three groups. Rural or urban dwellings did not make much difference in BC knowledge, skills of BSE, and attitude to prevention. More awareness regarding breast cancer symptoms with early detection and BSE need to be addressed with more information dissemination via social media, campaigns, and involvement of paramedics and social workers.

http://ift.tt/2f1lD1o

GNAQ and GNA11 mutations and downstream YAP activation in choroidal nevi

http://ift.tt/2vJXdng

Intracrine VEGF signalling mediates colorectal cancer cell migration and invasion

http://ift.tt/2wFpd8U

GEIS-21: a multicentric phase II study of intensive chemotherapy including gemcitabine and docetaxel for the treatment of Ewing sarcoma of children and adults: a report from the Spanish sarcoma group (GEIS)

http://ift.tt/2vJVher

Randomised Phase 2 study of maintenance linsitinib (OSI-906) in combination with erlotinib compared with placebo plus erlotinib after platinum-based chemotherapy in patients with advanced non-small cell lung cancer

http://ift.tt/2wG7cHG

Lauren subtypes of advanced gastric cancer influence survival and response to chemotherapy: real-world data from the AGAMENON National Cancer Registry

http://ift.tt/2vJUIl4

Cancer-associated fibroblasts promote bone invasion in oral squamous cell carcinoma

http://ift.tt/2wFPqUT

Choosing wisely: a model-based analysis evaluating the trade-offs in cancer benefit and diagnostic referrals among alternative HPV testing strategies in Norway

http://ift.tt/2vJBoEw

Vitamin D receptor and calcium-sensing receptor polymorphisms and colorectal cancer survival in the Newfoundland population

http://ift.tt/2wFDkuY

Pre-clinical imaging of transgenic mouse models of neuroblastoma using a dedicated 3-element solenoid coil on a clinical 3T platform

http://ift.tt/2vJGQay

Expression of L1CAM in curettage or high L1CAM level in preoperative blood samples predicts lymph node metastases and poor outcome in endometrial cancer patients

http://ift.tt/2wFFs5O

miR-125b predicts childhood acute lymphoblastic leukaemia poor response to BFM chemotherapy treatment

http://ift.tt/2vJBhc4

Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis

http://ift.tt/2wFPkwv

Regulation of hypoxia-induced autophagy in glioblastoma involves ATG9A

http://ift.tt/2vJBcFi

Predicting response to radical (chemo)radiotherapy with circulating HPV DNA in locally advanced head and neck squamous carcinoma

http://ift.tt/2wFGgrD

Novel immunohistochemistry-based signatures to predict metastatic site of triple-negative breast cancers

http://ift.tt/2vJGFfo

Evidence of advanced stage colorectal cancer with longer diagnostic intervals: a pooled analysis of seven primary care cohorts comprising 11 720 patients in five countries

http://ift.tt/2wFDdiX

Active multiple myeloma suppresses and typically eliminates coexisting MGUS

http://ift.tt/2vJB3le

The inflammatory potential of diet and ovarian cancer risk: results from two prospective cohort studies

http://ift.tt/2wFnron

ERAS—Anticipated outcomes and realistic goals

Enhanced recovery programs emphasize implementation of perioperative measures to reduce stress and restore baseline function. Complications and length of stay are greatly improved as a result, but the field is moving toward more patient centric and longer term outcomes that better reflect functional recovery. Programs demonstrating value in these domains will undoubtedly see corollary gains in traditional metrics. Thus, greater focus on patient well-being and treatment success is key to successful implementation of enhanced recovery.

The optimal approach when initiating an enhanced recovery program is to focus on patient-centric well-being and outcomes. Programs that demonstrate value in these domains will see corollary gains in more physician/hospital centric metrics. Basically, the residue of a well-intentioned enhanced recovery program is shorter LOS, decreased complication rates and lower costs of care.

http://ift.tt/2eDlMap

Enhanced recovery after surgery—Summary recommendations

http://ift.tt/2j1ep1M

ERAS—Value based surgery

This paper reviews implementation of ERAS and its financial implications. Literature on clinical outcomes and financial implications were reviewed. Reports from many different surgery types shows that implementation of ERAS reduces complications and shortens hospital stay. These improvements have major impacts on reducing the cost of care even when costs for implementation, and investment in time for personnel and training is accounted for. The conclusion is that ERAS is an excellent example of value based surgery.

http://ift.tt/2eDlArH

Enhanced recovery after surgery: Pain management

Effective pain management is fundamental to enhanced recovery after surgery. Selection of strategies should be tailored to patient and operation. As well as improving the quality of recovery, effective analgesia reduces the host stress response, facilitates mobilization and allows resumption of oral intake. Multi-modal regimens combining paracetamol, non-steroidal anti-inflammatory agents where indicated, a potent opioid and a local anaesthetic technique achieve effective analgesia while limiting the dose and thereby side effects of any one agent.

http://ift.tt/2j1elz4

Reactivation of TWIST1 contributes to Ewing sarcoma metastasis

Abstract

Background

Ewing sarcoma is a cancer of bone and soft tissue. Despite aggressive treatment, survival remains poor, particularly in patients with metastatic disease. Failure to treat Ewing sarcoma is due to the lack of understanding of the molecular pathways that regulate metastasis. In addition, no molecular prognostic markers have been identified for Ewing sarcoma to risk stratify patients.

Procedure

Ewing sarcoma patients were divided into high or low Twist1 gene expression and survival curves were generated using the R2 microarray-based Genomic Analysis platform (http://r2.amc.nl). Tumors from Ewing sarcoma patients were also evaluated for TWIST1 expression by immunohistochemistry. Ewing sarcoma xenografts were established to evaluate the role of TWIST1 in metastasis. The effects of Twist1 on migration and invasion were evaluated using migration and invasion assays in A673 and RDES cells.

Results

Twist1 expression was a negative prognostic marker for overall survival in a public Ewing sarcoma patient data set based on Twist1 mRNA levels and in patient tumor samples based on Twist1 immunohistochemistry. TWIST1 is detected in significantly higher percentage of patients with metastatic diseases than localized disease. Using Ewing sarcoma tumor xenografts in mice, we found that suppressing TWIST1 levels suppressed metastasis without affecting primary tumor development. Knockdown of Twist1 inhibited the migration and invasion capability, while overexpression of Twist1 promoted migration and invasion in Ewing sarcoma cells.

Conclusion

These results suggest that TWIST1 promotes metastasis in Ewing sarcoma and could be used as a prognostic marker for treatment stratification; however, further validation is required in a larger cohort of patients.

http://ift.tt/2j0WKau

The Effects of Selenium Supplementation on Gene Expression Related to Insulin and Lipid in Infertile Polycystic Ovary Syndrome Women Candidate for In Vitro Fertilization: a Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

This study was conducted to evaluate the effects of selenium supplementation on gene expression related to insulin and lipid in infertile women with polycystic ovary syndrome (PCOS) candidate for in vitro fertilization (IVF). This randomized double-blind, placebo-controlled trial was conducted among 40 infertile women with PCOS candidate for IVF. Subjects were randomly allocated into two groups to intake either 200-μg selenium (n = 20) or placebo (n = 20) per day for 8 weeks. Gene expression levels related to insulin and lipid were quantified in lymphocytes of women with PCOS candidate for IVF with RT-PCR method. Results of RT-PCR demonstrated that after the 8-week intervention, compared with the placebo, selenium supplementation upregulated gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) (1.06 ± 0.15-fold increase vs. 0.94 ± 0.18-fold reduction, P = 0.02) and glucose transporter 1 (GLUT-1) (1.07 ± 0.20-fold increase vs. 0.87 ± 0.18-fold reduction, P = 0.003) in lymphocytes of women with PCOS candidate for IVF. In addition, compared with the placebo, selenium supplementation downregulated gene expression of low-density lipoprotein receptor (LDLR) (0.88 ± 0.17-fold reduction vs. 1.05 ± 0.22-fold increase, P = 0.01) in lymphocytes of women with PCOS candidate for IVF. We did not observe any significant effect of selenium supplementation on gene expression levels of lipoprotein(a) [LP(a)] in lymphocytes of women with PCOS candidate for IVF. Overall, selenium supplementation for 8 weeks in lymphocytes of women with infertile PCOS candidate for IVF significantly increased gene expression levels of PPAR-γ and GLUT-1 and significantly decreased gene expression levels of LDLR, but did not affect LP(a).

Clinical trial registration number: http://www.irct.ir: IRCT201704245623N113.

http://ift.tt/2gIYch2

Novel SPG20 mutation in an extended family with Troyer syndrome

Abstract

Troyer Syndrome (TRS) is a rare autosomal recessive complicated spastic paraplegia disorder characterized by various neurological and musculoskeletal manifestations. Pathogenicity stems from mutations in SPG20 which encodes Spartin, a multifunctional protein that is thought to be essential for neuron viability. Here we report on the clinical and molecular characterization of TRS in five patients from an extended consanguineous family in the United Arab Emirates. Molecular analysis involved Whole Exome Sequencing and Sanger sequencing for identification and confirmation of the causative variant respectively. In silico tools including CADD and Polyphen-2 were used to assess pathogenicity of the variant. The clinical description of these patients included spastic paraparesis, motor and cognitive delay, gait abnormalities, musculoskeletal features, as well as white matter abnormalities and emotional liability. Molecular analysis revealed a novel homozygous missense mutation in SPG20 (c.1324G > C; p.Ala442Pro) occurring at an evolutionarily conserved residue in the Plant-Related Senescence domain of Spartin. The mutation segregated with the clinical phenotype in all patients. In silico algorithms predict the mutation to be disease causing, and the variant had not been previously reported in public or ethnic specific variant repositories.

http://ift.tt/2f0zfKe

Lactulose decreases neuronal activation and attenuates motor behavioral deficits in hyperammonemic rats

Abstract

Lactulose is a nonabsorbable disaccharide commonly used in clinical practice to treat hepatic encephalopathy. However, its effects on neuropsychiatric disorders and motor behavior have not been fully elucidated. Male Wistar rats were bile-duct ligated, and 3 weeks after surgery, treated with lactulose administrated by gavage (1.43 or 3.57 g/kg), once a day for seven days. Plasma levels of ammonia, aspartate aminotransferase, total bilirubin, and creatinine were quantified and histopathological analysis of the livers was performed. Locomotor activity measurements were performed in an open field. The expression of water channel aquaporin-4 was investigated and the analysis of Fos protein immunoreactivity was used to evaluate the pattern of neural activation in brain areas related to motor behavior. Bile-duct ligated rats showed hyperammonemia, loss of liver integrity and function, impaired locomotor activity, reduced aquaporin-4 protein expression, and neuronal hyperactivity. Lactulose treatment was able to reduce ammonia plasma levels, despite not having an effect on biochemical parameters of liver function, such as aspartate aminotransferase activity and total bilirubin levels, or on the cirrhotic hepatic architecture. Lactulose was also able to reduce the locomotor activity impairments and to mitigate or reverse most changes in neuronal activation. Lactulose had no effect on reduced aquaporin-4 protein expression. Our findings confirm the effectiveness of lactulose in reducing hyperammonemia and neuronal hyperactivity in brain areas related to motor behavior, reinforcing the importance of its clinical use in the treatment of the symptoms of cirrhosis-associated encephalopathy.

http://ift.tt/2gK8Aoz

The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer

Abstract

The transcription factor signal activator and transducer or transcription (STAT3), which regulates genes controlling proliferation, survival, and invasion, is activated inappropriately in many human cancers, including breast cancer. Activation of STAT3 can lead to both malignant cellular behavior and suppression of immune cell function in the tumor microenvironment. Through a chemical-biology screen, pyrimethamine (PYR), an FDA approved anti-microbial drug, was identified as an inhibitor of STAT3 function at concentrations known to be achieved safely in humans. We report that PYR shows therapeutic activity in two independent mouse models of breast cancer, with both direct tumor inhibitory and immune stimulatory effects. PYR-inhibited STAT3 activity in TUBO and TM40D-MB metastatic breast cancer cells in vitro and inhibited tumor cell proliferation and invasion into Matrigel basement membrane matrix. In tumor-transplanted mice, PYR had both direct and indirect tumor inhibitory effects. Tumor-bearing mice treated with PYR showed reduced STAT3 activation in tumor cells, attenuated tumor growth, and reduced tumor-associated inflammation. In addition, expression of Lamp1 by tumor infiltrating CD8⁺ T cells was elevated, indicating enhanced release of cytotoxic granules. These findings suggest that PYR may have beneficial effects in the treatment of breast cancer.

http://ift.tt/2vI73WF

Disparities in prognosis communication among parents of children with cancer: The impact of race and ethnicity

BACKGROUND

Most parents of children with cancer say they want detailed information about their child's prognosis. However, prior work has been conducted in populations of limited diversity. The authors sought to evaluate the impact of parental race/ethnicity on prognosis communication experiences among parents of children with cancer.

METHODS

In total, 357 parents of children with cancer and the children's physicians were surveyed at Dana-Farber Cancer Institute/Boston Children's Hospital and Children's Hospital of Philadelphia. Outcome measures were parental preferences for prognostic information, physician beliefs about parental preferences, prognosis communication processes, and communication outcomes. Associations were assessed by logistic regression with generalized estimating equations to correct for physician clustering.

RESULTS

Two hundred eighty-one parents (79%) were white, 23 (6%) were black, 29 (8%) were Hispanic, and 24 (7%) were Asian/other. Eighty-seven percent of parents wanted as much detail as possible about their child's prognosis, with no significant differences by race/ethnicity (P = .75). However, physician beliefs about parental preferences for prognosis communication varied based on parent race/ethnicity, with physicians considering black and Hispanic parents less interested in details about prognosis than whites (P = .003). Accurate understanding of a less favorable prognosis was greater among white (49%) versus nonwhite parents (range, 20%-29%), although this difference was not statistically significant (P = .14).

CONCLUSIONS

Most parents, regardless of racial and ethnic background, want detailed prognostic information about their child's cancer. However, physicians underestimate the information needs of black and Hispanic parents. To meet parents' information needs, physicians should ask about parents' information preferences before prognosis discussions. [See related editorial on pages 000-000, this issue.] Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2eCtp15

Don't let perfect be the enemy of good: How to improve prognostic communication in pediatric oncology

Parents of children with cancer desire detailed and honest information about their child's prognosis throughout the cancer experience and regardless of race or ethnicity. This essay describes barriers and opportunities for pediatric oncologists to meet their obligations of prognostic disclosure. See also pages 000-000.

http://ift.tt/2j2a0vF

Crizotinib Shows Promise for Childhood Cancers

In a small clinical trial, the drug crizotinib shrank tumors in children with cancers that have alterations in the ALK gene.

http://ift.tt/2eI6J32

The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer

Abstract

The transcription factor signal activator and transducer or transcription (STAT3), which regulates genes controlling proliferation, survival, and invasion, is activated inappropriately in many human cancers, including breast cancer. Activation of STAT3 can lead to both malignant cellular behavior and suppression of immune cell function in the tumor microenvironment. Through a chemical-biology screen, pyrimethamine (PYR), an FDA approved anti-microbial drug, was identified as an inhibitor of STAT3 function at concentrations known to be achieved safely in humans. We report that PYR shows therapeutic activity in two independent mouse models of breast cancer, with both direct tumor inhibitory and immune stimulatory effects. PYR-inhibited STAT3 activity in TUBO and TM40D-MB metastatic breast cancer cells in vitro and inhibited tumor cell proliferation and invasion into Matrigel basement membrane matrix. In tumor-transplanted mice, PYR had both direct and indirect tumor inhibitory effects. Tumor-bearing mice treated with PYR showed reduced STAT3 activation in tumor cells, attenuated tumor growth, and reduced tumor-associated inflammation. In addition, expression of Lamp1 by tumor infiltrating CD8⁺ T cells was elevated, indicating enhanced release of cytotoxic granules. These findings suggest that PYR may have beneficial effects in the treatment of breast cancer.

http://ift.tt/2vI73WF

A Radiomics Nomogram for the Preoperative Prediction of Lymph Node Metastasis in Bladder Cancer

Purpose: To develop and validate a radiomics nomogram for the preoperative prediction of lymph node (LN) metastasis in bladder cancer. Experimental Design: One hundred and eighteen eligible bladder cancer patients were divided into a training set (n =80) and a validation set (n =38). Radiomics features were extracted from arterial-phase computed tomography (CT) images of each patient. A radiomics signature was then constructed with the least absolute shrinkage and selection operator algorithm in the training set. Combined with independent risk factors, a radiomics nomogram was built with a multivariate logistic regression model. Nomogram performance was assessed in the training set and validated in the validation set. Finally, decision curve analysis was performed with the combined training and validation set to estimate the clinical usefulness of the nomogram. Results: The radiomics signature, consisting of 9 LN-status-related features, achieved favorable prediction efficacy. The radiomics nomogram, which incorporated the radiomics signature and CT-reported LN status, also showed good calibration and discrimination in the training set (AUC 0.9262; 95% CI, 0.8657-0.9868) and the validation set (AUC 0.8986; 95% CI, 0.7613-0.9901). The decision curve indicated the clinical usefulness of our nomogram. Encouragingly, the nomogram also showed favorable discriminatory ability in the CT-reported LN-negative (cN0) subgroup (AUC 0.8810; 95% CI, 0.8021-0.9598). Conclusions: The presented radiomics nomogram, a non-invasive preoperative prediction tool that incorporates the radiomics signature and CT-reported LN status, shows favorable predictive accuracy for LN metastasis in patients with bladder cancer. Multicenter validation is needed to acquire high-level evidence for its clinical application.

http://ift.tt/2eZMbjh

A Phase II trial of neoadjuvant MK2206, an AKT inhibitor, with anastrozole in clinical stage 2 or 3 PIK3CA mutant ER positive and HER2 negative breast cancer

Purpose: Hyper-activation of AKT is common and associated with endocrine resistance in estrogen receptor positive (ER+) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA mutant ER+ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER+ breast cancer. Experimental Design: Potential eligible patients with clinical stage II/III ER+/HER2- breast cancer were pre-registered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150mg PO weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of 4 28-days cycles of combination therapy before surgery. Serial biopsies were collected at pre-registration, C1D1 and C1D17. Results: Fifty-one patients pre-registered and 16 of 22 with PIK3CA mutant tumors received study drug. Three patients went off study due to C1D17 Ki67>10% (n=2) and toxicity (n=1). 13 patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 post MK-2206 persisted. One patient acquired an ESR1 mutation at surgery. Conclusions: MK2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA mutant ER+ breast cancer and should not be studied further in the target patient population.

http://ift.tt/2gJODyn

Patterns of unmet supportive needs and relationship to quality of life in Chinese cancer patients

Abstract

Objectives

This study aimed to (1) identify distinct patterns of unmet needs in Chinese cancer patients; (2) examine whether socio-demographic and medical characteristics distinguished these patterns; and (3) examine whether people with distinct patterns reported differential Quality of Life (QoL).

Methods

This cross-sectional study recruited 301 cancer patients from two hospitals in China. The 34-item Supportive Care Needs Survey Short-Form was used to measure unmet needs across five domains: physical and daily living, psychological, patient care and support, health systems and information, and sexuality. Latent class analysis was performed to identify patterns of unmet needs across these domains.

Results

Four patterns of unmet needs were identified, differing in levels and nature of unmet needs. Participants in Class 1 (47%) reported few unmet needs. Patients in Class 2 (15%) had moderate levels of unmet needs, displaying similar levels across five domains. People in Class 3 (25%) and Class 4 (13%) reported similarly high levels on "psychological", "health care system and information", "physical and daily living" and "patient care", but differing in "sexuality", with Class 3 reporting low levels while Class 4 high on "sexuality". None of socio-demographic and medical characteristics distinguished these patterns significantly. Compared to other classes, people in Class 1 reported highest levels of QoL.

Conclusions

This study demonstrates the existence of four patterns of unmet supportive needs in Chinese cancer patients. Patients with few unmet needs reported the best QoL.

http://ift.tt/2gDLNai

Dyadic effects of coping strategies, time perspectives, and personality on the quality of life of cancer patients and their caregivers

Abstract

Objective

Researchers are interested in studying whether the quality of life (QoL) of cancer patients and caregivers is influenced by internal psycho-behavioral processes (temporality and coping strategies) and the personality traits that they or their relatives experience. We examined these associations in a sample of patient-caregiver dyads using the actor-partner interdependence model (APIM).

Methods

This cross-sectional study involved 156 cancer patient-caregiver dyads. The self-reported data included QoL (Short-Form 36), coping strategies (BriefCope), time perspectives (Zimbardo Time Perspective Inventory), and personality (Big Five Inventory). The APIM was used to test the dyadic effects individualizing actor (degree to which the individual's characteristics were associated with their QoL) and partner (degree to which the individual's characteristics were associated with the QoL of the other dyad member) effects.

Results

Actor effects were found for patients and caregivers: the use of positive thinking and future/present-hedonistic perspectives were associated with higher QoL; the use of avoidance and past-negative perspective were associated with lower QoL. Partner effects were also found, highlighting the specific mechanisms of the interconnections in the patient-caregiver dyad. The patient's QoL was higher when the caregiver used social support and experienced openness. The caregiver's QoL was lower when the patient used social support and avoidance strategies and experienced future perspective.

Conclusions

The examination of the relationships between individuals' QoL and their internal psycho-behavioral processes and personality traits will have several applications in the routine clinical management. Individual-level and dyad-level interventions should be proposed: cognitive-rehabilitation, emotional and cognitive self-regulation for time perspectives and personality constructs.

http://ift.tt/2eIjoDj

Implication of connexin30 on the stemness of glioma: connexin30 reverses the malignant phenotype of glioma by modulating IGF-1R, CD133 and cMyc

Abstract

Gap-junctional intercellular communication (GJIC) plays a major role in the malignant growth of glioma. Although the mechanistic aspects of GJIC have been extensively studied, the role of connexins in the regulation of the malignant behavior of glioma stem cells (GSCs) remains unclear. In our previous studies, we have shown that connexin30 can interfere with the insulin-like growth factor 1 receptor (IGF-1R), which is known for self-renewal and pluripotency. Following our earlier in vitro observation, in this work, we aimed to study the consequence of this influence of Cx30 on IGF-1R by evaluating the marker of GSCs, CD133 and oncoprotein, cMyc. We strengthened our basis by examining human glioma samples of different grades as well as rat C6 xenografts (Cx30-transfected and -non-transfected C6 cells) along with the sphere formation assays in vitro. Investigation of stemness-related CD133 and cMyc in human samples and rat xenografts exhibited a reciprocal relationship between Cx30 and IGF-1R in the low and high grades (HG) of glioma. Cx30 was completely abolished in HG; levels of IGF-1R, CD133 and cMyc expression were positively correlated with HG. Cx30 transfection could attenuate the malignant burden of glioma in rat xenografts. Cx30 transfection also altered the tumor sphere formation of C6 glioma cells in vitro, an important property of GSCs, and there was a significant reduction of CD133 and cMyc expression by Cx30 both in vitro and in vivo. These factors indicate that dysfunction of Cx30 plays a crucial role in the prevention of the stemness of glioma, and the exploitation of this feature will help in the management of glioma.

http://ift.tt/2vIE7xK

A Double-Blind, Randomized, Placebo-Controlled Trial of Panax Ginseng for Cancer-Related Fatigue in Patients With Advanced Cancer

Background: Despite the high frequency, severity, and effects of cancer-related fatigue (CRF) on the quality of life (QoL) of patients with cancer, limited treatment options are available. The primary objective of this study was to compare the effects of oral Panax ginseng extract (PG) and placebo on CRF. Secondary objectives were to determine the effects of PG on QoL, mood, and function. Methods: In this randomized, double-blind, placebo-controlled study, patients with CRF ≥4/10 on the Edmonton Symptom Assessment System (ESAS) were eligible. Based on a pilot study, we randomized patients to receive either 400 mg of standardized PG twice daily or a matching placebo for 28 days. The primary end point was change in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) subscale from baseline to day 29. Results: Of 127 patients, 112 (88.2%) were evaluable. The mean (SD) FACIT-F subscale scores at baseline, day 15, and day 29 were 22.4 (10.1), 29.9 (10.6), and 30.1 (11.6) for PG (P<.001), and 24.0 (9.4), 30.0 (10.1), and 30.4 (11.5) for placebo (P<.001). Mean (SD) improvement in the FACIT-F subscale at day 29 was not significantly different in the PG than in the placebo group (7.5 [12.7] vs 6.5 [9.9]; P=.67). QoL, anxiety, depression, symptoms, and functional scores were not significantly different between the PG and placebo groups. Improvement in the FACIT-F subscale correlated with baseline scores (P=.0005), Hospital Anxiety and Depression Scale results (P=.032), and sex (P=.023). There were fewer any-grade toxicities in the PG versus placebo group (28/63 vs 33/64; P=.024). Conclusions: Both PG and placebo result in significant improvement in CRF. PG was not significantly superior to placebo after 4 weeks of treatment. There is no justification to recommend the use of PG for CRF. Further studies are needed. Trial Registration: ClinicalTrials.gov identifier: NCT01375114.

http://ift.tt/2wENw6Q

Survivorship Care Planning: Why Is It Taking So Long?

Survivorship care planning is a process that focuses on the transition from active cancer treatment to a coordinated and comprehensive care system to address patients' unique needs. Survivorship care plans (SCPs) are increasingly viewed as a key component of survivorship care planning. SCPs have been recommended for >10 years to promote care coordination, communication, and record-keeping efficiency; however, SCP implementation has been challenging. We elaborate on the challenges of SCP implementation, summarize evidence regarding potential methods of promoting SCP implementation, and describe a research agenda for generating more definitive evidence to support SCP implementation in practice.

http://ift.tt/2wEM0BW

NCCN News

http://ift.tt/2vIes8p

"Standard Care" in Cancer Clinical Trials: An Analysis of Care Provided to Women in the Control Arms of Breast Cancer Clinical Trials

Background: For trials to validly evaluate new treatments, comparison against the best existing alternative treatment is essential. We reviewed the care provided to women in control arms of breast cancer clinical trials to estimate the proportion consistent with the standard of care as defined in clinical guidelines. Methods: We analyzed phase III randomized controlled breast cancer trials comparing drug treatments with "standard care," enrolling between 2004 and 2014, and registered on ClinicalTrials.gov. Our primary outcome was the proportion of trials in which treatment in the control arm was consistent with concurrent NCCN Guidelines. A secondary analysis assessed trials recruiting outside the United States that provided control group therapy not consistent with NCCN Guidelines, comparing them with the German Gynecological Oncology Group (AGO) guidelines. We assessed associations between the primary outcome and a priori selected trial characteristics. Results: This study included 210 trials that recruited 229,182 women worldwide; 29% of trials (60/210) did not provide control group treatment that was consistent with NCCN Guidelines. For trials not recruiting in the United States, results were similar; in 21% of trials, control arm treatment was inconsistent with both AGO and NCCN Guidelines. Factors significantly associated with offering control arm treatment that were inconsistent with guidelines were time period (later trials were less likely to be consistent), breast cancer stage and type (trials in early-stage breast cancer and estrogen receptor–negative disease were less likely consistent), and recruitment in ≥4 countries and recruitment outside the United States. Conclusions: To ensure that clinical trials achieve their goal of obtaining the best information to guide patient treatment, the question of how investigators chose and describe "standard care" for control arm participants warrants further investigation.

http://ift.tt/2wFngtg

Your Genes: Getting the Best Fit

http://ift.tt/2wEC4bn

Oncology Research Program

http://ift.tt/2vIKEc6

EGFR Exon 19 Deletion in Pancreatic Adenocarcinoma Responds to Erlotinib, Followed by T790M-Mediated Resistance

The prognosis of metastatic pancreatic cancer remains poor despite recent advances in treatment with multidrug chemotherapy regimens. Use of immune checkpoint inhibitors and molecular targeted therapies has so far been disappointing. This report describes a patient with chemotherapy-refractory metastatic pancreatic ductal adenocarcinoma (PDAC) whose tumor was characterized by an activating mutation in exon 19 of the epidermal growth factor receptor (EGFR). He experienced response to erlotinib for 10 months, and then developed disease progression in association with emergence of the T790M mutation. Activating EGFR mutations in cancers other than lung are uncommon, but when present may predict response to EGFR tyrosine kinase inhibitors (TKIs). Development of the T790M mutation in this case suggests that EGFR-targeted TKIs may follow similar patterns of resistance regardless of tumor type. Although actionable mutations are detected infrequently in PDAC, this case illustrates the potential benefit of offering genomic analysis to all patients with advanced disease.

http://ift.tt/2wEw2Yp

Risk of Febrile Neutropenia Associated With Select Myelosuppressive Chemotherapy Regimens in a Large Community-Based Oncology Practice

Background: NCCN has classified commonly used chemotherapy regimens into high (>20%), intermediate (10%–20%), or low (<10%) febrile neutropenia (FN) risk categories based primarily on clinical trial evidence. Many chemotherapy regimens, however, remain unclassified by NCCN or lack FN incidence data in real-world clinical practice. Patients and Methods: We evaluated incidence proportions of FN and grade 4 and 3/4 neutropenia during the first chemotherapy course among patients from Kaiser Permanente Southern California who received selected chemotherapy regimens without well-established FN risk. Patients given granulocyte colony-stimulating factor (G-CSF) prophylaxis were excluded. Sensitivity analyses were performed to account for FN misclassification and censoring. Results: From 2008 to 2013, 1,312 patients with breast cancer who received docetaxel and cyclophosphamide (TC; n=853) or docetaxel, carboplatin, and trastuzumab (TCH; n=459); 1,321 patients with colorectal cancer who received capecitabine and oxaliplatin (XELOX; n=401) or leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX6; n=920); 307 patients with non-Hodgkin's lymphoma who received bendamustine with or without rituximab; and 181 patients with multiple myeloma who received lenalidomide with or without dexamethasone were included. Crude FN risk was >20% for both breast cancer regimens (TC and TCH). Crude FN risks for XELOX, FOLFOX6, bendamustine, and lenalidomide were <10%; however, when potential FN misclassification and censoring were considered, FN risks were >10%. Conclusions: Our results support published literature highlighting the real-world, "high" FN risk of the TC and TCH regimens for breast cancer. There is strong suggestive evidence that FN risks for XELOX, FOLFOX6, bendamustine, and lenalidomide are >10%. Calculation of chemotherapy course-level FN incidence without controlling for differential censoring for patients who discontinued regimens early, or possible FN misclassification, might have resulted in bias toward an underestimation of the true FN risk. These findings help define FN risk of the selected regimens in the real-world setting and inform prophylactic G-CSF use.

http://ift.tt/2vIZPlC

NCCN Guidelines Insights: Acute Lymphoblastic Leukemia, Version 1.2017

The prognosis for patients with newly diagnosed acute lymphoblastic leukemia (ALL) has improved with the use of more intensive chemotherapy regimens, tyrosine kinase inhibitors, targeted agents, and allogeneic hematopoietic cell transplantation. However, the management of relapsed or refractory (R/R) ALL remains challenging and prognosis is poor. The NCCN Guidelines for ALL provide recommendations on standard treatment approaches based on current evidence. These NCCN Guidelines Insights summarize treatment recommendations for R/R ALL and highlight important updates, and provide a summary of the panel's discussion and underlying data supporting the most recent recommendations for R/R ALL management.

http://ift.tt/2wEJYBt

Survivorship, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology

Many cancer survivors experience menopausal symptoms, including female survivors taking aromatase inhibitors or with a history of oophorectomy or chemotherapy, and male survivors who received or are receiving androgen-ablative therapies. Sexual dysfunction is also common in cancer survivors. Sexual dysfunction and menopause-related symptoms can increase distress and have a significant negative impact on quality of life. This portion of the NCCN Guidelines for Survivorship provide recommendations for screening, evaluation, and treatment of sexual dysfunction and menopausal symptoms to help healthcare professionals who work with survivors of adult-onset cancer in the posttreatment period.

http://ift.tt/2vIWnXZ

A Randomized Controlled Trial of an Additional Funding Intervention to Improve Clinical Trial Enrollment

Background: A low proportion of adults with cancer are recruited to clinical trials. Cancer Council Victoria provides funding to clinical trial sites through its statewide Cancer Trials Management Scheme (CTMS). Historically, there appeared to be a relationship between budget-allocated funding and the number of patients recruited. A randomized controlled trial was conducted to test whether additional funding in 2013 would increase trial recruitment. Methods: A total of 18 trial centers ("sites") received usual CTMS funds, whereas 16 intervention sites received usual funds plus additional funds, proportional to recruitment in 2011; additional payments to sites in the intervention group ranged from $6,750 to $234,000 AUD ($6,750–$234,000 USD at the time). This represented an average 11.8% (interquartile range [IQR], 8.0%, 12.3%) increase in sites' budgets. Sites were required to use the funds with the aim of increasing recruitment. The study end point was the number of new participants recruited to trials in 2013. An online survey assessed strategies used to increase recruitment. Results: The median number of new trial recruits per site in 2013 was 21 (IQR, 5–39) in the control arm and 12.5 (IQR, 3.5–44.5) in the intervention arm. The ratio of new trial recruitment numbers at the intervention sites compared with control sites in 2013, adjusting for respective 2012 numbers and institution type, was 0.99 (95% CI, 0.69, 1.43; P=.96). The survey revealed most intervention sites used funding to increase staffing. Conclusions: Additional funding at a site level did not lead to a contemporaneous increase in trial recruitment.

http://ift.tt/2wENprW

Trials and Tribulations for Adolescents and Young Adults with Cancer: Measuring the Impact of a Community-Based Program

http://ift.tt/2wEJmvC

Doses dans les organes à risque en radiothérapie conformationnelle et en radiothérapie en conditions stéréotaxiques : la vessie

Publication date: Available online 4 September 2017
Source:Cancer/Radiothérapie
Author(s): L. Duvergé, J. Castelli, T. Lizée, R. de Crevoisier, D. Azria
Les contraintes de dose à la vessie en cas de radiothérapie conformationnelle/radiothérapie conformationnelle avec modulation d'intensité (RCMI) et de radiothérapie en conditions stéréotaxiques sont rapportées à partir des données de la littérature et en particulier les recommandations Recorad de la Société française de radiothérapie oncologique (SFRO), selon les localisations tumorales pelviennes traitées. L'effet dose–volume sur la toxicité urinaire n'est pas clairement démontré, ce qui rend difficile l'établissement de contraintes absolues de dose pour la vessie. En cas de radiothérapie prostatique de haute dose, les contraintes de dose sont : V60Gy (VxGy : volume recevant x Gy) de moins de 50 % et dose maximale de moins de 80Gy en cas de fractionnement standard et V60Gy de moins de 5 %, V48Gy de moins de 25 % et V41Gy de moins de 50 % en cas d'hypofractionnement modéré (20 séances de 3Gy). En cas de radiothérapie stéréotaxique prostatique (cinq séances de 7,25Gy), les contraintes de dose les plus fréquentes dans la littérature sont V37Gy de moins de 10cm³ et V18Gy de moins de 40 %. En cas de radiothérapie conformationnelle du col utérin, de l'endomètre en situation postopératoire, du canal anal et du rectum, les recommandations sont : V40Gy de moins de 40 % et la D2 % (dose dans 2 % du volume) inférieure à la dose prescrite.Bladder dose constraints in case of conformational radiotherapy/intensity-modulated radiotherapy and stereotactic radiotherapy are reported from the literature, in particular from the French radiotherapy society RECORAD recommendations, according to the treated pelvic tumor sites. The dose–volume effect on urinary toxicity is not clearly demonstrated, making difficult to establish absolute dose constraints for the bladder. In case of high-dose prostate cancer radiotherapy, the bladder dose constraints are: V60Gy<50% and maximum dose<80Gy for standard fractionation and V60Gy<5%, V48Gy<25% and V41Gy<50% for moderate hypofractionation (20 fractions of 3Gy). In case of prostate stereotactic radiotherapy (five fractions of 7.25Gy), the most frequent dose constraints in the literature are V37Gy<10cm³ and V18Gy<40%. In case of conformational radiotherapy of cervix cancer, postoperative endometrium, anal canal and rectum, the recommendations are V40Gy<40% and D2% lower than the prescribed dose.



http://ift.tt/2w33mGp

Karyopherin α-2 is a reliable marker for identification of patients with high-risk stage II colorectal cancer

Abstract

Purpose

Adjuvant chemotherapy (AC) is frequently considered in patients with high-risk stage II colorectal cancer (CRC). Among patients with stage II CRC who do not receive AC because they are not considered to be at high risk, 20–25% will develop recurrence and die from the disease. Elevated levels of KPNA2 have been observed in various cancers, and overexpression of KPNA2 is related to CRC progression.

Methods

We examined the expression of KPNA2 using 293 CRC tissues, including 118 with stage II CRC, and investigated the applicability of KPNA2 as a biomarker to predict high-risk stage II CRC. Moreover, we further investigated the role of KPNA2 as an oncogene in CRC carcinogenesis using in vitro functional studies.

Results

High KPNA2 expression was associated with vascular (p = 0.027) and lymphatic invasion (p = 0.009) in patients with stage II CRC. On multivariate analysis, high KPNA2 expression (HR 3.174, 95% CI 2.060–4.889; p < 0.001) was independently associated with survival in patients with CRC. The overall survival rate in patients with high KPNA2 expression was higher than that in patients with low KPNA2 expression in CRC (p < 0.001), even in patients with stage II CRC (p = 0.001). Additionally, KPNA2 was associated with tumorigenesis and cancer progression in CRC cells; high KPNA2 expression was associated with increased cell proliferation (p < 0.05), migration (p = 0.03), invasion (p = 0.001), and semisolid agar colony formation (p < 0.001).

Conclusion

KPNA2 expression is useful for identification of patients with high-risk stage II CRC who could benefit from AC and that KPNA2 may also be a promising therapeutic target.

http://ift.tt/2wEiHPK

Tumor vessel disintegration by maximum tolerable PFKFB3 blockade

Abstract

Blockade of the glycolytic activator PFKFB3 in cancer cells (using a maximum tolerable dose of 70 mg/kg of the PFKFB3 blocker 3PO) inhibits tumor growth in preclinical models and is currently being tested as a novel anticancer treatment in phase I clinical trials. However, a detailed preclinical analysis of the effects of such maximum tolerable dose of a PFKFB3 blocker on the tumor vasculature is lacking, even though tumor endothelial cells are hyper-glycolytic. We report here that a high dose of 3PO (70 mg/kg), which inhibits cancer cell proliferation and reduces primary tumor growth, causes tumor vessel disintegration, suppresses endothelial cell growth for protracted periods, (model-dependently) aggravates tumor hypoxia, and compromises vascular barrier integrity, thereby rendering tumor vessels more leaky and facilitating cancer cell intravasation and dissemination. These findings contrast to the effects of a low dose of 3PO (25 mg/kg), which induces tumor vessel normalization, characterized by vascular barrier tightening and maturation, but reduces cancer cell intravasation and metastasis. Our findings highlight the importance of adequately dosing a glycolytic inhibitor for anticancer treatment.

http://ift.tt/2xM7gWb

Quantitative proteomic analysis of host responses triggered by Mycobacterium tuberculosis infection in human macrophage cells

Abstract

Macrophages are primary host of Mycobacterium tuberculosis (M.tb) and the central effector of in vivo innate immune responses against bacteria. Though the interaction between macrophages and mycobacteria has been widely investigated, the molecular mechanisms of M.tb pathogenesis in macrophages are still not clear. In this work, we investigated the altered protein expression profiles of macrophages after virulent H37Rv strain and avirulent H37Ra strain infection by tandem mass tag-based quantitative proteomics. Among 6762 identified proteins of macrophages, the expression levels of 235 proteins were significantly altered, which is supposed to be related to the infection of different strains. By bioinformatics analysis at systems level, we found that these proteins are mainly involved in the biological process of apoptosis, blood coagulation, oxidative phosphorylation, and others. The enormous variation in protein profiles between macrophages infected with H37Ra and H37Rv suggests the existence of four different immunity mechanisms that decide the fates of macrophages and M.tb. These data may provide a better understanding of M.tb pathogenesis within the host, which contributes to the prevention and clinical treatment of tuberculosis.

http://ift.tt/2eZzOnu

Neuroprotective effect of deferoxamine on N -methyl- d -aspartate-induced excitotoxicity in RGC-5 cells

Abstract

Many N-methyl-d-aspartate (NMDA) receptor antagonists have been used to treat neurodegenerative diseases induced by glutamate excitotoxicity in clinics. However, the universality of the glutamic acid neurotransmitter system makes the glutamic acid receptor blockers inefficient and unsafe. Thus, regulating the downstream signaling pathway in the excitotoxicity of glutamic acid may be a more effective and safer way to antagonize the glutamic acid receptor. In this study, we investigated the effect of deferoxamine (DFO), an iron chelator, on the NMDA-induced excitotoxicity. RGC-5 cells were cultured and identified in vitro, and the NMDA-induced injury was assessed. Then the MTT assay was used to estimate the cell survival and JC-1 staining was performed to detect changes in mitochondrial membrane potential. Immunofluorescent staining and western blot analysis were used to analyze the expressions of respiratory chain proteins. It was found that DFO increased the survival rate of RGC-5 cells and that this effect was positively correlated with the concentration of DFO and the treatment time. The mitochondrial membrane potential and the expression levels of succinate dehydrogenase subunit A and cytochrome c oxidase subunit IV were also increased after DFO treatment, while NMDA reduced their expression levels. These data demonstrate that DFO has significant neuroprotective activity against NMDA-induced excitotoxicity in RGC-5 cells.

http://ift.tt/2gK00q9

Exosomes containing miR-21 transfer the characteristic of cisplatin resistance by targeting PTEN and PDCD4 in oral squamous cell carcinoma

Abstract

Resistance to chemotherapy remains a major obstacle for the effective treatment of oral squamous cell carcinoma (OSCC). Evidence for the involvement of exosomes as important regulators of cisplatin chemoresistance in OSCC is still poorly understood. Our objective of this study was to explore the roles for exosomes in modulating key cellular pathways mediating response to chemotherapy. We first developed the cisplatin-resistant cell lines (HSC-3-R and SCC-9-R) and found that the conditioned media from cisplatin-resistant OSCC cells enhanced the chemoresistance of parental OSCC cell. The release of exosomes was blocked by inhibitor (GW4869) and exosomes were found to be involved in the chemoresistance of parental OSCC cell transferred from resistant cells. The exosomes derived from resistant cells and parental cells were isolated. Then, the isolated exosomes were characterized and quantified by electron microscopy, qNano analysis, and western blot analysis. Exosomes derived from cisplatin-resistant OSCC cells were found to enhance the chemoresistance of OSCC cell and decrease the DNA damage signaling in response to cisplatin. It was also found that exosomes derived from cisplatin-resistant OSCC cells transferred miR-21 to OSCC parental cells and induced cisplatin resistance by targeting phosphatase and tensin homolog and programmed cell death 4. Furthermore, the roles of cisplatin-resistant OSCC cells-derived exosomes in vivo were confirmed by subcutaneous xenograft mouse model. Collectively, the results suggest that exosomes released from cisplatin-resistant OSCC cells transmit miR-21 to induce cisplatin resistance of OSCC cells.

http://ift.tt/2eZKIKa

Distinct transcription profile of genes involved in carotenoid biosynthesis among six different color carrot ( Daucus carota L.) cultivars

Abstract

Carotenoid, a group of lipophilic molecules, is widely distributed in nature, and is important for plant photosynthesis and photoprotection. In carrot taproot, different types of dominant carotenoid accumulation lead to yellow, orange, and red colors. In this study, six different carrot cultivars were used to simultaneously analyze carotenoid contents by high performance liquid chromatography. The expression levels of genes involved in carotenoid biosynthesis of carrot were also detected by real-time quantitative PCR. It was found that genes involved in xanthophyll formation were expressed at high levels in yellow carrot cultivars. However, these genes were expressed at low levels in orange carrot cultivars. The contents of α- and β-carotene accounted for a large proportion in total carotenoid contents in orange carrot cultivars. These results indicate that α-carotene accumulation and xanthophyll formation may be related to the expression levels of carotene hydroxylase genes in carrot.

http://ift.tt/2gJZLvf

CRISPR/Cas9-based efficient genome editing in Staphylococcus aureus

Abstract

Staphylococcus aureus is an important pathogenic bacterium prevalent in nosocomial infections and associated with high morbidity and mortality rates, which arise from the significant pathogenicity and multi-drug resistance. However, the typical genetic manipulation tools used to explore the relevant molecular mechanisms of S. aureus have multiple limitations: leaving a scar in the genome, comparatively low gene-editing efficiency, and prolonged experimental period. Here, we present a single-plasmid based on the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) system which allows rapid and efficient chromosomal manipulation in S. aureus. The plasmid carries the cas9 gene under the control of the constitutive promoter P_xyl/tet, a single guide RNA-encoding sequence transcribed via a strong promoter P_spac, and donor DNA used to repair the double strand breaks. The function of the CRISPR/Cas9 vector was demonstrated by deleting the tgt gene and the rocA gene, and by inserting the erm R cassette in S. aureus. This research establishes a CRISPR/Cas9 genome editing tool in S. aureus, which enables marker-free, scarless and rapid genetic manipulation, thus accelerating the study of gene function in S. aureus.

http://ift.tt/2f00GUt

Emerging role of HuR in inflammatory response in kidney diseases

Abstract

Human antigen R (HuR) is a member of the embryonic lethal abnormal vision (ELAV) family which can bind to the A/U rich elements in 3' un-translated region of mRNA and regulate mRNA splicing, transportation, and stability. Unlike other members of the ELAV family, HuR is ubiquitously expressed. Early studies mainly focused on HuR function in malignant diseases. As researches proceed, more and more proofs demonstrate its relationship with inflammation. Since most kidney diseases involve pathological changes of inflammation, HuR is now suggested to play a pivotal role in glomerular nephropathy, tubular ischemia-reperfusion damage, renal fibrosis and even renal tumors. By regulating the mRNAs of target genes, HuR is causally linked to the onset and progression of kidney diseases. Reports on this topic are steadily increasing, however, the detailed function and mechanism of action of HuR are still not well understood. The aim of this review article is to summarize the present understanding of the role of HuR in inflammation in kidney diseases, and we anticipate that future research will ultimately elucidate the therapeutic value of this novel target.

http://ift.tt/2gJCfhW

Bisphenol A induced apoptosis and transcriptome differences of spermatogonial stem cells in vitro

Abstract

Bisphenol A (BPA) is widely used as an industrial plasticizer, which is also an endocrine disruptor and considered to have adverse effects on reproduction. In male mammals, the long-term production of billions of spermatozoa relies on the regulated proliferation and differentiation of spermatogonial stem cells (SSCs). However, little is known about the effects of BPA on the viability of SSCs. To investigate the influence of BPA exposure on SSCs in vitro, we isolated SSCs from mouse and successfully established in vitro propagation of SSCs. After BPA treatment, we found that BPA reduced the viability of SSCs and induced SSC apoptosis. For revealing the transcriptome differences of the BPA-treated SSCs, we performed high-throughput RNA sequencing and found that 860 genes were differentially expressed among 18,272 observed genes. The gene ontology (GO) terms, regulation of programmed cell death and apoptotic process, were enriched in the differentially expressed genes (DEGs). Among the cluster of DEGs associated with the kyoto encyclopedia of genes and genomes (KEGG) apoptosis pathway, activating transcription factor 4 (Atf4) and DNA damage inducible transcript 3 (Ddit3) genes were significantly up-regulated in BPA-treated SSCs, which were proved by qPCR. Taken together, these findings suggest that BPA can increase the mRNA expression of pro-apoptosis genes and reduce the viability of SSCs by inducing apoptosis.

http://ift.tt/2f00owR