The Stat3/5 signaling biosignature in hematopoietic stem/progenitor cells predicts response and outcome in myelodysplastic syndrome patients treated with azacitidine

Purpose:Azacitidine is the mainstay of high-risk myelodysplastic syndromes (MDS) therapy, but molecular predictors of response and the mechanisms of resistance to azacitidine remain largely unidentified. Deregulation of signaling via signal transducer and activator of transcription 3 (Stat3) and Stat5 in acute myeloid leukemia (AML) is associated with aggressive disease. Numerous genes involved in cell signaling are aberrantly methylated in MDS, yet the alterations and the effect of azacitidine treatment on Stat3/5 signaling in high-risk MDS have not been explored. Experimental Design:We assessed longitudinally constitutive and ligand-induced phospho-Stat3/5 signaling responses by multiparametric flow cytometry in 74 patients with MDS and low blast count AML undergoing azacitidine therapy. Pretreatment Stat3/5 signaling profiles in CD34+ cells were grouped by unsupervised clustering. The differentiation stage and the molecular properties of the CD34+ G-CSF-inducible Stat3/5 double-positive subpopulation were performed by flow cytometry and quantitative real-time PCR in isolated MDS progenitors. Results:The pretreatment Stat3/5 signaling profiles in CD34+ cells correlated strongly with response and cytogenetics and independently predicted event-free survival. We further identified a CD34+ G-CSF-inducible Stat3/5 double-positive subpopulation (DP subset) whose pretreatment levels were inversely associated with treatment response and cytogenetics. The kinetics of the DP subset followed the response to azacitidine and the disease course, whereas its molecular characteristics and cellular hierarchy were consistent with a leukemia propagating cell phenotype. Conclusions:Our findings provide a novel link among Stat3/5 signaling and MDS pathobiology and suggest that the Stat3/5 signaling biosignature may serve as both a response biomarker and treatment target.

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ESR1 Mutations in Breast Cancer: Proof of Concept Challenges Clinical Action

Wang and colleagues demonstrate that digital droplet PCR (ddPCR) identified ESR1 mutations in 7% of primary breast cancers. ESR1 mutations were also readily detected in metastatic tissues and circulating tumor DNA in the blood. These results suggest that ddPCR may be amendable for monitoring tumor burden, and to predict relapse.

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Recurrent mutations of chromatin remodeling genes and kinase receptors in pheochromocytomas and paragangliomas

Purpose: Pheochromocytomas and paragangliomas (PPGLs) are genetically heterogeneous tumors of neural crest origin, but the molecular basis of most PPGLs is unknown. Experimental Design: We performed exome or transcriptome sequencing of 43 samples from 41 patients. A validation set of 136 PPGLs was used for amplicon-specific resequencing. In addition, a subset of these tumors was used for microarray-based transcription, protein expression and histone methylation analysis by western blot or immunohistochemistry. In vitro analysis of mutants was performed in cell lines. Results: We detected mutations in chromatin remodeling genes, including histone-methyltransferases, histone-demethylases and histones in 11 samples from 8 patients (20%). In particular, we characterized a new cancer syndrome involving PPGLs and giant cell tumors of bone (GCT) caused by a postzygotic G34W mutation of the histone 3.3 gene, H3F3A. Furthermore, mutations in kinase genes were detected in samples from 15 patients (37%). Among those, a novel germline kinase domain mutation of MERTK detected in a patient with PPGL and medullary thyroid carcinoma was found to activate signaling downstream of this receptor. Recurrent germline and somatic mutations were also detected in MET, including a familial case and sporadic PPGLs. Importantly, in each of these three genes mutations were also detected in the validation group. Additionally, a somatic oncogenic hotspot FGFR1 mutation was found in a sporadic tumor. Conclusions: This study implicates chromatin-remodeling and kinase variants as frequent genetic events in PPGLs, many of which have no other known germline driver mutation. MERTK, MET, and H3F3A emerge as novel PPGL susceptibility genes.

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Award for outstanding contributions to the Chinese Journal of Cancer

Abstract

At the 4th Guangzhou International Symposium on Oncology, Rui-Hua Xu, Chao-Nan Qian, and Wei Zhang—the chairmen and editors of the Chinese Journal of Cancer—announced and presented awards to 14 authors in recognition of their outstanding contributions to the journal.

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Potential anti-cancer effect of N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), a novel histone deacetylase inhibitor, for the treatment of thyroid cancer

Abstract

Background

Thyroid cancer has been indicated to have a higher global proportion of DNA methylation and a decreased level of histone acetylation. Previous studies showed that histone gene reviser and epigenetic changes role significant parts in papillary and anaplastic thyroid cancer tumorigenesis. The goal of this research was to study the endoplasmic reticulum (ER) stress-mediated actions of the dominant histone deacetylase (HDAC) inhibitor, N-hydroxy-7-(2-naphthylthio) hepatonomide (HNHA), in thyroid cancer and to explore its effects on apoptotic cell death pathways.

Methods

Experiments were achieved to conclude the effects of HNHA in papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) cell lines and xenografts, as compared with two other established HDAC inhibitors (SAHA; suberoylanilide hydroxamic acid and TSA; trichostatin A).

Results

Apoptosis, which was induced by all HDAC inhibitors, was particularly significant in HNHA-treated cells, where noticeable B-cell lymphoma-2 (Bcl-2) suppression and caspase activation were observed both in vitro and in vivo. HNHA increased Ca²⁺ release from the ER to the cytoplasm. ER stress-dependent apoptosis was induced by HNHA, suggesting that it induced caspase-dependent apoptotic cell death in PTC and ATC. PTC and ATC xenograft studies demonstrated that the antitumor and pro-apoptotic effects of HNHA were greater than those of the established HDAC inhibitors. These HNHA activities reflected its induction of caspase-dependent and ER stress-dependent apoptosis on thyroid cancer cells.

Conclusions

The present study indicated that HNHA possibly provide a new clinical approach to thyroid cancers, including ATC.

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Hepatic falciform ligament clear cell myomelanocytic tumor: A case report and a comprehensive review of the literature on perivascular epithelioid cell tumors

Abstract

Background

The objective of the study was to explore the clinical expression, radiological and pathological features, differential diagnosis, and biological behavior of a clear cell myomelanocytic tumor. In a case involving a clear cell myomelanocytic tumor located in the hepatic falciform ligament, we evaluated clinical expression, radiological characteristics, histopathology, immunohistochemistry, and biological behavior; we also reviewed the relevant literature.

Case presentation

Clear cell myomelanocytic tumor is a benign soft-tissue neoplasm that often occurs in women, and is expressed as a painless mass. The falciform ligament is its most frequent site of occurrence. The imaging characteristics of this lesion were uneven enhancement in the arterial phase, continuing to strengthen in the venous phase, and equal density in the balance phase. Histological and immunohistochemical analysis revealed the main transparent epithelioid cells and smooth muscle spindle cells to be HMB-45(+), smooth muscle actin(+), and melan-A (+).

Conclusion

Hepatic vascular epithelioid cell tumors are very rare mesenchymal neoplasms. Few studies have investigated this tumor in the hepatic falciform ligament; consequently, its diagnosis and the selection of an appropriate treatment and follow-up protocol are challenging. Treatment outcome remains unpredictable. Therefore, clear cell myomelanocytic tumor should be viewed as a tumor with uncertain malignant potential requiring long-term follow-up.

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Prevalence of hepatitis B and C and sensibility of a selective screening questionnaire in patients receiving chemotherapy for solid tumors

Abstract

Background

Reactivation of hepatitis B or C virus can occur in patients undergoing chemotherapy. Recommendations for selective or systematic hepatitis B virus testing prior chemotherapy for solid tumors differ. The primary aim was to determine the seroprevalence of hepatitis B or C in a low endemic country. The second objective was to assess the relevance of a questionnaire on hepatitis B/C risk factors to consider a selective screening.

Methods

Patients were prospectively tested for hepatitis B/C markers. HBs antigen positive patients and isolated anti-HBc positive patients with detectable viral load received antiviral preventive treatment. Patients or physicians completed the questionnaire on infection risk factors.

Results

Among the 450 patients included, 388 were tested for all serological markers and had gastrointestinal (63.7 %), lung (31.2 %) and skin (4.6 %) cancers. The prevalence of subjects exposed to hepatitis B virus was 8.5 % (33/388). One patient tested positive for HBs antigen and received preventive treatment. Prevalence of subjects exposed to hepatitis C was 1.3 % (5/388). The questionnaire sensitivity was 45.5 %, 100 % and 50 % for detecting carriers of hepatitis B, C and one or the other, respectively.

Conclusions

Seroprevalence of hepatitis B was low. Selective screening with the questionnaire was insufficiently sensitive. Systematic screening with serological tests prior to chemotherapy in patients with solid tumors is therefore relevant.

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Conditional survival analysis in Korean patients with gastric cancer undergoing curative gastrectomy

Abstract

Background

Conditional survival (CS) measures the probability that patients will survive an additional number of years given that they have already survived for a certain period of time.

Methods

In total, 2935 gastric cancer patients who had undergone curative gastrectomy between 1995 and 2011 were enrolled. The Cox proportional hazard regression model was used to evaluate the factors associated with overall survival (OS). Three-year CS estimates at 't' years after surgery were calculated as follows: CS(t) = S(t + 3)/S(t).

Results

The 1-, 2-, 3-, 4- and 5-year OS rates of the 2935 patients were 96.6 %, 92.0 %, 88.7 %, 85.6 and 82.7 %, respectively. The probability of surviving an additional 3 years on the condition of having already survived 1, 2, 3, 4 and 5 years after surgery were 88.6 %, 89.9 %, 91.0 %, 92.2 % and 93.2 %, respectively. Patients with a higher risk at baseline showed a greater increase in CS over time.

Conclusions

CS estimates provide important information about dynamic prognostic changes over time for Korean gastric cancer patients, and as such, can be used to guide long-term follow-up strategies.

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A population based perspective on children and youth with brain tumours

Abstract

Background

There is currently no active surveillance of metastatic and non-malignant brain tumours in Canada as well as data on the health service use of children and youth with brain tumours. The objective of this study was to identify pediatric primary, metastatic, benign, and unspecified brain tumours in Ontario, Canada and to describe their health service use from a population based perspective.

Methods

The population based healthcare administrative databases National Ambulatory Care Reporting System and the Discharge Abstract Database were used. Patients with malignant (primary and metastatic), benign, and unspecified brain tumours in acute care between fiscal year 2003/04 and 2009/10 were identified using specified International Classification of Diseases version ten codes.

Results

Between fiscal year 2003/04 and 2009/10, there were 4022 brain tumour episodes of care (18.4 per 100,000 children and youth). Malignant brain tumors had the highest rates of episodes of care (14.9 times higher than that of benign and 5.7 times higher than that of unspecified brain tumours). Compared to patients with malignant brain tumours, those with benign brain tumours spent a longer period of time in acute care (p < .05) and patients with unspecified brain tumours stayed in the intensive care units for a longer period of time (p < .0001) with a lower proportion were discharged home (p < .0001).

Conclusion

Despite higher rates of malignant brain tumour episodes of care, patients with benign and unspecified brain tumours also use acute care services and post-acute services that are currently not taken into account in healthcare planning and resource allocation. Active surveillance and research of metastatic and non-malignant brain tumours that can inform the planning of healthcare services and resource allocation for this population is encouraged.

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Influences of cancer symptom knowledge, beliefs and barriers on cancer symptom presentation in relation to socioeconomic deprivation: a systematic review

Abstract

Background

People from lower socioeconomic groups have worse survival outcomes for cancer, which in part reflects later-stage disease at diagnosis. The mechanisms underlying delayed cancer symptom presentation in lower socioeconomic groups are not well understood.

Methods

Systematic review of studies of actual or anticipated symptom presentation across all tumour sites. Included studies measured socioeconomic group, symptom presentation and one or more of the following variables: cancer symptom knowledge, beliefs about cancer, barriers/facilitators to symptom presentation.

Results

A total of 60 studies was included. Symptom knowledge overall was lowest and actual presentation time was longest in lower socioeconomic groups. Knowledge for specific symptoms such as lumps and bleeding was good and encouraged timely symptom presentation, in contrast to non-specific symptoms which were not well recognised. The combination of fearful and fatalistic beliefs was typically associated with later presentation, especially in lower socioeconomic groups. Emotional barriers such as 'worry what the doctor might find' were more frequently reported in lower socioeconomic groups, and there was evidence to suggest that disclosing symptoms to family/friends could help or hinder early presentation.

Conclusions

Poor symptom knowledge, fearful and fatalistic beliefs about cancer, and emotional barriers combine to prolong symptom presentation among lower socioeconomic groups. Targeted interventions should utilise social networks to improve knowledge of non-specific symptoms, challenge negative beliefs and encourage help-seeking, in order to reduce avoidable delays and minimise socioeconomic group inequalities.

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Upregulation of NETO2 expression correlates with tumor progression and poor prognosis in colorectal carcinoma

Abstract

Background

Neuropilin and tolloid-like 2 (NETO2) has been found to be overexpressed in different human cancers, but its expression pattern and clinical relevance in colorectal carcinoma (CRC) remains unknown.

Methods

Real-time quantitative PCR, western blot and immunohistochemistry analyses were used to analyze the expression of NETO2 in CRC clinical samples. The correlation of NETO2 expression with clinicopathologic features was estimated in a cohort containing 292 patients with primary CRC. Kaplan-Meier and Cox proportional hazards regression analyses were used to assess the prognostic value of NETO2 expression in CRC.

Results

The expression of NETO2 was frequently upregulated in CRC clinical samples at both the mRNA and protein levels, and its upregulation was significantly correlated with poor tumor differentiation (p = 0.013), advanced local invasion (p = 0.049), increased lymph node metastasis (p = 0.009), advanced TNM stage (p = 0.041) and increased patient death (p = 0.001). Kaplan-Meier analysis of the complete study cohort revealed that patients with high-NETO2 tumors had a significantly shorter disease-specific survival (DSS) than those with low-NETO2 tumors (p < 0.001). Importantly, high levels of NETO2 protein predicted poor DSS for patients with early stage tumors (p = 0.027) and for those with advanced stage tumors (p = 0.020). Furthermore, multivariate analyses indicated that increased NETO2 expression was an independent unfavorable prognostic factor for patients with early stage tumors (hazard ratio [HR] = 1.937, 95 % CI = 1.107-3.390, p = 0.021) as well as patients with advanced stage tumors (HR = 2.241, 95 % CI = 1.245-4.035, p = 0.007).

Conclusions

Our findings suggest that NETO2 upregulation could serve as a potential biomarker for the prediction of advanced tumor progression and unfavorable prognosis in patients with CRC.

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Diagnostic performance of FDG-PET/MRI and WB-DW-MRI in the evaluation of lymphoma: a prospective comparison to standard FDG-PET/CT

Abstract

Background

Use of FDG-PET/CT for staging and restaging of lymphoma patients is widely incorporated into current practice guidelines. Our aim was to prospectively evaluate the diagnostic performance of FDG-PET/MRI and WB-DW-MRI compared with FDG-FDG-PET/CT using a tri-modality PET/CT-MRI system.

Methods

From 04/12 to 01/14, a total of 82 FDG-PET/CT examinations including an additional scientific MRI on a tri-modality setup were performed in 61 patients. FDG-PET/CT, FDG-PET/MRI, and WB-DW-MRI were independently analyzed. A lesion with a mean ADC below a threshold of 1.2 × 10⁻³ mm²/s was defined as positive for restricted diffusion. FDG-PET/CT and FDG-PET/MRI were evaluated for the detection of lesions corresponding to lymphoma manifestations according to the German Hodgkin Study Group. Imaging findings were validated by biopsy (n = 21), by follow-up imaging comprising CT, FDG-PET/CT, and/or FDG-PET/MRI (n = 32), or clinically (n = 25) (mean follow-up: 9.1 months).

Results

FDG-PET/MRI and FDG-PET/CT accurately detected 188 lesions in 27 patients. Another 54 examinations in 35 patients were negative. WB-DW-MRI detected 524 lesions, of which 125 (66.5 % of the aforementioned 188 lesions) were true positive. Among the 188 lesions positive for lymphoma, FDG-PET/MRI detected all 170 instances of nodal disease and also all 18 extranodal lymphoma manifestations; by comparison, WB-DW-MRI characterized 115 (67.6 %) and 10 (55.6 %) lesions as positive for nodal and extranodal disease, respectively. FDG-PET/MRI was superior to WB-DW-MRI in detecting lymphoma manifestations in patients included for staging (113 vs. 73), for restaging (75 vs. 52), for evaluation of high- (127 vs. 81) and low-grade lymphomas (61 vs. 46), and for definition of Ann Arbor stage (WB-DW-MRI resulted in upstaging in 60 cases, including 45 patients free of disease, and downstaging in 4).

Conclusion

Our results indicate that FDG-PET/CT and FDG-PET/MRI probably have a similar performance in the clinical work-up of lymphomas. The performance of WB-DW-MRI was generally inferior to that of both FDG-PET-based methods but the technique might be used in specific scenarios, e.g., in low-grade lymphomas and during surveillance.

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Accuracy of volatile urine biomarkers for the detection and characterization of lung cancer

Abstract

Background

The mixture of volatile organic compounds in the headspace gas of urine may be able to distinguish lung cancer patients from relevant control populations.

Methods

Subjects with biopsy confirmed untreated lung cancer, and others at risk for developing lung cancer, provided a urine sample. A colorimetric sensor array was exposed to the headspace gas of neat and pre-treated urine samples. Random forest models were trained from the sensor output of 70 % of the study subjects and were tested against the remaining 30 %. Models were developed to separate cancer and cancer subgroups from control, and to characterize the cancer. An additional model was developed on the largest clinical subgroup.

Results

90 subjects with lung cancer and 55 control subjects participated. The accuracies, reported as C-statistics, for models of cancer or cancer subgroups vs. control ranged from 0.795 – 0.917. A model of lung cancer vs. control built using only subjects from the largest available clinical subgroup (30 subjects) had a C-statistic of 0.970. Models developed and tested to characterize cancer histology, and to compare early to late stage cancer, had C-statistics of 0.849 and 0.922 respectively.

Conclusions

The colorimetric sensor array signature of volatile organic compounds in the urine headspace may be capable of distinguishing lung cancer patients from clinically relevant controls. The incorporation of clinical phenotypes into the development of this biomarker may optimize its accuracy.

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Exosomal transfer of functional small RNAs mediates cancer-stroma communication in human endometrium

Abstract

Exosomes are small membrane vesicles secreted from a variety of cell types. Recent evidence indicates that human cells communicate with each other by exchanging exosomes. Cancer cells closely interact with neighboring stromal cells, and together they cooperatively promote disease via bidirectional communication. Here, we investigated whether exosomes can play roles in intercellular communication between cancer cells and neighboring fibroblasts. Endometrial fibroblasts were isolated from normal endometrial tissues and from endometrial cancer tissues, and cell-to-cell transfer of endometrial cancer cell line Ishikawa-derived exosomes was examined. The isolated fibroblasts were cultured in conditioned media from CD63-GFP-expressing Ishikawa cells, and we found that GFP-positive exosomes were transferred from Ishikawa cells to the fibroblasts. Next, we introduced a shRNA for a luciferase gene into Ishikawa cells. This shRNA was encapsulated into exosomes, was transferred to the fibroblasts, and then downregulated luciferase expression in the fibroblasts. The mature microRNAs naturally expressed in Ishikawa-derived exosomes were also transported into the endometrial fibroblasts, and they altered the microRNA expression profiles of the fibroblasts. These results indicated that endometrial cancer cells could transmit small regulatory RNAs to endometrial fibroblasts via exosomes. Our findings document a previously unknown mode of intercellular communication between cancer cells and related fibroblasts in human endometrium.

Exosomes are small membrane vesicles secreted from a variety of cell types. Here, we uncovered that endometrial cancer cells transmit small regulatory RNAs to endometrial fibroblasts via exosomes.

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MTA1-upregulated EpCAM is associated with metastatic behaviors and poor prognosis in lung cancer

Abstract

Background

Overexpression of Metastasis-associated protein 1 (MTA1) in various cancer cells promotes tumor invasion and migration and predicts cancer patients' poor prognosis. The pilot RNA-Seq data from our laboratory indicated that Epithelial cell adhesion molecule (EpCAM) was statistically reduced in MTA1-silencing cells. EpCAM has been recognized as more than a mere cell adhesion molecule and recent findings have revealed its causal role in mediating migratory and invasive capacity. Thus, this study was aimed to explore whether MTA1 was able to upregulate EpCAM expression and, consequently, modulate its effects on invasion and migration of the lung cancer cells as well as patients' prognosis.

Methods

We checked the EpCAM expression by overexpressing or silencing MTA1 in lung cancer cells. Furthermore, these lung cancer cells with stably overexpressed or silenced MTA1 were transfected with siEpCAM or EpCAM-expressing plasmids and then subjected to western blot, invasion and migration assays. In addition, patients (n = 118) with early-stage lung cancer were enrolled in this study to confirm the correlations between MTA1 and EpCAM and pathoclinical parameters by using immunohistochemistry (IHC). All statistical analyses were performed with SPSS 20.0 statistical software.

Results

MTA1 upregulated EpCAM expression in lung cancer cell lines, and EpCAM overexpression rescued the inhibitory effects by silencing MTA1 on cell invasion and migration in vitro. What's more, both MTA1 and EpCAM, correlated to each other, were overexpressed in lung cancer tissues and significantly correlated with their clinical stages, tumor diameters, lymph node metastasis. Multivariate analysis indicated that local advancement (p = 0.03), MTA1 overexpression (p = 0.001) and EpCAM overexpression (p = 0.045) of the lung cancer tissues remained significant in predicting unfavorable overall survival.

Conclusions

We revealed a new molecular mechanism of MTA1-mediated invasion and metastasis in lung cancer through downstream target EpCAM, and interfering with EpCAM function may be a novel therapeutic strategy for treatment of MTA1-overexpressing lung carcinoma.

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Impressive Results With Daratumumab Plus Lenalidomide/Dexamethasone in Multiple Myeloma

The anti-CD38 monoclonal antibody daratumu­mab (Darzalex) took center stage among multiple myeloma studies presented at the 57th American Society of Hematology Annual Meeting and Exposition. In relapsed/refra

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Expert Point of View: Sagar Lonial, MD

At an educational session at the 2015 American Society of Hematology Annual Meeting and Exposition, Sagar Lonial, MD, of Emory University, Atlanta, elaborated upon this topic. The pooled analysis of daratumumab (Darzalex) monotherapy, he said, "dem

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A Shot to End Cancer: HPV Vaccination

As health-care providers, we have an obligation and a responsibility not only to care for our patients, but also to educate them—and the general public—about their cancer risk and ways to reduce or prevent it. We are living in the golden era of cancer pre

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Patients With Incomplete Response to Neoadjuvant Chemotherapy Benefit From Capecitabine

Treatment with capecitabine increased disease-free and overall survival in breast cancer patients with residual disease after neoadjuvant chemotherapy, according to a study reported by researchers from Japan and Korea at the 2015 San Antonio Breast Cancer

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Adjuvant Denosumab Improves Disease-Free Survival in Estrogen Receptor–Positive Postmenopausal Breast Cancer

There is good news about denosumab (Prolia). The primary analysis of the ABCSG-18 trial showed that adjuvant denosumab (given at low doses) reduces the risk of clinical fracture by 50% in postmenopausal women with early breast cancer who are taking an aro

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Post-chemotherapy laparoscopic retroperitoneal lymph node dissection is feasible for stage IIA/B non-seminoma germ cell tumors

Abstract

Objective

To assess the efficacy, outcome and complications of post-chemotherapy laparoscopic retroperitoneal lymph node dissection (L-RPLND) for stage IIA/B testicular germ cell tumor (GCT) patients in comparison with open RPLND (O-RPLND).

Methods

L-RPLND was performed in 14 patients with stage IIA/B non-seminoma GCTs among 154 non-seminoma patients who received RPLND after completion of chemotherapy with tumor marker normalization at our institution between 1998 and 2013. Their outcomes were compared with those of 14 patients with stage IIA/B non-seminoma GCTs treated with O-RPLND during the same period. Clinical parameters were compared between L-RPLND and O-RPLND.

Results

There were no significant differences in the background characteristics of the two groups except for follow-up duration (36 months for L-RPLND, 70 months for O-RPLND; p = 0.02). Blood loss during surgery was significantly less for the L-RPLND group than for the O-RPLND group (155 mL for L-RPLND, 700 mL for O-RPLND; p < 0.001). Parameters related to post-operative recovery were significantly better for the L-RPLND group than for the O-RPLND group. Histopathological examination showed no difference between the two groups. Neither group had disease recurrence.

Conclusion

Post-chemotherapy L-RPLND with a bilateral template and nerve-sparing method was safe, effective, and showed a high preservation rate of antegrade ejaculation with no deterioration of outcomes compared to O-RPLND.

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Effects of sorafenib combined with low-dose interferon therapy for advanced hepatocellular carcinoma: a pilot study

Abstract

Background

Sorafenib is a standard of care for advanced hepatocellular carcinoma (HCC). An in vitro study showed the synergistic effects of sorafenib and interferon for HCC. To clarify the efficacy, combination therapy with sorafenib and interferon was performed for patients with advanced HCC.

Methods

Pegylated interferon α-2a was administered every 2 weeks for the initial 4 weeks. Subsequently, it was combined with sorafenib. We evaluated the anti-tumor effect and biomarkers during treatment period.

Results

The subjects were 13 patients with advanced HCC complicated by hepatitis C virus (HCV)-related liver cirrhosis. A partial response, stable disease and progressive disease were noted in 4, 6, and 3 patients, respectively. The response rate, the disease control rate, the mean time to progression and the median survival time (MST) were 30.8 % (4/13), 76.9 % (10/13), 12.2 months, and 17.5 months, respectively. In 8 Child-Pugh class A and 5 Child-Pugh class B patients, the MST was 22.0 and 11.0 months, respectively (p = 0.001). In plasma vascular endothelial growth factor (VEGF), serum alpha-fetoprotein (AFP), AFP-L3, a protein induced by vitamin K absence or antagonist-II (PIVKA II), and hepatocyte growth factor (HGF), there was no pretreatment factor and no biomarker during the combination therapy to predict therapeutic effect in the present study.

Conclusions

The results of this study suggest that combination therapy with sorafenib and interferon could be effective and safe in advanced HCC patients with HCV-related liver cirrhosis.

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Dietary and Lifestyle Risk Factors for Colorectal Cancer in Apparently Healthy Adults in Jordanian Hospitals

Abstract

Colorectal cancer (CRC) is a frequently occurring cancer in Jordan. CRC risk is expected to continue rising due to dietary patterns, sedentary lifestyle, and other practices. The aim of this study was to describe the prevalence of dietary and lifestyle risk factors for CRC among patients attending outpatient gastroenterology clinics in Jordan. A descriptive, cross-sectional design was used to collect data from 713 asymptomatic participants. Data was collected using a self-report questionnaire measuring sociodemographic characteristics, dietary habits, physical activity, and lifestyle risk factors of CRC. The mean age of participants was 57.0 ± 8.56 years. The majority of participants were male (71.8 %) and with less than secondary school formal education (60.7 %). The commonest risk factors for CRC among the participants were overweight or obesity (76.1 %), lack of exercise (71.6 %), limited consumption of vegetables (70.8 %), smoking (60.6 %), over consumption of red meat (56.3 %), and diabetes mellitus (24.1 %). Dietary and lifestyle risk factors for CRC are prevalent in Jordan and likely to fuel an upsurge CRC if population-wide educational interventions are not implemented. There is need for greater attention and emphasis on strategies to educate the general population about healthy dietary and lifestyle habits as means of preventing CRC in Jordan.

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Book Review: Handbook of Oncology Social Work: Psychosocial Care for People with Cancer

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Pharmacokinetic evaluation of nanoparticle albumin-bound paclitaxel delivered via hepatic arterial infusion in patients with predominantly hepatic metastases

Abstract

Purpose

Cancer patients with predominantly hepatic metastases have poor outcomes and limited options. Hepatic arterial infusion (HAI) of a therapeutic agent may be an appropriate option for producing increased drug concentrations at the tumor sites while reducing systemic adverse effects in normal tissues.

Methods

Patients with predominantly hepatic metastases (n = 48) were placed in 6 groups according to nanoparticle albumin-bound paclitaxel (nab-paclitaxel) dose level using a 3 + 3 design plus dose expansion for responsive tumor types. We evaluated the toxicity, antitumor activity, and pharmacokinetics of nab-paclitaxel delivered via HAI.

Results

Thirty-eight and ten patients underwent HAI over 1 and 4 h, respectively, at doses of up to 300 mg/m². The treatment was safe and exhibited antitumor activity. Pharmacokinetic analyses revealed that HAI of nab-paclitaxel over 4 h resulted in markedly lower peak drug concentrations (C _max) and longer times to peak concentration (T _max) than that over 1 h. The self-control pharmacokinetic studies showed that HAI of nab-paclitaxel led to much lower C _max and areas under the curve (AUC), compared with intravenous infusion.

Conclusions

HAI of nab-paclitaxel at up to 300 mg/m² over 4 h was well tolerated. Pharmacokinetic evaluation of C _max, T _max, and AUC implied that 4-h HAI enhanced hepatic extraction of nab-paclitaxel. Further preclinical and clinical studies are required to develop reliable methods of evaluation of hepatic extraction (clinicaltrials.gov registration number NCT00732836, first registered on August 8, 2008, and last updated on October 27, 2014).

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p53 overexpression increases chemosensitivity in multidrug-resistant osteosarcoma cell lines

Abstract

Purpose

Multidrug resistance (MDR) is a major obstacle to the successful treatment of osteosarcoma with chemotherapy. Effectiveness of cancer therapy correlates with the ability to induce a p53-dependent apoptotic response. p53 is a tumor suppressor gene that is mutated in 22 % of osteosarcomas. While impaired p53 has been implicated in the oncogenesis of osteosarcoma, it is unclear whether overexpression of wild-type p53 can increase chemosensitivity in MDR osteosarcoma cells.

Methods

We transfected a plasmid encoding the wild-type p53 gene to MDR osteosarcoma cell lines, which have different p53 statuses, U-2OSR2 with wild-type p53 (Wt-p53) and KHOSR2 with mutant p53 (Mt-p53), and determined the effect of p53 overexpression on chemosensitivities.

Results

Both of the U-2OSR2 and KHOSR2 cell lines displayed similar trends in p53-induced drug sensitivities. However, it seems that the impact of p53 overexpression is different based on the differential intrinsic p53 status in these cell lines. In the KHOSR2 cell line (Mt-p53), overexpression of p53 up-regulates the expression of pro-apoptotic protein p21 and Bax, while in the U-2OSR2 cell line (Wt-p53), overexpression of p53 down-regulates IGF-1r expression significantly.

Conclusions

These results demonstrated that transfection of wild-type p53 increases chemosensitivity either through inhibiting IGF-1r or through increasing the expression of pro-apoptotic proteins p21 and Bax in human MDR osteosarcoma cell lines.

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Human IGF1 pro-forms induce breast cancer cell proliferation via the IGF1 receptor

Abstract

Background

IGF1 is a key regulator of tissue growth and development and has been implicated in the initiation and progression of various cancers, including breast cancer. Through IGF1 mRNA splicing different precursor pro-peptides, i.e., the IGF1Ea, IGF1Eb and IGF1Ec pro-forms, are formed whose biological roles in the pathogenesis of breast cancer have not been established yet. The objective of this study was to assess the biological activity of the IGF1 pro-forms in human breast cancer-derived cells.

Methods

The different IGF1 pro-forms were generated through transient transfection of HEK293 cells with the respective vector constructs. The resulting conditioned media were applied in vitro to MCF7, T47D and ZR751 breast cancer-derived cell cultures. The recombinant human IGF1 pro-forms were also tested for their binding affinity to an anti-IGF1 specific antibody by immunoprecipitation. To determine whether the IGF1 pro-forms induce cell proliferation, mature IGF1 was neutralised in HEK293-derived conditioned media.

Results

We found that the IGF1 pro-forms were the only forms that were produced intra-cellularly, whereas both mature IGF1 and the IGF1 pro-forms were detected extra-cellularly. We also found that E peptides can impair the IGF1 pro-form binding affinity for the anti-IGF1 antibody and, thus, hamper an accurate measurement of the IGF1 pro-forms. Additionally, we found that the IGF1 antibody can completely inhibit IGF1-induced breast cancer cell proliferation and IGF1 receptor (IGF1R) phosphorylation, wheras the same antibody was found to only partially inhibit the biological activity of the pro-forms. Moreover, we found that the IGF1 pro-form activities can completely be inhibited by neutralising the IGF1R. Finally, we compared the bioactivity of the IGF1 pro-forms to that of mature IGF1, and found that the IGF1 pro-forms were less capable of phosphorylating the IGF1R in the breast cancer-derived cells tested.

Conclusions

Our data indicate that IGF1 pro-forms can induce breast cancer cell proliferation via the IGF1R, independent from the mature IGF1 form. These results underline the importance of an accurate assessment of the presence of IGF1 pro-forms within the breast cancer microenvironment.

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Human IGF1 pro-forms induce breast cancer cell proliferation via the IGF1 receptor

Abstract

Background

IGF1 is a key regulator of tissue growth and development and has been implicated in the initiation and progression of various cancers, including breast cancer. Through IGF1 mRNA splicing different precursor pro-peptides, i.e., the IGF1Ea, IGF1Eb and IGF1Ec pro-forms, are formed whose biological roles in the pathogenesis of breast cancer have not been established yet. The objective of this study was to assess the biological activity of the IGF1 pro-forms in human breast cancer-derived cells.

Methods

The different IGF1 pro-forms were generated through transient transfection of HEK293 cells with the respective vector constructs. The resulting conditioned media were applied in vitro to MCF7, T47D and ZR751 breast cancer-derived cell cultures. The recombinant human IGF1 pro-forms were also tested for their binding affinity to an anti-IGF1 specific antibody by immunoprecipitation. To determine whether the IGF1 pro-forms induce cell proliferation, mature IGF1 was neutralised in HEK293-derived conditioned media.

Results

We found that the IGF1 pro-forms were the only forms that were produced intra-cellularly, whereas both mature IGF1 and the IGF1 pro-forms were detected extra-cellularly. We also found that E peptides can impair the IGF1 pro-form binding affinity for the anti-IGF1 antibody and, thus, hamper an accurate measurement of the IGF1 pro-forms. Additionally, we found that the IGF1 antibody can completely inhibit IGF1-induced breast cancer cell proliferation and IGF1 receptor (IGF1R) phosphorylation, wheras the same antibody was found to only partially inhibit the biological activity of the pro-forms. Moreover, we found that the IGF1 pro-form activities can completely be inhibited by neutralising the IGF1R. Finally, we compared the bioactivity of the IGF1 pro-forms to that of mature IGF1, and found that the IGF1 pro-forms were less capable of phosphorylating the IGF1R in the breast cancer-derived cells tested.

Conclusions

Our data indicate that IGF1 pro-forms can induce breast cancer cell proliferation via the IGF1R, independent from the mature IGF1 form. These results underline the importance of an accurate assessment of the presence of IGF1 pro-forms within the breast cancer microenvironment.

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18 F-FDG PET scanning of abdominal aortic aneurysms and correlation with molecular characteristics: a systematic review

Abstract

Purpose

The purpose of this study is to give an overview of studies investigating the role of fludeoxyglucose F18 (¹⁸F-FDG) positron emission tomography (PET) scanning in patients with aortic aneurysms with a focus on molecular characteristics of the aneurysm wall.

Methods

MEDLINE, EMBASE, and the Cochrane database were searched for relevant articles. After inclusion and exclusion, we selected 18 relevant articles reporting on ¹⁸F-FDG PET scanning of aortic aneurysms.

Results

The sample size of studies is limited, and there are no standardized imaging protocols and quantification methods. ¹⁸F-FDG PET scanning was shown to display molecular characteristics of the aortic wall. Different studies showed contradictory findings of aortic ¹⁸F-FDG uptake in aneurysm patients compared to controls.

Conclusions

Non-invasively determining molecular characteristics of aortic wall weakening might lead to better rupture and growth prediction. This might influence the decision of the surgeon between conservative and surgical treatment of aneurysms. To date, there is conflicted evidence regarding the use of ¹⁸F-FDG PET scanning to predict aneurysm rupture and growth. The role of ¹⁸F-FDG PET scanning in rupture risk prediction needs to be further investigated, and standardized imaging protocols and quantification methods need to be implemented.

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Survival and tumor recurrence in patients with brain metastases treated by surgical resection with or without adjuvant whole brain radiation therapy

Abstract

Objective

Tumors that metastasize to the brain are associated with poor survival and tend to recur at the original site after treatment. Adjuvant whole brain radiation therapy (WBRT) is recommended after surgical resection in order to decrease recurrence rates. However, prognostic factors that determine which patients may benefit from WBRT remain limited. We set out to characterize our experience with WBRT in these patients and identify prognostic factors.

Methods

Ninety-eight patients who underwent surgical resection for metastatic brain tumors were identified by retrospective chart review. Demographic data was collected, patient survival and tumor recurrence rate after treatment were assessed using the Kaplan-Meier analysis and the Cox-proportional hazard regression while controlling for confounders.

Results

Median overall patient survival was 175 days. There was tumor recurrence in 17 cases and median time to recurrence was 148.5 days. Adjuvant WBRT was significantly associated with increased patient survival (p = 0.04) and decreased tumor recurrence (p = 0.01). Increased patient survival was also associated with the presence of salvage radiation, the Karnofsky performance score (KPS) of equal to or greater than 70, and supratentorial metastases. Decreased survival was associated with lesions of the temporal lobe and presence of extra-cranial metastases. Increased tumor recurrence rate was associated with the presence of salvage radiation, the presence of prophylactic radiation, and lesions of the occipital lobe.

Conclusion

We found that adjuvant whole brain radiation was associated with decreased tumor recurrence and longer survival in our patient cohort. Location of the metastasis influenced recurrence and survival. Also, patients receiving prophylactic radiation may harbor tumors more prone to recur.

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Biweekly gemcitabine and low-dose cisplatin in the treatment of locally advanced or metastatic pancreatic cancer patients: a single institute experience

Abstract

Gemcitabine in combination with low-dose cisplatin has shown promising activity in pancreatic cancer with manageable toxicities. The purpose of this study is to assess the activity of a combination of gemcitabine and low-dose cisplatin in the first-line treatment of metastatic and locally advanced pancreatic cancer patients. We conducted a retrospective analysis of all patients diagnosed with metastatic and locally advanced pancreatic cancer who received a combination of gemcitabine and cisplatin in the first-line setting. Patients with baseline cytopenias and elevated liver function tests were included. Patients received cisplatin at 20 mg per square meter followed by gemcitabine at a dose of 1000 mg per square meter at fixed dose rate every 2 weeks. Patients were treated until disease progression or unacceptable toxicities. A total of 58 patients were included in the analysis. The median progression-free survival was 4.4 months [95 % confidence interval (CI) 3.6–6.4], and median overall survival was 6.7 months (95 % CI 4.4–10.9). Thirty-eight patients (66 %) experienced at least one grade 3 or 4 toxicity. The most common grade 3 or 4 toxicity was hematologic toxicity (25 patients, 43 %). Biweekly fixed dose rate gemcitabine combined with low-dose cisplatin shows interesting activity in advanced pancreatic cancer. This regimen is an acceptable alternative for patients ineligible for gemcitabine plus nab-paclitaxel (i.e., those with elevated bilirubin at baseline) or clinical trials. Additionally, this regimen should be considered as a first-line option for those patients with breast cancer susceptibility gene mutations (BRCA1 and/or BRCA2).

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A comparison between fentanyl plus celecoxib therapy and epidural anesthesia for postoperative pain management following laparoscopic gastrectomy

Abstract

Purpose

To clarify the efficacy of postoperative pain management following laparoscopic gastrectomy (LG), we retrospectively compared pain assessments in patients who received fentanyl plus celecoxib with those who received epidural anesthesia.

Methods

From 2011 to 2012, 55 consecutive LG patients at our institution received 48 h of epidural anesthesia for postoperative pain management (group-E). Since September 2013, epidural anesthesia was replaced with 24 h of intravenous fentanyl and 4 days of oral celecoxib. Thirty-three consecutive LG patients who received this analgesic method (group-FC) were included in this analysis. The severity of postoperative pain as assessed by the FACES Pain Rating Scale and the frequency of rescue pain medication were retrospectively compared between the two groups.

Results

No significant difference in the severity of postoperative pain on postoperative day (POD) 0 or 1 was observed between the two groups. In contrast, pain was significantly lower in group-FC than group-E on PODs 2, 3, 4, and 7. The total use of rescue pain medications during the first 7 days following LG did not differ between the two groups.

Conclusion

Pain management using 24 h of intravenous fentanyl and 4 days of oral celecoxib is comparable to epidural anesthesia following LG.

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BALR-6 regulates cell growth and cell survival in B-lymphoblastic leukemia

Abstract

Background

A new class of non-coding RNAs, known as long non-coding RNAs (lncRNAs), has been recently described. These lncRNAs are implicated to play pivotal roles in various molecular processes, including development and oncogenesis. Gene expression profiling of human B-ALL samples showed differential lncRNA expression in samples with particular cytogenetic abnormalities. One of the most promising lncRNAs identified, designated B-ALL associated long RNA-6 (BALR-6), had the highest expression in patient samples carrying the MLL rearrangement, and is the focus of this study.

Results

Here, we performed a series of experiments to define the function of BALR-6, including several novel splice forms that we identified. Functionally, siRNA-mediated knockdown of BALR-6 in human B-ALL cell lines caused reduced cell proliferation and increased cell death. Conversely, overexpression of BALR-6 isoforms in both human and mouse cell lines caused increased proliferation and decreased apoptosis. Overexpression of BALR-6 in murine bone marrow transplantation experiments caused a significant increase in early hematopoietic progenitor populations, suggesting that its dysregulation may cause developmental changes. Notably, the knockdown of BALR-6 resulted in global dysregulation of gene expression. The gene set was enriched for leukemia-associated genes, as well as for the transcriptome regulated by Specificity Protein 1 (SP1). We confirmed changes in the expression of SP1, as well as its known interactor and downstream target CREB1. Luciferase reporter assays demonstrated an enhancement of SP1-mediated transcription in the presence of BALR-6. These data provide a putative mechanism for regulation by BALR-6 in B-ALL.

Conclusions

Our findings support a role for the novel lncRNA BALR-6 in promoting cell survival in B-ALL. Furthermore, this lncRNA influences gene expression in B-ALL in a manner consistent with a function in transcriptional regulation. Specifically, our findings suggest that BALR-6 expression regulates the transcriptome downstream of SP1, and that this may underlie the function of BALR-6 in B-ALL.

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Akt activation correlates with the tumor aggressiveness in Tunisian patients with bladder cancer

Abstract

Various studies in western countries found Akt amplification to be a frequent event in human cancers, including bladder, but the correlation with clinicopathological features is controversial. Such studies have not been reported in African populations, including Tunisians. The purpose of this study was to assess expression of the phosphorylated/activated forms of Akt in tumors from Tunisian patients with bladder cancer and to correlate its expression with pathological and clinical parameters of the disease. The study included 72 patients of whom 34 were diagnosed as low- to medium-grade and 35 as high-grade; 30 were muscle stage and 39 non-muscle stage. Primary tumors from these patients, normal adjacent tissues, or bladder cancer cell-lines were analyzed for Ser473 phosphorylated Akt expression by Western blot. Seventy-two percent of primary tumors from patients with bladder cancer had increased levels of p-Akt. The p-Akt levels in patients with high-grade bladder cancer were significantly elevated compared to patients with low- or medium-grade bladder cancer. In invasive carcinoma, the p-Akt level was significantly higher than in superficial non-invasive bladder tumors. Concerning the influence of tobacco on Akt activation, no significant differences of p-Akt expression were found between non-smoker and smoker patients. Altogether, our results suggest that Akt activation can provide useful prognostic information and that tobacco represents a serious risk factor for recurrence in a cohort of Tunisian patients.

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Small molecule inhibitor of c-Met (PHA665752) suppresses the growth of ovarian cancer cells and reverses cisplatin resistance

Abstract

c-Met as a tyrosine-kinase receptor plays a major role in tumorigenesis, invasion, and metastatic spread of human tumors, including ovarian cancer. Expressing high levels of c-Met proteins is often associated with resistance to chemotherapy and an adverse prognosis. In this study, we have determined the effect of PHA665752, a small molecule inhibitor of c-Met proteins, with and without cisplatin and the role of c-Met in several ovarian cancer cell lines having high c-Met expression. The methyl thiazolyl tetrazolium (MTT) assay was used to detect cell proliferation, and apoptosis was evaluated by flow cytometry. Western blotting was carried out to determine protein expression levels. Gene silencing was used to detect the influence of c-Met gene silence on the resistance to cisplatin. Compared to more sensitive ovarian cancer cell lines SKOV3 and 3AO, we found that the expression of c-Met was significantly increased in SKOV3^DDP, OVCAR3, and OV-90 ovarian cancer cell lines, which were resistant to cisplatin. Our data indicated that cisplatin sustained activated phosphor-Met in SKOV3^DDP, OVCAR3, and OV-90 cell lines. We also observed a significant transient activation of c-Met phosphorylation in SKOV3 and 3AO cells. Treatment with PHA665752 inhibited c-Met expression inhibited cell growth, induced apoptosis, and enhanced cisplatin-induced proliferation inhibition and apoptosis in c-Met over-expressed cell lines. In addition, blocking c-Met expression with small interfering RNA (siRNA) overcame the resistance of cancer cells to cisplatin. Thus, blocking c-Met expression presents a promising therapeutic approach for ovarian cancer.

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Expression and prognosis value of SHP2 in patients with pancreatic ductal adenocarcinoma

Abstract

SHP2 is an src homology (SH) 2 domain-containing protein tyrosine phosphatase (PTP). SHP2 implicitly contributes to tumorigenesis, but the role of SHP2 in pancreatic ductal adenocarcinoma is still unknown. The purpose of this study was to evaluate the prognostic significance and associated expression of SHP2 in pancreatic ductal adenocarcinoma (PDAC) patients. We used immunohistochemistry to assess the protein expression levels of SHP2 in 79 PDAC specimens. The correlations between SHP2 expression and various clinicopathological features were evaluated by Pearson's chi-square (χ ²) test, Fisher's exact test, and Spearman's rank. Univariate and multivariate Cox regression analyses were used to identify correlations between the immunohistochemical data for SHP2 expression and the clinicopathologic characteristics in PDAC. Kaplan-Meier survival analysis was used to demonstrate the relation between overall survival and the expression of SHP2. Immunohistochemistry revealed significantly higher rates of high SHP2 expression in PDAC tissues (55.7 %) versus adjacent non-cancer tissues (10.1 %) (P < 0.05). Expression of SHP2 was only significantly correlated with histological differentiation (P = 0.033) and vital status (P = 0.025). Patients with high SHP2 expression had shorter overall survival times compared to those with low SHP2 expression (P = 0.000). Multivariate Cox regression analysis revealed that SHP2 overexpression was an independent prognostic factor in PDAC (P = 0.012). Our study demonstrated for the first time that higher expression of SHP2 might be involved in the progression of pancreatic ductal adenocarcinoma, suggesting that SHP2 may be a potential prognostic marker and target for therapy.

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Hypoxia-induced secretion of IL-10 from adipose-derived mesenchymal stem cell promotes growth and cancer stem cell properties of Burkitt lymphoma

Abstract

In this study, we explored how the altered paracrine of adipose mesenchymal stem cells (ADSCs) contributed to the growth and cancer stem cell (CSC) properties of the Burkitt lymphoma cells. Condition mediums from normoxia or hypoxia cultured ADSC (CM-ADSC-N or CM-ADSC-H) were collected, and their effects on growth, colony formation, and apoptosis of Burkitt's lymphoma cells were investigated. Differentially expressed cytokines and inflammatory factors were compared between CM-ADSC-N and CM-ADSC-H. The involvement of differentially expressed IL-10 in growth and CSC properties of Burkitt lymphoma was investigated using both in vitro and in vivo models. Findings of this study showed that hypoxia increased IL-10 secretion from ADSCs, through which the growth and CSC properties of BL2 cells were enhanced. Intratumoral injection of CM-ADSC-H or IL-10 enhanced in vivo Burkitt lymphoma growth in nude mice model at least partly via the JAK2/STAT3 signaling pathway.

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Integrative computational in-depth analysis of dysregulated miRNA-mRNA interactions in drug-resistant pediatric acute lymphoblastic leukemia cells: an attempt to obtain new potential gene-miRNA pathways involved in response to treatment

Abstract

Acute lymphoblastic leukemia (ALL) is the major neoplasia type among children. Despite the tremendous success of current treatment strategies, drug resistance still remains a major cause of chemotherapy failure and relapse in pediatric patients. Overwhelming evidence illustrates that microRNAs (miRNAs) act as post-transcriptional regulators of drug-resistance-related genes. The current study was aimed at how dysregulated miRNA-mRNA-signaling pathway interaction networks mediate resistance to four commonly used chemotherapy agents in pediatric ALL, including asparaginase, daunorubicin, prednisolone, and vincristine. Using public expression microarray datasets, a holistic in silico approach was utilized to investigate candidate drug resistance miRNA-mRNA-signaling pathway interaction networks in pediatric ALL. Our systems biology approach nominated significant drug resistance and cross-resistance miRNAs, mRNAs, and cell signaling pathways based on anti-correlative relationship between miRNA and mRNA expression pattern. To sum up, our systemic analysis disclosed either a new potential role of miRNAs, or a possible mechanism of cellular drug resistance, in chemotherapy resistance of pediatric ALL. The current study may shed light on predicting drug response and overcoming drug resistance in childhood ALL for subsequent generations of chemotherapies.

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Note of the methodological flaws in the paper entitled “Polymorphisms in IL-4/IL-13 pathway genes and glioma risk: an updated meta-analysis”

Abstract

With great interest, we read the paper "Polymorphisms in IL-4/IL-13 pathway genes and glioma risk: an updated meta-analysis" (by Chen PQ et al.) [1], which has reached important conclusions about the relationship between polymorphisms in interleukin (IL)-4/IL-13 pathway genes and glioma risk. Through quantitative analysis, the meta-analysis found no association between IL-4/IL-13 pathway genetic polymorphisms and glioma risk (Chen et al. in Tumor Biol 36:121–127, 2015). The meta-analysis is the most comprehensive study of polymorphisms in the IL-4/IL-13 pathway and glioma risk. Nevertheless, some deficiencies still exist in this meta-analysis that we would like to raise.

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Inhibition of Vav3 gene can promote apoptosis of human gastric cancer cell line MGC803 by regulating ERK pathway

Abstract

Previous studies proved that Vav3 gene was overexpressed in cancers. However, the molecular mechanism of Vav3 in apoptosis still keeps unclear; therefore, the relationship between Vav3 gene and apoptosis of gastric cancer (GC) was explored in the present study. Vav3-siRNA was transfected into MGC803 cells, and then cell activity and apoptosis rate were tested with MTT and FCM; apoptosis-related genes and proteins in MAPK signaling pathway were also tested. Results showed that Vav3 was overexpressed in GC than in adjacent normal tissues (all P < 0.05), and expression of Vav3 was related to degree of histological differentiation, cancer invasion depth, and lymphatic metastasis (Χ ²  = 7.185, P = 0.007; Χ ²  = 18.654, P < 0.001; Χ ²  = 5.058, P = 0.025). Vav3 silencing inhibited activity of MGC803 cells, and apoptosis rate of cells was affected. Vav3-siRNA transfection led to changes of apoptosis-related genes such as Survivin, xIAP, Bcl-2, caspase-3, and Bax (all P < 0.01). After transfection, ratio of phosphorylation of ERK significantly reduced. We concluded that Vav3 inhibition can suppress cell activity and promote apoptosis by regulating the apoptosis-related genes through the ERK pathway.

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PTEN polymorphisms contribute to clinical outcomes of advanced lung adenocarcinoma patients treated with platinum-based chemotherapy

Abstract

This study aimed to elucidate the impact of PTEN single nucleotide polymorphism (SNP) on clinical outcomes for advanced lung adenocarcinoma (LAC) patients treated with platinum-based chemotherapy. Three functional SNPs (rs11202607 G>A, rs701848 A>G, and rs11202592 G>C) of PTEN gene were genotyped by using DNA from blood samples of 618 advanced LAC patients, and their relationships with clinical outcomes were analyzed. The carriers of homozygous mutant of rs701848 and rs11202592 polymorphisms revealed significantly worse overall survival (OS) than those with heterozygote or wild-type homozygote (18.83 vs. 21.47 vs. 24.37 months, P = 0.034 and 13.40 vs. 19.03 vs. 21.90 months, P = 0.025, respectively). Subgroup analysis revealed that this association was particularly significant in tumor-lymph-node metastasis (TNM) stage III patients. The objective response rates (ORR) and disease control rates (DCR) of patients with genotype AA, AG, and GG in PTEN rs701848 polymorphism were statistically different (24.1 vs 16.6 vs 12.2 %, P = 0.017 and 82.7 vs 76.0 vs 70.2 %, P = 0.029, respectively). Haplotype analysis revealed a protective effect of the haplotype G-A-A (in the order of rs11202592, rs701848, and rs11202607) on chemotherapy efficacy and survival. Taken together, PTEN polymorphisms may contribute to survival and chemotherapy efficacy of advanced LAC patients treated with platinum-based agents.

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Predictive factors for recurrence of differentiated thyroid cancer in patients under 21 years of age and a meta-analysis of the current literature

Abstract

The influence of predictors for recurrence in relation to recurrence-free survival was analyzed retrospectively in differentiated thyroid cancer (DTC) patients under 21 years of age who underwent primary surgical treatment and who had a pathological diagnosis of DTC between 1983 and 2012 at Fudan University Cancer Hospital. Recurrences were retrospectively analyzed using a Cox regression model for the hazard ratio (HR) according to the clinicopathological features. A meta-analysis was performed with respect to the potential predictors for recurrence from current related studies. In the present study, there were 146 young patients aged from 7 to 20 years, with a female/male ratio of 2.65/1. Female gender was the only factor significantly associated with recurrence according to univariate (HR = 2.812, P = 0.037) and multivariate (HR = 4.107, P = 0.024) Cox regression analyses. Meta-analyses revealed that multifocality (HR = 1.91, P < 0.05) and presentation at diagnosis (HR = 1.39, P < 0.05) were highly associated with recurrence in young DTC patients. However, female gender and other factors, such as age (≤10 vs. 11–20 years), PTC (PTC vs. FTC), extrathyroidal extension, lymph node metastasis, total thyroidectomy (total vs. less than total), radioiodine therapy, and radiation history, were not associated with recurrence in young DTC patients. In conclusion, multifocality and presentation at diagnosis are strong predictive factors of recurrence in relation to recurrence-free survival. We recommend studies with larger sample sizes and longer follow-up to verify the influence of predictors for disease recurrence in young patients.

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Adding Mendelian randomization to a meta-analysis—a burgeoning opportunity

Abstract

Current literature is teeming with tens of thousands of meta-analyses, but only a small fraction made seminal contributions to enriching our understanding of the mechanisms of carcinogenesis, possibly due to chance, bias, confounding, or reverse causality. The incorporation of Mendelian randomization (MR) with a meta-analysis has revolutionized traditional practice and is emerging as a viable technique to strengthen causal unconfounded inferences from observational data. We therefore highlight the importance of integrated MR meta-analysis in cancer epidemiology and provide an overview of three existing instrumental selection strategies in medical literature.

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Pencil Beam Scanning Proton Therapy for Pediatric Parameningeal Rhabdomyosarcomas: Clinical Outcome of Patients Treated at the Paul Scherrer Institute

Background

Parameningeal rhabdomyosarcomas (PM-RMSs) represent approximately 25% of all rhabdomyosarcoma (RMS) cases. These tumors are associated with early recurrence and poor prognosis. This study assessed the clinical outcome and late toxicity of pencil beam scanning (PBS) proton therapy (PT) in the treatment of children with PM-RMS.

Procedures

Thirty-nine children with PM-RMS received neoadjuvant chemotherapy followed by PBS-PT at the Paul Scherrer Institute, with concomitant chemotherapy. The median age was 5.8 years (range, 1.2–16.1). Due to young age, 25 patients (64%) required general anesthesia during PT. The median time from the start of chemotherapy to PT was 13 weeks (range, 3–23 weeks). Median prescription dose was 54 Gy (relative biologic effectiveness, RBE).

Results

With a mean follow-up of 41 months (range, 9–106 months), 10 patients failed. The actuarial 5-year progression-free survival (PFS) was 72% (95% CI, 67–94%) and the 5-year overall survival was 73% (95% CI, 69–96%). On univariate analysis, a delay in the initiation of PT (>13 weeks) was a significant detrimental factor for PFS. Three (8%) patients presented with grade 3 radiation-induced toxicity. The estimated actuarial 5-year toxicity ≥grade 3 free survival was 95% (95% CI, 94–96%).

Conclusions

Our data contribute to the growing body of evidence demonstrating the safety and effectiveness of PT for pediatric patients with PM-RMS. These preliminary results are encouraging and in line with other combined proton–photon and photons series; observed toxicity was acceptable.

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Cancer Can Lead to Financial Hardship, Study Confirms

In a survey of cancer survivors, many reported having experienced financial difficulties—such as going into debt, filing for bankruptcy, and consistent worry about financial issues—related to their disease and its treatment.

The findings from the study were published November 7 in the Journal of Clinical Oncology.

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Phase 2 trial of neoadjuvant bevacizumab plus pemetrexed and carboplatin in patients with unresectable stage III lung adenocarcinoma (GASTO 1001)

BACKGROUND

The objective of this phase 2 trial was to assess the efficacy and safety of induction bevacizumab plus chemotherapy followed by surgery in patients with unresectable stage III lung adenocarcinoma.

METHODS

The authors investigated induction bevacizumab (7.5 mg/kg) plus pemetrexed (500 mg/m² and carboplatin (area under the receiver operating characteristic curve = 5) followed by surgery for patients with unresectable stage III lung adenocarcinoma ages 18 to 65 years. The patients received neoadjuvant therapy every 3 weeks for 4 cycles. Surgery was scheduled 3 to 4 weeks after the last neoadjuvant therapy; then, the medical team assessed each patient's resectability status. The primary endpoint was the resectability rate.

RESULTS

From April 2012 to April 2014, 42 patients were enrolled and received bevacizumab plus pemetrexed and carboplatin. Grade 3 or 4 induction-related AEs included fatigue in 5 patients, neutropenia in 4 patients, hypertension in 1 patient, anemia in 1 patient, and thrombocytopenia in 1 patient. One patient achieved a complete response, 22 achieved a partial response, 17 had stable disease, and 2 had progressive disease. After neoadjuvant therapy, 31 patients (73.8%) underwent surgery, including 11 who underwent pneumonectomy. Complete (R0) resection was achieved in 22 patients (52.4%). Reoperation was required in 1 patient because of a bleeding intercostal artery. No perioperative thromboembolic events or wound-healing problems were observed. The median event-free survival was 15.4 months, and the 1-year event-free survival rate was 56.1%.

CONCLUSIONS

Treatment with neoadjuvant bevacizumab in combination with pemetrexed and carboplatin followed by surgery appears to be feasible and safe in patients with unresectable stage III lung adenocarcinoma. Cancer 2015. © 2015 American Cancer Society.

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Neoadjuvant combination chemotherapy for unresectable stage III non–small cell lung cancer

Neoadjuvant chemotherapy and chemoradiation therapy can be considered for patients with potentially resectable stage III Non–Small cell lung cancer. The use of antiangiogenic agents, the best systemic therapy, and the best radiation field and dose require further study.

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Acute respiratory infections in children and adolescents with acute lymphoblastic leukemia

BACKGROUND

Knowledge regarding the incidence, clinical course, and impact of respiratory viral infections in children with acute lymphoblastic leukemia (ALL) is limited.

METHODS

A retrospective cohort of patients with newly diagnosed ALL who were treated on the Total Therapy XVI protocol at St Jude Children's Research Hospital between 2007 and 2011 was evaluated.

RESULTS

Of 223 children, 95 (43%) developed 133 episodes of viral acute respiratory illness (ARI) (incidence, 1.1 per 1000 patient-days). ARI without viral etiology was identified in 65 patients (29%) and no ARI was detected in 63 patients (28%). There were no significant associations noted between race, sex, age, or ALL risk group and the development of ARI. Children receiving induction chemotherapy were found to be at the highest risk of viral ARI (incidence, 2.3 per 1000 patient-days). Influenza virus was the most common virus (38%) followed by respiratory syncytial virus (33%). Of 133 episodes of viral ARI, 61% of patients were hospitalized, 26% experienced a complicated course, 80% had their chemotherapy delayed, and 0.7% of patients died. Twenty-four patients (18%) developed viral lower respiratory tract infections (LRTI), 5 of whom (21%) had complications. Patients with viral LRTI had a significantly lower nadir absolute lymphocyte count; were sicker at the time of presentation; and were more likely to have respiratory syncytial virus, to be hospitalized, and to have their chemotherapy delayed for longer compared with those with viral upper respiratory tract infections.

CONCLUSIONS

Despite the low incidence of viral ARI in children with ALL, the associated morbidity, mortality, and delay in chemotherapy remain clinically significant. Viral LRTI was especially associated with high morbidity requiring intensive care-level support. Cancer 2015. © 2015 American Cancer Society.

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