The role of the neural niche in brain metastasis

Abstract

Cancers with neurologic metastasis are a burdensome affliction. As primary cancer care improves, the incidence of metastatic cancer increases as a result of prolonged survival time. Because of this, advances in the understanding of the mechanisms of metastasis are important for the development of continuing management strategies. Knowing how metastatic tumor cells engage, survive, and proliferate in the central nervous system (CNS) is an important first step in developing treatment paradigms. The neural niche is the soil of the CNS that accommodates tumor cells, is a microenvironment of cell signaling that exists between the tumor cell and the native neural cellular network. Elements of the neural niche have been identified as acquaintances for metastatic tumor growth. As more is known about the neural niche, treatment strategies can be developed to target these networks of metastatic tumor progression.

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Pembrolizumab in the treatment of advanced urothelial cancer

Future Oncology, Ahead of Print.


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Tumour-infiltrating lymphocytes (TILs)-related genomic signature predicts chemotherapy response in breast cancer

Abstract

Purpose

The present study evaluated whether morphological-measured stromal and intra-tumour tumour-infiltrating lymphocytes (TILs) levels were associated with gene expression profiles, and whether TILs-associated genomic signature (GS) could be used to predict clinical outcomes and response to therapies in several breast cancer subtypes.

Methods

We retrospectively evaluated haematoxylin eosin (HE)-TILs levels and gene expression profiling data from 40 patients with primary breast cancer and extracted the 22 overexpressed genes in cases with high TILs scores as the TILs-GS. The TILs-GS were compared with breast cancer subtype and were evaluated predictive values for prognosis and response to therapies.

Results

Higher TILs-GS expressions were observed for triple-negative and human epidermal growth factor receptor 2 (HER2) positive (+) breast cancers, compared to the luminal types (P < 0.001). With the exception of HER2+, the TILs-GS had no prognostic value in subtypes of breast cancers. The Wilcoxon test revealed significantly different TILs-GS levels between the cases with pathological complete response (pCR) and residual disease after anthracycline and taxane-based neoadjuvant chemotherapy, with the exception of the luminal-low proliferation subtype. In the multivariate analysis, pCR was independently associated with smaller tumour size, higher histological grade, ER negativity, HER2 positivity and higher TILs-GS scores (OR 2.02, 95% CI 1.30–3.14, P = 0.025).

Conclusions

TILs-GS was associated with stromal and intra-tumour TILs levels, as evaluated using HE, which predicted prognosis and chemotherapy response in several breast cancer subtypes. Further studies are needed to perform stratification according to TILs-GS levels and the conventional breast cancer subtypes.

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Antagonism of EG-VEGF receptors as targeted therapy for choriocarcinoma progression in vitro and in vivo

Purpose: Choriocarcinoma (CC) is the most malignant gestational trophoblastic disease that often develops from complete hydatidiform moles (CHM). Neither the mechanism of CC development nor its progression is yet characterized. We have recently identified EG-VEGF as a novel key placental growth factor that controls trophoblast proliferation and invasion. EG-VEGF acts via two receptors PROKR1 and PROKR2. Here, we demonstrate that EG-VEGF receptors can be targeted for CC therapy. Experimental design: Three approaches were used, i) a clinical investigation comparing circulating EG-VEGF in Control (n=20) and in distinctive CHM (n=38) and CC (n=9) cohorts, ii) an in vitro study investigating EG-VEGF effects on the CC cell line JEG3, and iii) an in vivo study including the development of a novel CC mouse model, through a direct injection of JEG3-luciferase into the placenta of gravid SCID-mice. Results: Both placental and circulating EG-VEGF levels were increased in CHM and CC (x5) patients. EG-VEGF increased JEG3 proliferation, migration and invasion, in 2D and 3D culture systems. JEG3 injection in the placenta caused CC development with large metastases compared to their injection into the uterine horn. Treatment of the animal model with EG-VEGF receptor's antagonists significantly reduced tumor development and progression and preserved pregnancy. Antibody-array and immunohistological analyses further deciphered the mechanism of the antagonist's actions. Conclusions: Our work describes a novel pre-clinical animal model of CC and brings evidences that EG-VEGF receptors can be targeted for CC therapy. This may provide safe and less toxic therapeutic options compared to the currently used multi-agent chemotherapies.

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Circulating Cell-free DNA for Metastatic Cervical Cancer Detection, Genotyping and Monitoring

Purpose: Circulating cell-free (ccf) human papillomavirus (HPV) DNA may serve as a unique tumor marker for HPV-associated malignancies, including cervical cancer. We developed a method to genotype and quantify circulating HPV DNA in patients with HPV16- or HPV18-positive metastatic cervical cancer for potential disease monitoring and treatment-related decision making. Patients and Methods: In this retrospective study, HPV ccfDNA was measured in serum samples from 19 metastatic cervical cancer patients by duplex digital droplet (dd) PCR. Nine patients had received tumor-infiltrating lymphocyte (TIL) immunotherapy. ccfDNA data were aligned with the tumor HPV genotype, drug treatment, and clinical outcome. Results: In blinded tests, HPV ccfDNA was detected in 19/19 (100%) patients with HPV-positive metastatic cervical cancer but not in any of the 45 healthy blood donors. The HPV genotype harbored in the patients' tumors was correctly identified in 87/87 (100%) sequential patient serum samples from 9 patients who received TIL immunotherapy. In three patients who experienced objective cancer regression after TIL treatment, a transient HPV ccfDNA peak was detected 2-3 days after TIL infusion. Furthermore, persistent clearance of HPV ccfDNA was only observed in two patients who experienced complete response (CR) after TIL immunotherapy. Conclusions: HPV ccfDNA represents a promising tumor marker for non-invasive HPV genotyping and may be used in selecting patients for HPV type-specific T cell based immunotherapies. It may also have value in detecting anti-tumor activity of therapeutic agents and in the long-term follow-up of cervical cancer patients in remission.

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TMEM16A/ANO1 inhibits apoptosis via down-regulation of Bim expression

Purpose: TMEM16A is a calcium-activated chloride channel that is amplified in a variety of cancers, including 30% of head and neck squamous cell carcinomas (HNSCC), raising the possibility of an anti-apoptotic role in malignant cells. The present study investigated this using a multi-modal, translational investigation. Experimental Design: Combination of 1) in vitro HNSCC cell culture experiments assessing cell viability, apoptotic activation, and protein expression 2) in vivo studies assessing similar outcomes, and 3) molecular and staining analysis of human HNSCC samples. Results: TMEM16A expression was found to correlate with greater tumor size, increased Erk 1/2 activity, less Bim expression, and less apoptotic activity overall in human HNSCC. These findings were corroborated in subsequent in vitro and in vivo studies and expanded to include a cisplatin-resistant phenotype with TMEM16A overexpression. A cohort of 41 patients with laryngeal cancer demonstrated that cases that recurred after chemoradiation failure were associated with a greater TMEM16A overexpression rate than HNSCC that did not recur. Conclusions: Ultimately, this study implicates TMEM16A as a contributor to tumor progression by limiting apoptosis and as a potential biomarker of more aggressive disease.

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Facts and Hopes in Immunotherapy of Lymphoma and Myeloma

Immune checkpoint blockade has driven a revolution in modern oncology, and robust drug development of immune checkpoint inhibitors is underway in both solid tumors and hematologic malignancies. High response rates to programmed cell death 1 (PD-1) blockade using nivolumab or pembrolizumab in classical Hodgkin lymphoma (cHL) and several variants of non-Hodgkin lymphoma (NHL) revealed an intrinsic biologic sensitivity to this approach, and work is ongoing exploring combinations with immune checkpoint inhibitors in both cHL and NHL. There are also preliminary data suggesting antitumor efficacy of PD-1 inhibitors used in combination with immunomodulatory drugs in multiple myeloma (MM), and effects of novel monoclonal antibody therapies on the tumor microenvironment may lead to synergy with checkpoint blockade. Although immune checkpoint inhibitors are generally well-tolerated, clinicians must use caution and remain vigilant when treating patients with these agents in order to identify immune related toxicities and prevent treatment-related morbidity and mortality. Autologous stem cell transplant is a useful tool for treatment of hematologic malignancies and has potential as a platform for use of immune checkpoint inhibitors. An important safety signal has emerged surrounding the risk of graft-versus-host-disease (GVHD) associated with use of PD-1 inhibitors before and after allogeneic stem cell transplant. We aim to discuss the facts known to date in the use of immune checkpoint inhibitors for patients with lymphoid malignancies, and discuss our hopes for expanding the benefits of immunotherapy to patients in the future.

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Matrix screen identifies synergistic combination of PARP inhibitors and nicotinamide phosphoribosyltransferase (NAMPT) inhibitors in Ewing sarcoma

Purpose: While many cancers are showing remarkable responses to targeted therapies, pediatric sarcomas, including Ewing sarcoma, remain recalcitrant. To broaden the therapeutic landscape, we explored the in vitro response of Ewing sarcoma cell lines against a large collection of investigational and approved drugs to identify candidate combinations. Experimental Design: Drugs displaying activity as single agents were evaluated in combinatorial (matrix) format to identify highly active, synergistic drug combinations, and combinations were subsequently validated in multiple cell lines using various agents from each class. Comprehensive metabolomic and proteomic profiling was performed to better understand the mechanism underlying the synergy. Xenograft experiments were performed to determine efficacy and in vivo mechanism. Results: Several promising candidates emerged, including the combination of small molecule poly ADP-ribose polymerase (PARP) and nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, a rational combination as NAMPT inhibitors block the rate-limiting enzyme in the production of NAD+, a necessary substrate of PARP. Mechanistic drivers of the synergistic cell killing phenotype of these combined drugs included depletion of NMN and NAD+, diminished PAR activity, increased DNA damage, and apoptosis. Combination PARP and NAMPT inhibitors in vivo resulted in tumor regression, delayed disease progression and increased survival. Conclusions: These studies highlight the potential of these drugs as a possible therapeutic option in Ewing sarcoma.

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Targeting Prostate Cancer Subtype 1 by Forkhead box M1 Pathway Inhibition

Purpose: Prostate cancer was recently classified to three clinically relevant subtypes (PCS) demarcated by unique pathway activation and clinical aggressiveness. In this preclinical study, we investigated molecular targets and therapeutics for PCS1, the most aggressive and lethal subtype with no treatment options available in the clinic. Experimental Design: We utilized the PCS1 gene set and our model of enzalutamide (ENZR) castration-resistant prostate cancer (CRPC) to identify targetable pathways and inhibitors for PCS1. The findings were evaluated in vitro and ENZR CRPC xenograft model in vivo. Results: The results revealed that ENZR CRPC cells are enriched with PCS1 signature and that Forkhead box M1 (FOXM1) pathway is the central driver of this subtype. Notably, we identified Monensin as a novel FOXM1 binding agent that selectively targets FOXM1 to reverse the PCS1 signature and its associated stem-like features and reduces the growth of ENZR CRPC cells and xenograft tumors. Conclusions: Our preclinical data indicate FOXM1 pathway as a master regulator of PCS1 tumours, namely in ENZR CRPC, and targeting FOXM1 reduces cell growth and stemness in ENZR CRPC in vitro and in vivo. These preclinical results may guide clinical evaluation of targeting FOXM1 to eradicate highly aggressive and lethal PCS1 prostate cancer tumours.

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TOP2A and EZH2 provide early detection of an aggressive prostate cancer subgroup

Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer (PCa). Aggressive PCa, defined by the progression from localized disease to metastasis, is responsible for the majority of PCa-associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of PCa patients, however they have yet to provide targeted therapy approaches that could inhibit a patient's progression to metastatic disease. Experimental Design: We have interrogated a total of seven primary PCa cohorts (N = 1,900), two metastatic castration resistant PCa datasets (N = 293) and one prospective cohort (N = 1,385) to assess the impact of TOP2A and EZH2 expression on PCa cellular program and patient outcomes. We also performed immunohistochemical staining for TOP2A and EZH2 in a cohort of primary PCa patients (N = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel PCa-derived murine cell lines. Results: We demonstrate by genome-wide analysis of independent primary and metastatic PCa datasets that concurrent TOP2A and EZH2 mRNA and protein up-regulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in PCa cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy. Conclusions: Overall, our data supports further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neo-adjuvant targeted therapy approaches.

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Genomic characterisation of vulvar (pre)cancers identifies distinct molecular subtypes with prognostic significance

Background Vulvar cancer (VC) can be sub-classified by human papilloma virus (HPV) status. HPV negative VCs frequently harbour TP53 mutations, however in-depth analysis of other potential molecular genetic alterations is lacking. We comprehensively assessed somatic mutations in a large series of vulvar (pre)cancers. Methods We performed targeted next generation sequencing (17 genes), p53 immunohistochemistry and HPV-testing on 36 VC and 82 precursors (sequencing cohort). Subsequently, the prognostic significance of the three subtypes identified in the sequencing cohort was assessed in a series of 236 VC-patients (follow-up cohort). Results Frequent recurrent mutations were identified in HPV negative vulvar (pre)cancers in TP53 (42% and 68%), NOTCH1 (28% and 41%) and HRAS (20% and 31%). Mutation frequency in HPV positive vulvar (pre)cancers was significantly lower (p-value = 0.001). Furthermore, a substantial subset of the HPV negative precursors (35/60, 58.3%) and VC (10/29, 34.5%) were TP53 wild type (wt), suggesting a third, not-previously described, molecular subtype. Clinical outcomes in the three different subtypes (HPV+, HPV-/p53wt, HPV-/p53abn) were evaluated in a follow-up cohort consisting of 236 VC patients. Local recurrence rate was 5.3% for HPV+, 16.3% for HPV-/p53wt and 22.6% for HPV-/p53abn tumors (p=0.044). HPV positivity remained an independent prognostic factor for favourable outcome in the multivariable analysis (p=0.020). Conclusion HPV- and HPV+ vulvar (pre)cancers display striking differences in somatic mutation patterns. HPV-/p53wt VC appear to be a distinct clinicopathologic subgroup with frequent NOTCH1 mutations. HPV+ VC have a significant lower local recurrence rate, independent of clinicopathological variables, opening opportunities for reducing overtreatment in VC.

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Multi-Spectral Optoacoustic Tomography (MSOT) of human breast cancer.

Purpose: In a pilot study, we introduce fast handheld Multi-Spectral Optoacoustic Tomography (MSOT) of the breast at 28 wavelengths, aiming to identify high-resolution optoacoustic (photoacoustic) patterns of breast cancer and non-cancerous breast tissue. Experimental Design: We imaged 10 female patients aged 48-81 years with malignant non-specific breast cancer or invasive lobular carcinoma. Three healthy volunteers aged 31-36 years were also imaged. Fast-MSOT was based on unique single-frame-per-pulse (SFPP) image acquisition employed to improve the accuracy of spectral differentiation over using a small number of wavelengths. Breast tissue was illuminated at the 700 - 970 nm spectral range over 0.56 seconds total scan time. MSOT data were guided by ultrasonography and X-ray mammography or MRI. Results: The extended spectral range allowed the computation of oxygenated hemoglobin (HBO2), deoxygenated hemoglobin (HB), total blood volume (TBV), lipid and water contributions, allowing first insights into in-vivo high-resolution breast tissue MSOT cancer patterns. TBV and Hb/HBO2 images resolved marked differences between cancer and control tissue, manifested as a vessel rich tumor periphery with highly heterogeneous spatial appearance compared to healthy tissue. We observe significant TBV variations between different tumors and between tumors over healthy tissues. Water and fat lipid layers appear disrupted in cancer vs. healthy tissue; however offer weaker contrast compared to TBV images. Conclusion: In contrast to optical methods, MSOT resolves physiological cancer features with high resolution and revealed patterns not offered by other radiological modalities. The new features relate to personalized and precision medicine potential.

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Stereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTL-4 treatment is associated with improved intracranial control

Numerous studies suggest that radiation can boost antitumor immune response by stimulating release of tumor-specific antigens. However, the optimal timing between radiotherapy and immune checkpoint blockade to achieve potentially synergistic benefits is unclear.

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BET-bromodomain inhibitors modulate epigenetic patterns at the diacylglycerol kinase alpha enhancer associated with radiation-induced fibrosis

Fibrosis is a frequent adverse effect of radiotherapy and no effective treatments are currently available to prevent or reverse fibrotic disease. We have previously identified altered epigenetic patterns at a gene enhancer of the diacylglycerol kinase alpha (DGKA) locus in normal skin fibroblasts derived from fibrosis patients. An open chromatin pattern related to radiation-inducibility of DGKA is associated with onset of radiation-induced fibrosis. Here, we explore epigenetic modulation of DGKA as a way to mitigate predisposition to fibrosis.

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Lack of differences in radiation-induced immunogenicity parameters between HPV-positive and HPV-negative human HNSCC cell lines

Clinical studies indicate that patients with HPV/p16-associated head & neck squamous cell carcinoma (HNSCC) represent a subgroup with a better prognosis and improved response to conventional radiotherapy. Involvement of immune-based factors has been hypothesized. In the present study, we investigated radiation-induced differences in release of damage associated molecular patterns (DAMPs), cytokines and activation of dendritic cells (DCs) in HPV-positive and negative HNSCC cancer cell lines.

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Postoperative Delirium in Indian Patients Following Major Abdominal Surgery for Cancer: Risk Factors and Associations

Abstract

Postoperative delirium (POD) is not uncommon following major abdominal surgery with its incidence ranging between five and 51%. As cancer affects disproportionately, the population older than 65 years and as delirium is more common in the elderly, surgical oncology patients are at a higher risk of developing POD. The present study was undertaken to explore the impact and associations of POD in Indian patients undergoing oncological major abdominal surgery. A retrospective review of the electronic medical records in a tertiary cancer care institution of all postoperative patients who had undergone major gastrointestinal gynaecological and urological abdominal surgery for cancer and required psycho-oncology referral was performed. Patient, surgery and postoperative outcome-related data were collected. Statistical analysis was performed using univariate and multivariate logistic regression analysis. Out of 824 patients who underwent major abdominal surgery, 33 patients (4.0%) were diagnosed with POD. In univariate analysis, older age and history of addiction were found to be statistically significantly associated with POD (p < 0.001). Among the postoperative factors, respiratory complications (p < 0.001), sepsis (p < 0.05), ICU stay > 24 h (p < 0.05) and electrolyte impairment (p < 0.05) were the significant associations with the POD. Thirty-day mortality was higher in the POD group (p < 0.05). In multivariate logistic regression analysis, advanced age, addictions, respiratory complications and sepsis were found to be significant associations with POD, p < 0.001. Postoperative delirium is associated with higher mortality. Older age, postoperative respiratory complications and sepsis are common contributory factors of postoperative delirium.

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Second generation of familial nonmedullary thyroid carcinoma: a meta-analysis on the clinicopathologic features and prognosis

Publication date: Available online 12 September 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Yi-mei Zhou, Han Luo, Ju-xiang Gou, Wan-jun Zhao, Wen-yu Dai, Jingqiang Zhu, Zhi-hui Li
Whether the second generation of parent/offspring type familial nonmedullary thyroid carcinoma (FNMTC) is more aggressive and has worse prognosis than their first generation counterpart is controversial. To evaluate the clinicopathologic features and prognosis of the second generation via a comparison between the two groups, We searched three databases (PubMed, EMBASE and the Cochrane library) to review studies published before November 25, 2016. All original studies comparing the clinicopathologic features and prognosis in the first generation of parent/offspring type FNMTC with its second generation counterpart were included. The Q-test and I² test were used to evaluate homogeneity and funnel plot with Egger's test was used to evaluate publication bias. 6 studies, including 424 subjects were included. There was significant difference between the first and second generation of parent/offspring type FNMTC in the age of onset (SMD=-1.20, 95% CI: -2.38, -0.03, p=0.045), gender distribution (OR=0.48, 95% CI: 0.25, 0.90, p=0.022) and lymph node metastasis (OR=1.84, 95%CI: 1.16, 2.92, p=0.01), while no significant difference in other variables. Thus we conclude that the second generation of parent/offspring type FNMTC patients is in higher risk than their first generation counterpart. We believe continuous study is needed to confirm the result.



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Cognitive reactions of nurses exposed to cancer patients' traumatic experiences: A qualitative study to identify triggers of the onset of compassion fatigue

Abstract

Objective

Nurses in cancer care are considered to be at risk for compassion fatigue because they are frequently exposed to patients' traumatic experiences. However, only a few effective empirical studies have been conducted in this field, and cognitive factors in particular have not been sufficiently studied. This study aims to describe the components of nurses' cognitive reactions from their exposure to cancer patients' traumatic experience to the onset of compassion fatigue.

Methods

In this qualitative study, 30 nurses in cancer care were purposively selected. Data were collected through semi-structured interviews and analyzed using content analysis and the constant comparative method.

Results

Forty attributes were identified from 613 statements and classified into 11 categories: sense of professional inadequacy, compassion for patients and their families, desire to support patients and their families, rumination on oneself or one's family, sense of professional mission, dissatisfaction with medical staff, desire to integrate with colleagues, desire to avoid one's duties, conflict between one's belief and reality, reconsideration of the meaning of life, and sense of powerlessness over cancer.

Conclusions

This study identified important components of cognitive reactions of nurses who encounter the traumatic experiences of cancer patients in Japan. This information can contribute to the understanding of the onset of compassion fatigue and provide the foundation for nurses in cancer care to avoid and recover from compassion fatigue.

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BRAF mutation as a novel driver of eosinophilic cystitis

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A study on different therapies and prognosis-related factors for 101 patients with SCLC and brain metastases

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Clinicopathological characteristics and experience in the treatment of giant retroperitoneal liposarcoma: A case report and review of the literature

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Targeted Therapy and Local Control: The Dynamic Duo

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Usefulness of Mapping Biopsy in the Treatment of Penoscrotal Extramammary Paget’s Disease

Abstract

Background

Extramammary Paget's disease (EMPD) is a rare cutaneous malignancy; however, the standard treatment of EMPD has not been established. In this study, we applied mapping biopsy to penoscrotal EMPD and evaluated its effects.

Methods

A retrospective chart review was performed to determine the outcomes of patients with primary penoscrotal EMPD who underwent surgery at our institution between 2007 and 2014. Patients were divided into two groups (one group underwent mapping biopsy, while the other group did not), and the difference between the two groups was analyzed. The 5-year tumor-free rate was estimated using the Kaplan–Meier method, and the risk factors for local recurrence were also estimated.

Results

A total of 44 patients were analyzed, and the mean follow-up of patients was 50.27 months. Patients who underwent mapping biopsy showed significantly lower tumor involvement at permanent and frozen biopsies and a lower local recurrence rate than those who did not undergo mapping biopsy. The 5-year tumor-free rate was significantly higher in the mapping biopsy group than in the non-mapping biopsy group. Multivariable analysis demonstrated that age at operation, mapping biopsy, and false-negative results at frozen biopsy were associated with local recurrence.

Conclusions

Mapping biopsy is beneficial to reduce local recurrence in penoscrotal EMPD.

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Impact of Sustained Virological Response to Interferon Therapy on Recurrence of Hepatitis C Virus-Related Hepatocellular Carcinoma

Abstract

Background

Although achieving a sustained virological response (SVR) in hepatitis C virus (HCV) infection is recognized as improving liver function and reducing hepatocellular carcinoma (HCC) development, its impact on HCC recurrence is unclear. This study investigated how preoperative SVR achievement by interferon treatment affects HCC recurrence in patients undergoing hepatic resection.

Methods

The study subjects were 521 patients with HCV infection who underwent initial and curative hepatic resection for HCC. To adjust for confounding factors between the SVR and non-SVR groups, propensity score-matching analysis was performed.

Results

After propensity score matching, 45 of the 49 patients in the SVR group, and an equal number of the 472 patients in the non-SVR group, were matched. The two groups had similar distributions of clinicopathological characteristics. In the matched cohort, the 3-, 5-, and 7-year recurrence-free survival rates after surgery were 56, 45, and 37%, respectively, in the SVR group, and 34, 23, and 7.2%, respectively, in the non-SVR group (p = 0.033). Additionally, the 3-, 5-, and 7-year overall survival rates after surgery were 82, 80, and 75%, respectively, in the SVR group, and 78, 64, and 44%, respectively, in the non-SVR group (p = 0.065). The 1- and 2-year cumulative recurrence rates in the early phase showed no significant difference between the SVR and non-SVR groups (p = 0.27). however, the 3-, 5-, and 7-year cumulative recurrence rates in the late phase were 14, 32, and 43%, respectively, in the SVR group, and 33, 55, and 86%, respectively, in the non-SVR group (p = 0.037).

Conclusion

Achievement of SVR may reduce postoperative recurrence after hepatic resection.

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Impact of Patient Age on the Postoperative Survival in Pancreatic Head Cancer

Abstract

Background

Some reports have stated that pancreatoduodenectomy for elderly patients have comparable morbidity and mortality to that of young patients. However, the long-term outcomes of these patients have not been fully evaluated, especially for pancreatic head cancer.

Methods

A total of 227 patients who underwent pancreatoduodenectomy for pancreatic head cancer between 2007 and 2014 were included. They were stratified according to age: young (<70 years), elderly (70 to <80 years), and very elderly (≥80 years). The short- and long-term outcomes were evaluated.

Results

There were no significant differences in terms of morbidity among the three groups. The median disease-free survival times were 15 months in the young, 11 months in the elderly, and 7 months in the very elderly. The disease-free survival of the young patients was significantly better than that in both the elderly and the very elderly (p = 0.012 and p = 0.016). The median overall survival times were 30 months in the young, 20 months in the elderly, and 14 months in the very elderly. The overall survival of the young patients was significantly better than that in both the elderly and the very elderly (p = 0.007 and p < 0.001). The difference was marginal between the elderly and the very elderly (p = 0.053). Multivariate analysis revealed that lymph node metastasis (p < 0.001), age ≥80 years (p = 0.013), lack of adjuvant chemotherapy (p = 0.003), blood transfusion (p = 0.015), and CA 19-9 ≥300 U/ml (p = 0.040) were significant prognostic factors.

Conclusions

Patient age influenced the survival after pancreatoduodenectomy for pancreatic cancer.

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2017 Update on the Querleu–Morrow Classification of Radical Hysterectomy

Abstract

Background

One of the most important principles in modern cervical cancer surgery is the concept of tailoring surgical radicality. In practice, this means abandoning the "one-fits-all" concept in favor of tailored operations. The term "radical hysterectomy" is used to describe many different procedures, each with a different degree of radicality. Anatomic structures are subjected to artificial dissection artifacts, as well as different interpretations and nomenclatures. This study aimed to refine and standardize the principles and descriptions of the different classes of radical hysterectomy as defined in the Querleu–Morrow classification and to propose its universal applicability.

Methods

All three authors independently examined the current literature and undertook a critical assessment of the original classification. Images and pathologic slides demonstrating different types of radical hysterectomy were examined to document a consensual vision of the anatomy. The Cibula 3-D concept also was included in this update.

Results

The Querleu–Morrow classification is based on the lateral extent of resection. Four types of radical hysterectomy are described, including a limited number of subtypes when necessary. Two major objectives remain constant: excision of central tumor with clear margins and removal of any potential sites of nodal metastasis.

Conclusion

Studies evaluating radicality in the surgical management of cervical cancer should be based on precise, universally accepted descriptions. The authors' updated classification presents standardized, universally applicable descriptions of different types of hysterectomies performed worldwide, categorized according to degree of radicality, independently of theoretical considerations.

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Sustained Growth of a University-Based Endocrine Surgery Program Over 10 Years

Abstract

Background

Endocrine surgery continues to mature as a subspecialty field. We describe the clinical performance of an academic endocrine surgery program (ESP) over its first 10 years.

Methods

We examined all endocrine procedures performed during the 10-year period (2006–2015) following the inception of the ESP. Institutional and state-level data on case volume, patient geographic origin, and hospital-side costs were obtained.

Results

Endocrine case volume increased by approximately ninefold over the study period (from 102 cases in 2006 to 919 cases in 2015). The rate of growth remained approximately linear, and was driven by geographic expansion of referral regions coupled with transitioning low- to moderate-acuity operations to venues outside of the main tertiary care hospital. Market share across the eight-county Southern California region grew by more than twofold over the study period. Increased utilization of outpatient surgery led to cost reductions, averaging 11.1% per case by 2015.

Conclusions

Establishment of an academic ESP can lead to sustained clinical growth and a fundamental shift in regional referral patterns. The nation's continued need for skilled high-volume endocrine surgeons represents opportunities for medical centers to institute their own dedicated endocrine surgery programs.

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Usefulness of Mapping Biopsy in the Treatment of Penoscrotal Extramammary Paget’s Disease

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Reappraisal of Staging Laparoscopy for Patients with Pancreatic Adenocarcinoma: A Contemporary Analysis of 1001 Patients

Abstract

Background

Recent advances in imaging and the increasing use of neoadjuvant therapy puts the contemporary utility of staging laparoscopy for patients with pancreatic adenocarcinoma (PDAC) into question. This study aimed to develop a prognostic score to optimize prevention of an unnecessary laparotomy and minimize the rate for unnecessary laparoscopy.

Methods

Clinicopathologic data were evaluated for all patients undergoing surgical intervention for PDAC between 2001 and 2015, who were stratified into group 1 (2001–2008) and group 2 (2009–2014).

Results

The study identified 1001 patients eligible for analysis, 331 (33%) of whom underwent a staging laparoscopy before exploration. An unnecessary laparotomy was prevented for 44.4% of the patients in period 1 and for 24% of the patients in period 2 (p < 0.001). Male gender [odds ratio (OR), 1.8; p < 0.05], preoperative resectability (borderline resectable OR 2.1; p < 0.019; locally advanced OR 7.6; p < 0.001), CA 19-9 levels higher than 394 U/L (OR 3.1; p < 0.001), no neoadjuvant chemotherapy (OR 2.7; p = 0.012), and pancreatic body or tail lesions (OR 1.8; p = 0.063) were predictive of occult metastatic disease. The developed scoring index demonstrated a c-statistic of 0.729. The observed-to-expected ratio for the index at every score level validated the index's model. A score cutoff at 4 was able to detect 76.1% of radiographically occult metastatic disease.

Conclusion

The rate for unnecessary laparotomy among patients with PDAC has decreased in contemporary times, but unnecessary laparotomy still occurs for 1 in 4 patients. Using our scoring system, a cutoff of 4 allows 76% of radiographically occult metastases to be predicted, thereby selecting high-risk patients for laparoscopic biopsy and potentially avoiding a non-therapeutic laparotomy.

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Optimal Lymphadenectomy for Duodenal Adenocarcinoma: Does the Number Alone Matter?

Abstract

Background

Duodenal adenocarcinoma (DA) is a rare disease, and the optimal extent of lymphadenectomy and the role of limited resection remain controversial.

Objective

The aim of our study was to assess the pattern of regional lymph node spread of DA and to determine the optimal extent of resection.

Methods

A total of 65 patients who underwent curative resection for DA at our institution from 1989 through 2015 were included in this study. Clinicopathologic factors associated with long-term outcomes and the patterns of regional node spread per primary tumor location were evaluated.

Results

Fifty-one patients (78%) underwent pancreaticoduodenectomy (PD), with the remainder undergoing limited resection. The median number of retrieved lymph nodes was 24 (range 1–63) and 48% of patients had regional node metastasis. The 5-year overall survival (OS) rate was 67%. In the multivariate analysis, regional node and para-aortic lymph node metastasis were risk factors associated with poorer OS (hazard ratio [HR] 12.1 [p = 0.025], and HR 3.2 [p = 0.045], respectively). While pancreaticoduodenal (#13) and superior mesenteric (#14) lymph node stations were commonly involved by both distal and proximal DA (33 vs. 39% for #13, p = 0.39; and 33 vs. 22% for #14, p = 0.27), the pyloric lymph node station was much less involved by distal DA than proximal DA (0 vs. 37%, p = 0.036).

Conclusion

The pancreaticoduodenal lymph node station was the most commonly involved lymph node in DA, and PD should be the standard operation for DA. Segmental resection should only be reserved for patients with distal DA who are physically unfit for PD.

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Survival Rates for Patients with Resected Gastric Adenocarcinoma Finally have Increased in the United States

Abstract

Background

In the United States, the overall survival rates for gastric adenocarcinoma have remained low, with surgical resection as the only therapy for many patients. Given the advances in multimodality treatment and the development of guidelines recommending adequate lymph node evaluation, the authors determined whether overall survival rates for patients with gastric adenocarcinoma have increased in the United States.

Methods

The study used the Surveillance Epidemiology and End Results (SEER) database to examine overall survival for patients with the diagnosis of gastric adenocarcinoma between 1988 and 2013. The study cohort was divided into five periods: 1988–1992, 1993–1997, 1998–2002, 2003–2007, and 2008–2013. Kaplan–Meier methods and Cox proportional hazards modeling were used to determine the effect that year of diagnosis had on overall survival.

Results

The diagnosis was determined for 13,470 patients between 1988 and 2013. The use of radiation therapy and the proportion of patients who had at least 15 lymph nodes evaluated significantly increased during the study period. Unadjusted Kaplan–Meier estimates demonstrated significantly better survival rates for the patients with a diagnosis of gastric cancer in the later periods (2003–2007 and 2008–2013) than for those in the three earlier periods. In our Cox proportional hazards model, recent period was associated with a significantly lower hazard of 5-year mortality.

Conclusion

This analysis demonstrated for the first time that gastric cancer survival rates have significantly improved in the United States during the past 2 decades. This observation likely reflects improved adherence to cancer treatment guidelines, including adequate lymph node evaluation and delivery of adjuvant treatment more consistently.

http://ift.tt/2gZA0XE

Prognostic value of systemic immune-inflammation index in patients with gastric cancer

Inflammation-based indexes have been used to predict survival and recurrence in cancer patients. Systemic immune-inflammation index (SII) was reported to be associated with prognosis in some malignant tumors. ...

http://ift.tt/2f2LqcH

Neuropilin-2 rs849563 gene variations and susceptibility to autism in Iranian population: A case-control study

Abstract

Autism spectrum disorders (ASD) are neurodevelopmental disruptions usually diagnosed in the first three years of child's life that characterized by some impairments in verbal and nonverbal communication, problems in social interactions and repetitive behaviors. The neuropilin-2 (NRP2) gene has been shown to both guide axons and control neuronal migration in the central nervous system (CNS). In this study the association between the NRP2 gene and autism using a cohort of 120 Iranian children (50 cases with autism and 70 control cases) was analyzed. Single nucleotide polymorphism (SNP) was genotyped by the polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analyses. There was significant difference between the genotype and allele frequency between control and patient groups (P = 0.003 and P = 0.01, respectively). The prevalence of genotype frequencies of TT and TG in autistic children were 40% and 60%, respectively, while in controls were 68.5% and 31.5%, respectively. The heterozyote TG was associated with an increased risk of autism compared with TT genotype (OR = 3.72, 95%CI = 1.53–6.95, P = 0.02). The allele frequencies of T and G in autistic children were 78.5% and 21.4%, respectively and in controls were 84.2% and 15.7%, respectively. The NRP2 G allele conferred a 2.29-fold increased risk to autism relative to the T allele (OR = 2.29, 95%CI = 1.23–4.29, P = 0.009). The results of this study showed that there is a significant association between rs849563 polymorphism and autism in the studied population. However in order to obtain a definitive conclusion larger studies with more samples are required to confirm the results of this study.

http://ift.tt/2xvGnZI

DRα1-MOG-35-55 treatment reduces lesion volumes and improves neurological deficits after traumatic brain injury

Abstract

Traumatic brain injury (TBI) results in severe neurological impairments without effective treatments. Inflammation appears to be an important contributor to key pathogenic events such as secondary brain injury following TBI and therefore serves as a promising target for novel therapies. We have recently demonstrated the ability of a molecular construct comprised of the human leukocyte antigen (HLA)-DRα1 domain linked covalently to mouse (m)MOG-35-55 peptide (DRα1-MOG-35-55 construct) to reduce CNS inflammation and tissue injury in animal models of multiple sclerosis and ischemic stroke. The aim of the current study was to determine if DRα1-MOG-35-55 treatment of a fluid percussion injury (FPI) mouse model of TBI could reduce the lesion size and improve disease outcome measures. Neurodeficits, lesion size, and immune responses were determined to evaluate the therapeutic potential and mechanisms of neuroprotection induced by DRα1-MOG-35-55 treatment. The results demonstrated that daily injections of DRα1-MOG-35-55 given after FPI significantly reduced numbers of infiltrating CD74⁺ and CD86⁺ macrophages and increased numbers of CD206⁺ microglia in the brain concomitant with smaller lesion sizes and improvement in neurodeficits. Conversely, DRα1-MOG-35-55 treatment of TBI increased numbers of circulating CD11b⁺ monocytes and their expression of CD74 but had no detectable effect on cell numbers or marker expression in the spleen. These results demonstrate that DRα1-MOG-35-55 therapy can reduce CNS inflammation and significantly improve histological and clinical outcomes after TBI. Future studies will further examine the potential of DRα1-MOG-35-55 for treatment of TBI.

http://ift.tt/2gZ0pFe

A patient with mitochondrial disorder due to a novel mutation in MRPS22

Abstract

MRPS22 gene defect is a very rare newly discovered mitochondrial disorder. We report a 4-month-old severely affected male infant with MRPS22 mutation. Whole exome sequencing revealed a novel homozygous splicing mutation c.339 + 5 G > A in MRPS22 gene. He has mild dysmorphism, hypotonia, developmental delay but not hypertrophic cardiomyopathy and tubulopathy which differ from other majority of reported patients. Therefore, hypertrophic cardiomyopathy and tubulopathy may not be considered as constant features of MRPS22. With this case report, we also present first symmetrical bilateral brainstem and medial thalamic lesions, and cerebellar and cerebral atrophy on a brain MR imaging follow-up of ten months.

http://ift.tt/2xXV5Fm

Coenzyme Q10 and niacin mitigate streptozotocin- induced diabetic encephalopathy in a rat model

Abstract

Diabetic encephalopathy is an important complication of diabetes characterized by cognitive impairment, neurochemical and structural abnormalities. This study aimed to investigate the effect of coenzyme Q10 (CoQ10) and niacin as well as their combination in the treatment of encephalopathy associated with streptozotocin (STZ)- induced diabetes in rats. Glibenclamide (reference diabetic drug) and donepezil hydrochloride (acetylcholinesterase inhibitor) were also evaluated. Diabetes was induced by a single intraperitoneal injection of STZ (60 mg/kg). One month after STZ injection, diabetic rats were treated with the aforementioned drugs for two weeks. The evaluation was done through measuring glucose level, total antioxidant capacity (TAC), interleukin 6 (IL6), DNA degradation as well as serotonin and noradrenaline as neurotransmitters. The present data illustrated that combining CoQ10 and niacin exhibiting the most potent effect in improving the measured parameters and ameliorating some of diabetes complications.

http://ift.tt/2gZ0h8I

Spatial discrimination of glioblastoma and treatment effect with histologically-validated perfusion and diffusion magnetic resonance imaging metrics

Abstract

The goal of this study is to spatially discriminate tumor from treatment effect (TE), within the contrast-enhancing lesion, for brain tumor patients at all stages of treatment. To this end, the diagnostic accuracy of MRI-derived diffusion and perfusion parameters to distinguish pure TE from pure glioblastoma (GBM) was determined utilizing spatially-correlated biopsy samples. From July 2010 through June 2015, brain tumor patients who underwent pre-operative DWI and DSC-MRI and stereotactic image-guided biopsy were considered for inclusion in this IRB-approved study. MRI-derived parameter maps included apparent diffusion coefficient (ADC), normalized cerebral blood flow (nCBF), normalized and standardized relative cerebral blood volume (nRCBV, sRCBV), peak signal-height (PSR) and percent signal-recovery (PSR). These were co-registered to the Stealth MRI and median values extracted from the spatially-matched biopsy regions. A ROC analysis accounting for multiple subject samples was performed, and the optimal threshold for distinguishing TE from GBM determined for each parameter. Histopathologic diagnosis of pure TE (n = 10) or pure GBM (n = 34) was confirmed in tissue samples from 15 consecutive subjects with analyzable data. Perfusion thresholds of sRCBV (3575; SN/SP% = 79.4/90.0), nRCBV (1.13; SN/SP% = 82.1/90.0), and nCBF (1.05; SN/SP% = 79.4/80.0) distinguished TE from GBM (P < 0.05), whereas ADC, PSR, and PH could not (P > 0.05). The thresholds for CBF and CBV can be applied to lesions with any admixture of tumor or treatment effect, enabling the identification of true tumor burden within enhancing lesions. This approach overcomes current limitations of averaging values from both tumor and TE for quantitative assessments.

http://ift.tt/2y3aeG3

Her2 positive subtype and breast cancer brain metastasis: any effect of anti-Her2 targeted therapy?

http://ift.tt/2w5U55s

Assessment of acute bowel function after radiotherapy for prostate cancer: Is it accurate enough?

Abstract

Background and purpose

Pelvic radiotherapy for prostate cancer can be associated with bowel toxicity, which may have a significant impact on quality of life. Our aim was to assess the adequacy of the tools currently used to assess bowel symptoms after radiotherapy, including physician and patient reported outcomes. This sub-study on acute toxicity was part of a prospective trial assessing long-term bowel dysfunction.

Materials and methods

Between February 2013 and July 2015, 75 patients with prostate cancer who received radiotherapy completed the LENT/SOMA and the EPIC questionnaires baseline and 2 weeks after the treatment. The Bristol stool scale and two additional questions on faecal urgency were added. Physicians assessed toxicity using Common Terminology Criteria for Adverse Events v.4.0. Agreement between patients and clinicians was assessed using the Cohen's κ coefficient.

Results

Acute toxicity during radiotherapy was very low. The pattern of overall bowel bother was similar before and after treatment. Faecal urgency significantly increased after radiotherapy compared to baseline but was only detected by the additional questions and not by the physicians or the patient-reported outcomes (PRO) questionnaires. Correlation between physician and PRO was poor for most symptoms.

Conclusion

Bowel symptoms such as urgency may remain undetected by usual tools to assess toxicity after radiotherapy. Assessment of bowel toxicity should be reappraised in order to identify those patients who may have symptoms with an impact on their quality of life.

http://ift.tt/2wXPwHD

Nucleolar and spindle associated protein 1 promotes the aggressiveness of astrocytoma by activating the Hedgehog signaling pathway

Abstract

Background

The prognosis of human astrocytoma is poor, and the molecular alterations underlying its pathogenesis still needed to be elucidated. Nucleolar and spindle associated protein 1 (NUSAP1) was observed in several types of cancers, but its role in astrocytoma remained unknown.

Methods

The expression of NUSAP1 in astrocytoma cell lines and tissues were measured with western blotting and Real-Time PCR. Two hundred and twenty-one astrocytoma tissue samples were analyzed by immunochemistry to demonstrate the correlation between the NUSAP1 expression and clinicopathological characteristics. 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay, colony formation, transwell matrix penetration assay, wound healing assay and anchorage-independent growth assay were used to investigate the biological effect of NUSAP1 in astrocytoma. An intracranial brain xenograft tumor model was used to confirm the oncogenic role of NUSAP1 in human astrocytoma. Luciferase reporter assay was used to investigate the effect of NUSAP1 on Hedgehog signaling pathway.

Results

NUSAP1 was markedly overexpressed in astrocytoma cell lines and tissues compared with normal astrocytes and brain tissues. NUSAP1 was found to be overexpressed in 152 of 221 (68.78%) astrocytoma tissues, and was significantly correlated to poor survival. Further, ectopic expression or knockdown of NUSAP1 significantly promoted or inhibited, respectively, the invasive ability of astrocytoma cells. Moreover, intracranial xenografts of astrocytoma cells engineered to express NUSAP1 were highly invasive compared with the parental cells. With regard to its molecular mechanism, upregulation of NUSAP1 in astrocytoma cells promoted the nuclear translocation of GLI family zinc finger 1 (GLI1) and upregulated the downstream genes of the Hedgehog pathway.

Conclusion

These findings indicate that NUSAP1 contributes to the progression of astrocytoma by enhancing tumor cell invasiveness via activation of the Hedgehog signaling pathway, and that NUSAP1 might be a potential prognostic biomarker as well as a target in astrocytoma.

http://ift.tt/2wY93Yc

Integrator complex subunit 6 (INTS6) inhibits hepatocellular carcinoma growth by Wnt pathway and serve as a prognostic marker

Abstract

Background

Integrator complex subunit 6 (INTS6) was found to play a tumour suppressing role in certain types of solid tumours. In this study, we wanted to determine the expression level of INTS6 in hepatocellular carcinoma (HCC) and evaluate its clinical characteristics and mechanisms in HCC patients (Lui and Lu, European Journal of Cancer, 51:S94, 2015).

Methods

First, we used a microarray analysis to explore the mRNA expression levels in HCC and paired normal liver tissues; second, we used qRT-PCR to measure the INTS6 mRNA levels in a cohort of 50 HCC tissues and adjacent normal liver tissues; third, we used Western blot analyses to detect the INTS6 protein levels in 20 paired HCC and normal liver tissues; fourth, we used immunohistochemistry to determine the INTS6 expression levels in 70 archived paraffin-embedded HCC samples. Finally, we investigated the suppressive function of INTS6 in the Wnt pathway.

Results

Herein, according to the microarray data analysis, the expression levels of INTS6 were dramatically down-regulated in HCC tissues vs. those in normal liver tissues (p<0.05). qRT-PCR and Western blot analyses showed that the INTS6 mRNA and protein expression was significantly down-regulated in tumour tissues compared to the adjacent normal liver tissues (p<0.05). Immunohistochemical assays revealed that decreased INTS6 expression was present in 62.9% (44/70) of HCC patients. Correlation analyses showed that INTS6 expression was significantly correlated with serum alpha-fetoprotein levels (AFP, p =0.004), pathology grade (p =0.005), and tumour recurrence (p =0.04). Kaplan-Meier analysis revealed that patients with low INTS6 expression levels had shorter overall and disease-free survival rates than patients with high INTS6 expression levels (p =0.001 and p =0.001). Multivariate regression analysis indicated that INTS6 was an independent predictor of overall survival and disease-free survival rates. Mechanistically, INTS6 increased WIF-1 expression and then inhibited the Wnt/β-catenin signalling pathway.

Conclusion

The results of our study show that down-regulated INTS6 expression is associated with a poorer prognosis in HCC patients. This newly identified INTS6/WIF-1 axis indicates the molecular mechanism of HCC and may represent a therapeutic target in HCC patients.

http://ift.tt/2xj4p9p

Prognostic value of systemic immune-inflammation index in patients with gastric cancer

Abstract

Background

Inflammation-based indexes have been used to predict survival and recurrence in cancer patients. Systemic immune-inflammation index (SII) was reported to be associated with prognosis in some malignant tumors. In the present study, we aimed to explore the association between SII and the prognosis of patients with gastric cancer.

Methods

We retrospectively analyzed data from 444 gastric cancer patients who underwent gastrectomy at the First Affiliated Hospital of Sun Yat-sen University between January 1994 and December 2005. Preoperative SII was calculated. The Chi square test or Fisher's exact test was used to determine the relationship between preoperative SII and clinicopathologic characteristics. Overall survival (OS) rates were estimated using the Kaplan–Meier method, and the effect of SII on OS was analyzed using the Cox proportional hazards model. Receiver operating characteristic (ROC) curves were used to compare the predictive ability of SII, NLR, and PLR.

Results

SII equal to or higher than 660 was significantly associated with old age, large tumor size, unfavorable Borrmann classification, advanced tumor invasion, lymph node metastasis, distant metastasis, advanced TNM stage, and high carcino-embryonic antigen level, high neutrophil–lymphocyte ratio, and high platelet–lymphocyte ratio (all P < 0.05). High SII was significantly associated with unfavorable prognosis (P < 0.001) and SII was an independent predictor for OS (P = 0.015). Subgroups analysis further showed significant associations between high SII and short OS in stage I, II, III subgroups (all P < 0.05). SII was superior to NLR and PLR for predicting OS in patients with gastric cancer.

Conclusion

Preoperative SII level is an independent prognostic factor for OS in patients with gastric cancer.

http://ift.tt/2jn16c8

Take care of your neighborhood

Abstract

Purpose

Urban women in certain Washington, DC neighborhoods present with advanced breast cancer at high rates despite access to health insurance and health care.

Methods

Through a two-phase intervention, community health workers (CHWs) educated and surveyed individuals regarding healthcare utilization and breast health and cancer awareness. In phase I, CHWs educated and administered a survey to 1092 women, of whom 95.1% had health insurance, in an attempt to explain the high rate of advanced breast cancer despite having health insurance. In phase II, a targeted CHW-administered intervention was designed based on data collected from the phase I survey, and provided to 658 women. Preintervention and postintervention surveys were administered to assess its impact on knowledge and beliefs about breast health and cancer screening.

Results

During phase I, respondents most often identified personal factors (28.7%) and fear (27.7%) to explain the high rate of advanced breast cancer despite health insurance status. In phase II, the intervention improved perceptions of the safety and efficacy of mammograms with an absolute 15.4% increase in the respondents who believed that "A mammogram is the safest and most effective test available for finding early breast cancer." Perceived barriers discouraging mammograms were access (17.0%), pain (13.2%), and education (13.1%).

Conclusions

Among an urban population of predominantly insured women with high rates of advanced breast cancer at diagnosis, personal factors and fear were cited as the greatest barriers to breast cancer screening. Educational intervention by CHWs showed a positive impact on respondents' perceptions regarding mammogram safety and efficacy.

http://ift.tt/2xj3S7B

What’s new in chemotherapy for non-small cell lung cancer?

Summary

The last few years have seen an explosion of novel treatment options for patients diagnosed with lung cancer, mostly for those with stage IV non-small cell lung cancer. On the one hand, this was due to the development of modern diagnostic tools permitting accurate molecular diagnoses leading to the identification of several oncogenic driver mutations which can be therapeutically targeted. On the other hand, the advent of immunotherapy in medical oncology in general, but in thoracic oncology in particular, has changed the treatment landscape first in second-line systemic treatment, but recently also in first-line treatment in patients with programmed death ligand-1 (PD-L1) expression in their tumors of >50%. Despite those advances, the majority of patients we treat in our daily routine will still receive chemotherapy: a so-called druggable aberration is only found in approximately 20% of cases. Some 25% present with an activating KRAS mutation, which despite decades of research still cannot be directly targeted. In the remainder, no genomic aberration of direct clinical consequences has been identified. On the other hand, the rate of PD-L1 positivity >50% at diagnosis has been reported to be between 24.9 and 30.2%. Overall, this leaves the majority of patients without any of those options in first-line therapy and they will receive standard of care chemotherapy. This minireview discusses the latest developments in the field of chemotherapy for non-small cell lung cancer.

http://ift.tt/2jnqBd8

Assessment of acute bowel function after radiotherapy for prostate cancer: Is it accurate enough?

Abstract

Background and purpose

Pelvic radiotherapy for prostate cancer can be associated with bowel toxicity, which may have a significant impact on quality of life. Our aim was to assess the adequacy of the tools currently used to assess bowel symptoms after radiotherapy, including physician and patient reported outcomes. This sub-study on acute toxicity was part of a prospective trial assessing long-term bowel dysfunction.

Materials and methods

Between February 2013 and July 2015, 75 patients with prostate cancer who received radiotherapy completed the LENT/SOMA and the EPIC questionnaires baseline and 2 weeks after the treatment. The Bristol stool scale and two additional questions on faecal urgency were added. Physicians assessed toxicity using Common Terminology Criteria for Adverse Events v.4.0. Agreement between patients and clinicians was assessed using the Cohen's κ coefficient.

Results

Acute toxicity during radiotherapy was very low. The pattern of overall bowel bother was similar before and after treatment. Faecal urgency significantly increased after radiotherapy compared to baseline but was only detected by the additional questions and not by the physicians or the patient-reported outcomes (PRO) questionnaires. Correlation between physician and PRO was poor for most symptoms.

Conclusion

Bowel symptoms such as urgency may remain undetected by usual tools to assess toxicity after radiotherapy. Assessment of bowel toxicity should be reappraised in order to identify those patients who may have symptoms with an impact on their quality of life.

http://ift.tt/2wXPwHD

When LMO1 Meets MYCN, Neuroblastoma Is Metastatic

Publication date: 11 September 2017
Source:Cancer Cell, Volume 32, Issue 3
Author(s): Zhihui Liu, Carol J. Thiele
LMO1 is a high-risk neuroblastoma susceptibility gene, but how LMO1 cooperates with MYCN in neuroblastoma tumorigenesis is unclear. In this issue of Cancer Cell, Zhu et al. develop a novel zebrafish model that elucidates a mechanism by which LMO1 and MYCN synergistically initiate neuroblastoma and contribute to metastatic disease progression.

Teaser

LMO1 is a high-risk neuroblastoma susceptibility gene, but how LMO1 cooperates with MYCN in neuroblastoma tumorigenesis is unclear. In this issue of Cancer Cell, Zhu et al. develop a novel zebrafish model that elucidates a mechanism by which LMO1 and MYCN synergistically initiate neuroblastoma and contribute to metastatic disease progression.


http://ift.tt/2xY11Oq

Leukemic Cells “Gas Up” Leaky Bone Marrow Blood Vessels

Publication date: 11 September 2017
Source:Cancer Cell, Volume 32, Issue 3
Author(s): Tomer Itkin, Shahin Rafii
In this issue of Cancer Cell, Passaro et al. demonstrate how leukemia through aberrant induction of reactive oxygen species and nitric oxide production trigger marrow vessel leakiness, instigating pro-leukemic function. Disrupted tumor blood vessels promote exhaustion of non-malignant stem and progenitor cells and may facilitate leukemia relapse following chemotherapeutic treatment.

Teaser

In this issue of Cancer Cell, Passaro et al. demonstrate how leukemia through aberrant induction of reactive oxygen species and nitric oxide production trigger marrow vessel leakiness, instigating pro-leukemic function. Disrupted tumor blood vessels promote exhaustion of non-malignant stem and progenitor cells and may facilitate leukemia relapse following chemotherapeutic treatment.


http://ift.tt/2jlrF1u

Smoke-Induced Changes to the Epigenome Provide Fertile Ground for Oncogenic Mutation

Publication date: 11 September 2017
Source:Cancer Cell, Volume 32, Issue 3
Author(s): Susan J. Clark, Peter L. Molloy
How genetic and epigenetic events synergize to generate the oncogenic state is not well understood. In this issue of Cancer Cell, Vaz et al. provide compelling evidence that exposure to chronic cigarette smoke causes progressive epigenetic alterations that prime for key genetic events to drive the development of lung cancer.

Teaser

How genetic and epigenetic events synergize to generate the oncogenic state is not well understood. In this issue of Cancer Cell, Vaz et al. provide compelling evidence that exposure to chronic cigarette smoke causes progressive epigenetic alterations that prime for key genetic events to drive the development of lung cancer.


http://ift.tt/2xXIEsP

No Oxygen? No Glucose? No Problem: Fatty Acid Catabolism Enhances Effector CD8+ TILs

Publication date: 11 September 2017
Source:Cancer Cell, Volume 32, Issue 3
Author(s): Will Bailis, Justin A. Shyer, Michael Chiorazzi, Richard A. Flavell
The tumor microenvironment presents metabolic constraints to immunosurveiling cells. In this issue of Cancer Cell, Zhang et al. demonstrate that CD8⁺ TILs reprogram under hypoxic and hypoglycemic conditions, regaining effector function by engaging fatty acid catabolism, which is promoted by fenofibrate and synergistic with immune checkpoint blockade therapy.

Teaser

The tumor microenvironment presents metabolic constraints to immunosurveiling cells. In this issue of Cancer Cell, Zhang et al. demonstrate that CD8⁺ TILs reprogram under hypoxic and hypoglycemic conditions, regaining effector function by engaging fatty acid catabolism, which is promoted by fenofibrate and synergistic with immune checkpoint blockade therapy.


http://ift.tt/2xXM1Qz

Intravascular Survival and Extravasation of Tumor Cells

Publication date: 11 September 2017
Source:Cancer Cell, Volume 32, Issue 3
Author(s): Boris Strilic, Stefan Offermanns
Most metastasizing tumor cells reach distant sites by entering the circulatory system. Within the bloodstream, they are exposed to severe stress due to loss of adhesion to extracellular matrix, hemodynamic shear forces, and attacks of the immune system, and only a few cells manage to extravasate and to form metastases. We review the current understanding of the cellular and molecular mechanisms that allow tumor cells to survive in the intravascular environment and that mediate and promote tumor cell extravasation. As these processes are critical for the metastatic spread of tumor cells, we discuss implications for potential therapeutic approaches and future research.

Teaser

Most metastasizing tumor cells reach distant sites by entering the circulatory system. Within the bloodstream, they are exposed to severe stress due to loss of adhesion to extracellular matrix, hemodynamic shear forces, and attacks of the immune system, and only a few cells manage to extravasate and to form metastases. We review the current understanding of the cellular and molecular mechanisms that allow tumor cells to survive in the intravascular environment and that mediate and promote tumor cell extravasation. As these processes are critical for the metastatic spread of tumor cells, we discuss implications for potential therapeutic approaches and future research.


http://ift.tt/2jlZteE

Scratching the Surface of Immunotherapeutic Targets in Neuroblastoma

Publication date: 11 September 2017
Source:Cancer Cell, Volume 32, Issue 3
Author(s): Clare F. Malone, Kimberly Stegmaier
In this issue of Cancer Cell, Bosse et al. report GPC2 as a therapeutic target in neuroblastoma. They show that GPC2 is selectively expressed on the cell surface of neuroblastoma and is a dependency in this disease. Moreover, they demonstrate the therapeutic potential of an antibody-drug conjugate targeting GPC2.

Teaser

In this issue of Cancer Cell, Bosse et al. report GPC2 as a therapeutic target in neuroblastoma. They show that GPC2 is selectively expressed on the cell surface of neuroblastoma and is a dependency in this disease. Moreover, they demonstrate the therapeutic potential of an antibody-drug conjugate targeting GPC2.


http://ift.tt/2xXLvlB

Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma

Publication date: 11 September 2017
Source:Cancer Cell, Volume 32, Issue 3
Author(s): Kristopher R. Bosse, Pichai Raman, Zhongyu Zhu, Maria Lane, Daniel Martinez, Sabine Heitzeneder, Komal S. Rathi, Nathan M. Kendsersky, Michael Randall, Laura Donovan, Sorana Morrissy, Robyn T. Sussman, Doncho V. Zhelev, Yang Feng, Yanping Wang, Jennifer Hwang, Gonzalo Lopez, Jo Lynne Harenza, Jun S. Wei, Bruce Pawel, Tricia Bhatti, Mariarita Santi, Arupa Ganguly, Javed Khan, Marco A. Marra, Michael D. Taylor, Dimiter S. Dimitrov, Crystal L. Mackall, John M. Maris
We developed an RNA-sequencing-based pipeline to discover differentially expressed cell-surface molecules in neuroblastoma that meet criteria for optimal immunotherapeutic target safety and efficacy. Here, we show that GPC2 is a strong candidate immunotherapeutic target in this childhood cancer. We demonstrate high GPC2 expression in neuroblastoma due to MYCN transcriptional activation and/or somatic gain of the GPC2 locus. We confirm GPC2 to be highly expressed on most neuroblastomas, but not detectable at appreciable levels in normal childhood tissues. In addition, we demonstrate that GPC2 is required for neuroblastoma proliferation. Finally, we develop a GPC2-directed antibody-drug conjugate that is potently cytotoxic to GPC2-expressing neuroblastoma cells. Collectively, these findings validate GPC2 as a non-mutated neuroblastoma oncoprotein and candidate immunotherapeutic target.

Graphical abstract

Teaser

Bosse et al. show that GPC2 is expressed at high levels on most neuroblastomas (NB) but not at appreciable levels in normal childhood tissues and that GPC2 is critical for NB maintenance. They develop a GPC2-directed antibody-drug conjugate that is cytotoxic to GPC2-expressing NB cells in vitro and in vivo.


http://ift.tt/2jmzaF5

A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development

Publication date: 11 September 2017
Source:Cancer Cell, Volume 32, Issue 3
Author(s): Yannick Boege, Mohsen Malehmir, Marc E. Healy, Kira Bettermann, Anna Lorentzen, Mihael Vucur, Akshay K. Ahuja, Friederike Böhm, Joachim C. Mertens, Yutaka Shimizu, Lukas Frick, Caroline Remouchamps, Karun Mutreja, Thilo Kähne, Devakumar Sundaravinayagam, Monika J. Wolf, Hubert Rehrauer, Christiane Koppe, Tobias Speicher, Susagna Padrissa-Altés, Renaud Maire, Jörn M. Schattenberg, Ju-Seong Jeong, Lei Liu, Stefan Zwirner, Regina Boger, Norbert Hüser, Roger J. Davis, Beat Müllhaupt, Holger Moch, Henning Schulze-Bergkamen, Pierre-Alain Clavien, Sabine Werner, Lubor Borsig, Sanjiv A. Luther, Philipp J. Jost, Ricardo Weinlich, Kristian Unger, Axel Behrens, Laura Hillert, Christopher Dillon, Michela Di Virgilio, David Wallach, Emmanuel Dejardin, Lars Zender, Michael Naumann, Henning Walczak, Douglas R. Green, Massimo Lopes, Inna Lavrik, Tom Luedde, Mathias Heikenwalder, Achim Weber
Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apoptotic function of caspase-8, but no caspase-3 or caspase-8 cleavage. It may represent a DNA damage-sensing mechanism in hepatocytes that can act via JNK and subsequent phosphorylation of the histone variant H2AX.

Teaser

Boege et al. identify persistent hepatocyte apoptosis as a determinant of hepatocellular carcinoma development. They show that caspase-8 not only executes hepatocyte apoptosis but also has a non-apoptotic role in proliferation-associated DNA damage response mediated by a caspase-8/RIPK1/FADD/c-FLIP complex.


http://ift.tt/2jmyU95

Chronic Cigarette Smoke-Induced Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single-Step Transformation by KRAS Mutations

Publication date: 11 September 2017
Source:Cancer Cell, Volume 32, Issue 3
Author(s): Michelle Vaz, Stephen Y. Hwang, Ioannis Kagiampakis, Jillian Phallen, Ashwini Patil, Heather M. O'Hagan, Lauren Murphy, Cynthia A. Zahnow, Edward Gabrielson, Victor E. Velculescu, Hariharan P. Easwaran, Stephen B. Baylin
We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells for transformation by a single oncogene. The smoke-induced chromatin changes include initial repressive polycomb marking of genes, later manifesting abnormal DNA methylation by 10 months. At this time, cells exhibit epithelial-to-mesenchymal changes, anchorage-independent growth, and upregulated RAS/MAPK signaling with silencing of hypermethylated genes, which normally inhibit these pathways and are associated with smoking-related non-small cell lung cancer. These cells, in the absence of any driver gene mutations, now transform by introducing a single KRAS mutation and form adenosquamous lung carcinomas in mice. Thus, epigenetic abnormalities may prime for changing oncogene senescence to addiction for a single key oncogene involved in lung cancer initiation.

Graphical abstract

Teaser

Vaz et al. show that long-term exposure of untransformed human bronchial epithelial cells to cigarette smoke condensate induces epigenetic changes, consistent with those commonly seen in smoking-related non-small cell lung cancer, that sensitize the cells to transformation with a single KRAS mutation.


http://ift.tt/2xXASzh

Enhancing CD8+ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy

Publication date: 11 September 2017
Source:Cancer Cell, Volume 32, Issue 3
Author(s): Ying Zhang, Raj Kurupati, Ling Liu, Xiang Yang Zhou, Gao Zhang, Abeer Hudaihed, Flavia Filisio, Wynetta Giles-Davis, Xiaowei Xu, Giorgos C. Karakousis, Lynn M. Schuchter, Wei Xu, Ravi Amaravadi, Min Xiao, Norah Sadek, Clemens Krepler, Meenhard Herlyn, Gordon J. Freeman, Joshua D. Rabinowitz, Hildegund C.J. Ertl
How tumor-infiltrating T lymphocytes (TILs) adapt to the metabolic constrains within the tumor microenvironment (TME) and to what degree this affects their ability to combat tumor progression remain poorly understood. Using mouse melanoma models, we report that CD8⁺ TILs enhance peroxisome proliferator-activated receptor (PPAR)-α signaling and catabolism of fatty acids (FAs) when simultaneously subjected to hypoglycemia and hypoxia. This metabolic switch partially preserves CD8⁺ TILs' effector functions, although co-inhibitor expression increases during tumor progression regardless of CD8⁺ TILs' antigen specificity. Further promoting FA catabolism improves the CD8⁺ TILs' ability to slow tumor progression. PD-1 blockade delays tumor growth without changing TIL metabolism or functions. It synergizes with metabolic reprogramming of T cells to achieve superior antitumor efficacy and even complete cures.

Graphical abstract

Teaser

Zhang et al. show that CD8⁺ T cells enhance PPAR-α signaling and fatty acid catabolism under the hypoglycemic and hypoxic condition to partially preserve effector functions. Metabolic reprogramming of T cells using a PPAR-α agonist improves tumor growth control, which is enhanced in combination with PD-1 blockade.


http://ift.tt/2xXP0sa

MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer

Publication date: 11 September 2017
Source:Cancer Cell, Volume 32, Issue 3
Author(s): Surendra K. Shukla, Vinee Purohit, Kamiya Mehla, Venugopal Gunda, Nina V. Chaika, Enza Vernucci, Ryan J. King, Jaime Abrego, Gennifer D. Goode, Aneesha Dasgupta, Alysha L. Illies, Teklab Gebregiworgis, Bingbing Dai, Jithesh J. Augustine, Divya Murthy, Kuldeep S. Attri, Oksana Mashadova, Paul M. Grandgenett, Robert Powers, Quan P. Ly, Audrey J. Lazenby, Jean L. Grem, Fang Yu, José M. Matés, John M. Asara, Jung-whan Kim, Jordan H. Hankins, Colin Weekes, Michael A. Hollingsworth, Natalie J. Serkova, Aaron R. Sasson, Jason B. Fleming, Jennifer M. Oliveto, Costas A. Lyssiotis, Lewis C. Cantley, Lyudmyla Berim, Pankaj K. Singh




http://ift.tt/2jlZqiY

Redefining Hormonal Therapy for Advanced Prostate Cancer: Results from the LATITUDE and STAMPEDE Studies

Publication date: 11 September 2017
Source:Cancer Cell, Volume 32, Issue 3
Author(s): Eric J. Small




http://ift.tt/2xXOSsG

A phase I open-label dose-escalation study of the anti-HER3 monoclonal antibody LJM716 in patients with advanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer

Abstract

Background

Human epidermal growth factor receptor 3 (HER3) is important in maintaining epidermal growth factor receptor-driven cancers and mediating resistance to targeted therapy. A phase I study of anti-HER3 monoclonal antibody LJM716 was conducted with the primary objective to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), and dosing schedule. Secondary objectives were to characterize safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.

Methods

This open-label, dose-finding study comprised dose escalation, followed by expansion in patients with squamous cell carcinoma of the head and neck or esophagus, and HER2-overexpressing metastatic breast cancer or gastric cancer. During dose escalation, patients received LJM716 intravenous once weekly (QW) or every two weeks (Q2W), in 28-day cycles. An adaptive Bayesian logistic regression model was used to guide dose escalation and establish the RDE. Exploratory pharmacodynamic tumor studies evaluated modulation of HER3 signaling.

Results

Patients received LJM716 3–40 mg/kg QW and 20 mg/kg Q2W (54 patients; 36 patients at 40 mg/kg QW). No dose-limiting toxicities (DLTs) were reported during dose-escalation. One patient experienced two DLTs (diarrhea, hypokalemia [both grade 3]) in the expansion phase. The RDE was 40 mg/kg QW, providing drug levels above the preclinical minimum effective concentration. One patient with gastric cancer had an unconfirmed partial response; 17/54 patients had stable disease, two lasting >30 weeks. Down-modulation of phospho-HER3 was observed in paired tumor samples.

Conclusions

LJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing.

Trial registration

Clinicaltrials.gov registry number NCT01598077 (registered on 4 May, 2012).

http://ift.tt/2f4epg9

Radiomic features predict Ki-67 expression level and survival in lower grade gliomas

Abstract

To investigate the radiomic features associated with Ki-67 expression in lower grade gliomas and assess the prognostic values of these features. Patients with lower grade gliomas (n = 117) were randomly assigned into the training (n = 78) and validation (n = 39) sets. A total of 431 radiological features were extracted from each patient. Differential radiological features between the low and high Ki-67 expression groups were screened by significance analysis of microarrays. Then, generalized linear analysis was performed to select features that could predict the Ki-67 expression level. Predictive efficiencies were further evaluated in the validation set. Cox regression analysis was performed to investigate the prognostic values of Ki-67 expression level and Ki-67-related radiological features. A group of nine radiological features were screened for prediction of Ki-67 expression status; these achieved accuracies of 83.3% and 88.6% (areas under the curves, 0.91 and 0.93) in the training and validation sets, respectively. Of these features, only spherical disproportion (SD) was found to be a prognostic factor. Patients in the high SD group exhibited worse outcomes in the whole cohort (overall survival, p < 0.0001; progression-free survival, p < 0.0001). Ki-67 expression level and SD were independent prognostic factors in the multivariate Cox regression analysis. This study identified a radiomic signature for prediction of Ki-67 expression level as well as a prognostic radiological feature in patients with lower grade gliomas.

http://ift.tt/2w4OaO5

Methodological Aspects in Studies Based on Clinical Routine Data

Abstract

Abstract

Randomized controlled clinical trials are regarded as the gold standard for comparing different clinical interventions, but generally their conduct is operationally cumbersome, time-consuming, and expensive. Studies and investigations based on clinical routine data on the contrary utilize existing data acquired under real-life conditions and are increasingly popular among practitioners. In this paper, methodological aspects of studies based on clinical routine data are discussed. Important limitations and considerations as well as unique strengths of these types of studies are indicated and exemplarily demonstrated in a recent real-case study based on clinical routine data. In addition two simulation studies reveal the impact of bias in studies based on clinical routine data on the type I error rate and false decision rate in favor of the inferior intervention. It is concluded that correctly analyzing clinical routine data yields a valuable addition to clinical research; however, as a result of a lack of statistical foundation, internal validity, and comparability, generalizing results and inferring properties derived from clinical routine data to all patients of interest has to be considered with extreme caution.

Funding

Grünenthal GmbH.

http://ift.tt/2xv72pV

Healthcare utilization, Medicare spending, and sources of patient distress identified during implementation of a lay navigation program for older patients with breast cancer

Abstract

Purpose

Despite benefits for patients, sustainability of breast cancer navigation programs is challenging due to the lack of reimbursement for navigators. This analysis describes distress reported by breast cancer patients to navigators and the impact of navigation on healthcare utilization for older adults with breast cancer.

Methods

We conducted a retrospective cohort study of Medicare administrative claims data and patient-reported distress assessments. The primary outcome was Medicare spending per beneficiary per quarter. Secondary outcomes included (1) the number of hospitalizations or ER visits in each quarter; (2) distress levels; and (3) causes of distress reported by patients to their navigators. A subset analysis was conducted for stage I/II/III versus stage IV patients.

Results

776 navigated and 776 control patients were included in the analysis. The average age at diagnosis was 74 years; 13% of the subjects were African American; 95% of patients had stage I–III. Medicare spending declined faster for the navigated group than the matched comparison group by $528 per quarter per patient (95% CL −$667, −$388). Stage I/II/III navigated patients showed a statistically significant decline in Medicare spending, ER visits, and hospitalizations over time compared to the matched comparison group. No differences were observed for stage IV patients. Eighteen percent of patients reported moderate distress. Informational and physical distress were more common in late stage than in early-stage breast cancer.

Conclusions

Lay navigation reduced healthcare utilization in older adults with breast cancer, with the greatest impact observed in early-stage breast cancer patients.

http://ift.tt/2vSyDNe

The safety and efficacy of transarterial chemoembolization combined with sorafenib and sorafenib mono-therapy in patients with BCLC stage B/C hepatocellular carcinoma

Abstract

Background

Sorafenib and transarterial chemoembolization (TACE) are recommended therapies for advanced hepatocellular carcinoma (HCC), but their combined efficacy remains unclear.

Methods

Between August 2004 and November 2014, 104 patients with BCLC stage B/C HCC were enrolled at the Affiliated Tumor Hospital of Guangxi Medical University, China. Forty-eight patients were treated with sorafenib alone (sorafenib group) and 56 with TACE plus sorafenib (TACE + sorafenib group). Baseline demographic/clinical data were collected. The primary outcomes were median overall survival (OS) and progression-free survival (PFS). Secondary outcomes were overall response rate (ORR) and sorafenib-related adverse events (AEs). Baseline characteristics associated with disease prognosis were identified using multivariate Cox hazards regression.

Results

The mean age of the 104 patients (94 males; 90.38%) was 49.02 ± 12.29 years. Of the baseline data, only albumin level (P = 0.028) and Child-Pugh class (P = 0.017) differed significantly between groups. Median OS did not differ significantly between the sorafenib and TACE + sorafenib groups (18.0 vs. 22.0 months, P = 0.223). Median PFS was significantly shorter in the sorafenib group than that in the TACE + sorafenib group (6.0 vs. 8.0 months, P = 0.004). Six months after treatments, the ORRs were similar between the sorafenib and TACE + sorafenib groups (12.50% vs. 18.75%, P = 0.425). The rates of grade III–IV adverse events in sorafenib and TACE + sorafenib groups were 29.2% vs. 23.2%, respectively. TACE plus sorafenib treatment (HR = 0.498, 95% CI = 0.278–0.892), no vascular invasion (HR = 0.354, 95% CI = 0.183–0.685) and Child-Pugh class A (HR = 0.308, 95% CI = 0.141–0.674) were significantly associated with better OS, while a larger tumor number was predictive of poorer OS (HR = 1.286, 95% CI = 1.031–1.604). TACE plus sorafenib treatment (HR = 0.461, 95% CI = 0.273–0.780) and no vascular invasion (HR = 0.557, 95% CI = 0.314–0.988) were significantly associated with better PFS.

Conclusions

Compared with sorafenib alone, combining TACE with sorafenib might prolong survival and delay disease progression in patients with advanced HCC.

http://ift.tt/2y32kMU

Peroxynitrite induces apoptosis of mouse cochlear hair cells via a Caspase-independent pathway in vitro

Abstract

Peroxynitrite (ONOO⁻) is a potent and versatile oxidant implicated in a number of pathophysiological processes. The present study was designed to investigate the effect of ONOO⁻ on the cultured cochlear hair cells (HCs) of C57BL/6 mice in vitro as well as the possible mechanism underlying the action of such an oxidative stress. The in vitro primary cultured cochlear HCs were subjected to different concentrations of ONOO⁻, then, the cell survival and morphological changes were examined by immunofluorescence and transmission electron microscopy (TEM), the apoptosis was determined by Terminal deoxynucleotidyl transferase dUNT nick end labeling (TUNEL) assay, the mRNA expressions of Caspase-3, Caspase-8, Caspase-9, Apaf1, Bcl-2, and Bax were analyzed by RT-PCR, and the protein expressions of Caspase-3 and AIF were assessed by immunofluorescence. This work demonstrated that direct exposure of primary cultured cochlear HCs to ONOO⁻ could result in a base-to-apex gradient injury of HCs in a concentration-dependent manner. Furthermore, ONOO⁻ led to much more losses of outer hair cells than inner hair cells mainly through the induction of apoptosis of HCs as evidenced by TEM and TUNEL assays. The mRNA expressions of Caspase-8, Caspase-9, Apaf1, and Bax were increased and, meanwhile, the mRNA expression of Bcl-2 was decreased in response to ONOO⁻ treatment. Of interesting, the expression of Caspase-3 had no significant change, whereas, the expression alteration of AIF was observed. These results suggested that ONOO⁻ can effectively damage the survival of cochlear HCs via triggering the apoptotic pathway. The findings from this work suggest that ONOO⁻-induced apoptosis is mediated, at least in part, via a Caspase-independent pathway in cochlear HCs.

http://ift.tt/2y2tyn2

A frameshift mutation in BRCA1 leads to hereditary breast and ovarian cancer in one part of a family and to familial pancreatic cancer in another

http://ift.tt/2xiAaQ4

Outcome of childhood leukaemia survivors and necrosis of the femoral head treated with autologous mesenchymal stem cells

Abstract

Purpose

Corticoid-induced osteonecrosis (ON) of femoral head can lead to severe hip joint impairment and hip replacement, with negative impact in young survivors of acute lymphoblastic leukaemia (ALL) with long life expectancy. We aim to improve quality of life in these patients with a novel approach.

Methods/patients

Based on the regenerative capacities of mesenchymal stem cells (MSCs), we performed locally implanted autologous cell therapy in two adolescents suffering of bilateral femoral ON. This required a simple, minimally invasive surgical procedure.

Results

Both patients experienced significant pain relief and restoration of gait kinematic values. Radiographic evaluation showed cessation of hip collapse. No toxicities/complications were observed after a 4-year follow-up.

Conclusions

Our preliminary results suggest that autologous MSCs can be considered as a novel treatment for children and young adults with ON after overcoming ALL. It may avoid hip replacement and improve quality of life of leukaemia survivors.

http://ift.tt/2xhHk7p

Diagnostic accuracy of serum antibodies to human papillomavirus type 16 early antigens in the detection of human papillomavirus–related oropharyngeal cancer

BACKGROUND

Because of the current epidemic of human papillomavirus (HPV)–related oropharyngeal cancer (OPC), a screening strategy is urgently needed. The presence of serum antibodies to HPV-16 early (E) antigens is associated with an increased risk for OPC. The purpose of this study was to evaluate the diagnostic accuracy of antibodies to a panel of HPV-16 E antigens in screening for OPC.

METHODS

This case-control study included 378 patients with OPC, 153 patients with nonoropharyngeal head and neck cancer (non-OPC), and 782 healthy control subjects. The tumor HPV status was determined with p16 immunohistochemistry and HPV in situ hybridization. HPV-16 E antibody levels in serum were identified with an enzyme-linked immunosorbent assay. A trained binary logistic regression model based on the combination of all E antigens was predefined and applied to the data set. The sensitivity and specificity of the assay for distinguishing HPV-related OPC from controls were calculated. Logistic regression analysis was used to calculate odds ratios with 95% confidence intervals for the association of head and neck cancer with the antibody status.

RESULTS

Of the 378 patients with OPC, 348 had p16-positive OPC. HPV-16 E antibody levels were significantly higher among patients with p16-positive OPC but not among patients with non-OPC or among controls. Serology showed high sensitivity and specificity for HPV-related OPC (binary classifier: 83% sensitivity and 99% specificity for p16-positive OPC).

CONCLUSIONS

A trained binary classification algorithm that incorporates information about multiple E antibodies has high sensitivity and specificity and may be advantageous for risk stratification in future screening trials. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2h1L4Qw

Cancers, Vol. 9, Pages 122: EMT and Treatment Resistance in Pancreatic Cancer

Cancers, Vol. 9, Pages 122: EMT and Treatment Resistance in Pancreatic Cancer

Cancers doi: 10.3390/cancers9090122

Authors: Nicola Gaianigo Davide Melisi Carmine Carbone

Pancreatic cancer (PC) is the third leading cause of adult cancer mortality in the United States. The poor prognosis for patients with PC is mainly due to its aggressive course, the limited efficacy of active systemic treatments, and a metastatic behavior, demonstrated throughout the evolution of the disease. On average, 80% of patients with PC are diagnosed with metastatic disease, and the half of those who undergo surgery and adjuvant therapy develop liver metastasis within two years. Metastatic dissemination is an early event in PC and is mainly attributed to an evolutionary biological process called epithelial-to-mesenchymal transition (EMT). This innate mechanism could have a dual role during embryonic growth and organ differentiation, and in cancer progression, cancer stem cell intravasation, and metastasis settlement. Many of the molecular pathways decisive in EMT progression have been already unraveled, but little is known about the causes behind the induction of this mechanism. EMT is one of the most distinctive and critical features of PC, occurring even in the very first stages of tumor development. This is known as pancreatic intraepithelial neoplasia (PanIN) and leads to early dissemination, drug resistance, and unfavorable prognosis and survival. The intention of this review is to shed new light on the critical role assumed by EMT during PC progression, with a particular focus on its role in PC resistance.

http://ift.tt/2xuuV0y

Clinical, radiological, pathological and prognostic aspects of intraventricular oligodendroglioma: comparison with central neurocytoma

Abstract

Studies comparing intraventricular oligodendroglioma (IVO) and central neurocytoma (CN) in terms of their clinical, radiological and pathological features are scarce. We, therefore, investigated the similarities and differences between these types of tumors to get a better understanding of how they may be more properly diagnosed and treated. The clinical manifestations, CT/MRI findings, pathological characteristics and clinical outcomes of 8 cases of IVOs and 12 cases of CNs were analyzed retrospectively. Both IVO and CN occurred most commonly in young adults and manifested with symptoms of increased intracranial pressure secondary to obstructive hydrocephalus. However, they were radiologically different in location (p = 0.007), diffusion-weighted imaging (p = 0.001), "scalloping" appearance (p = 0.006), flow void sign (p = 0.006) and ventricular wall invasion (p = 0.000). Histologically, significant differences in mitotic count (p = 0.008) and parenchymal infiltration (p = 0.01) were noted. Immunohistochemically, significant differences in the expression of Olig2 (p = 0.000), Syn (p = 0.01) and NeuN (p = 0.000) were observed. In addition, MIB-1 labeling index (p = 0.035) and case fatality rate (p = 0.021) of IVO were much higher than those of CN, while survival rate of IVO was much lower than that of CN (p = 0.028). IVO and CN are similar in onset age and clinical manifestations, but have different imaging and pathological features. Patients with IVOs may have a relatively poorer prognosis compared to those with CNs.

http://ift.tt/2wXRsQx

Outcome of childhood leukaemia survivors and necrosis of the femoral head treated with autologous mesenchymal stem cells

Abstract

Purpose

Corticoid-induced osteonecrosis (ON) of femoral head can lead to severe hip joint impairment and hip replacement, with negative impact in young survivors of acute lymphoblastic leukaemia (ALL) with long life expectancy. We aim to improve quality of life in these patients with a novel approach.

Methods/patients

Based on the regenerative capacities of mesenchymal stem cells (MSCs), we performed locally implanted autologous cell therapy in two adolescents suffering of bilateral femoral ON. This required a simple, minimally invasive surgical procedure.

Results

Both patients experienced significant pain relief and restoration of gait kinematic values. Radiographic evaluation showed cessation of hip collapse. No toxicities/complications were observed after a 4-year follow-up.

Conclusions

Our preliminary results suggest that autologous MSCs can be considered as a novel treatment for children and young adults with ON after overcoming ALL. It may avoid hip replacement and improve quality of life of leukaemia survivors.

http://ift.tt/2xhHk7p

The pattern of secondary cancers in patients with Kaposi sarcoma in the United States

Abstract

Purpose

In the U.S., Kaposi sarcoma (KS) occurs mostly in HIV-infected patients, who are also at increased risk of developing secondary cancers. The trends in secondary cancer risk are unclear in the HAART era.

Methods

We extracted data from the SEER database on patients diagnosed with KS between 1981 and 2013, stratified into the pre-HAART (1981–1995) and HAART (1996–2013) eras. We compared the risk of secondary cancer in KS patients and the general population, and estimated the absolute risk.

Results

We followed 13,535 KS patients for 49,813 person-years, during which 1,041 secondary cancers were diagnosed: 774 in the pre-HAART and 267 in the HAART era. In the pre-HAART era, non-Hodgkin's lymphoma (NHL) and anal carcinomas were the most common secondary cancers. The standard incidence ratio of secondary cancers decreased from 3.44 (pre-HAART era) to 1.94 (HAART era) in patients aged <70 years. The absolute excess risk decreased from 178 to 68 cases per 10,000 person-years. The risk of NHL decreased, while the risk of anal carcinoma did not change significantly. The risk of lung cancer was lower in KS patients than in the general population. The absolute risk of non-AIDS-defining cancers increased fourfold in the HAART era.

Conclusions

The absolute risk of non-AIDS-defining secondary cancers has increased in KS patients in the HAART era. However, the overall relative risk of secondary cancers has decreased, mainly due to a significant decrease in the risk of NHL.

http://ift.tt/2jke5v7

Serum 25-hydroxyvitamin D concentrations and lung cancer risk in never-smoking postmenopausal women

Abstract

Purpose

Vitamin D has been implicated in lowering lung cancer risk, but serological data on the association among never-smoking women are limited. We report results examining the association of serum 25-hydroxyvitamin D [25(OH)D] concentrations with lung cancer risk among female never smokers. We also examined whether the association was modified by vitamin D supplementation and serum vitamin A concentrations.

Methods

In the Women's Health Initiative, including the calcium/vitamin D (CaD) Trial, we selected 298 incident cases [191 non-small cell lung cancer (NSCLC) including 170 adenocarcinoma] and 298 matched controls of never smokers. Baseline serum 25(OH)D was assayed by a chemiluminescent method. Logistic regression was used to estimate odds ratios (ORs) for quartiles and predefined clinical cutoffs of serum 25(OH)D concentrations.

Results

Comparing quartiles 4 versus 1 of serum 25(OH)D concentrations, ORs were 1.06 [95% confidence interval (CI) 0.61–1.84] for all lung cancer, 0.94 (95% CI 0.52–1.69) for NSCLC, and 0.91 (95% CI 0.49–1.68) for adenocarcinoma. Comparing serum 25(OH)D ≥ 75 (high) versus <30 nmol/L (deficient), ORs were 0.76 (95% CI 0.31–1.84) for all lung cancer, 0.71 (95% CI 0.27–1.86) for NSCLC, and 0.81 (95% CI 0.31–2.14) for adenocarcinoma. There is suggestive evidence that CaD supplementation (1 g calcium + 400 IU D₃/day) and a high level of circulating vitamin A may modify the associations of 25(OH)D with lung cancer overall and subtypes (p interaction <0.10).

Conclusions

In this group of never-smoking postmenopausal women, the results did not support the hypothesis of an association between serum 25(OH)D and lung cancer risk.

http://ift.tt/2xhYK3p

Residential magnetic fields exposure and childhood leukemia: a population-based case–control study in California

Abstract

Purpose

Studies have reported an increased risk of childhood leukemia associated with exposure to magnetic fields. We conducted a large records-based case–control study of childhood leukemia risk and exposure to magnetic fields from power lines in California.

Methods

The study included 5,788 childhood leukemia cases (born in and diagnosed in California 1986–2008) matched to population-based controls on age and sex. We calculated magnetic fields at birth addresses using geographic information systems, aerial imagery, historical information on load and phasing, and site visits.

Results

Based on unconditional logistic regression controlling for age, sex, race/ethnicity, and socioeconomic status using subjects geocoded to a basic standard of accuracy, we report a slight risk deficit in two intermediate exposure groups and a small excess risk in the highest exposure group (odds ratio of 1.50 (95% confidence interval [0.70, 3.23])). Subgroup and sensitivity analyses as well as matched analyses gave similar results. All estimates had wide confidence intervals.

Conclusion

Our large, statewide, record-based case–control study of childhood leukemia in California does not in itself provide clear evidence of risk associated with greater exposure to magnetic fields from power lines, but could be viewed as consistent with previous findings of increased risk.

http://ift.tt/2feA5TB

An exploration of genotype-phenotype link between Peutz-Jeghers syndrome and STK11: a review

Abstract

Peutz-Jeghers Syndrome (PJS) is an autosomal dominant hereditary polyposis syndrome. Clinical features include hamartomatous polyps, mucocutaneous pigmentation and an increased predisposition towards developing malignancy. Variants in STK11, a tumour suppressor gene, located on Chromosome 19, predispose to PJS. Peutz-Jeghers Syndrome is associated with increased rates of malignancy, particularly gastrointestinal. However, PJS is also associated with increased gynaecological, testicular and thyroid papillary malignancy. Truncating variants in STK11 are thought to predispose to a more severe phenotype. Phenotype severity is based on earlier onset of gastrointestinal pathology arising from the polyps, such as intussusception or earlier onset malignancy. Missense variants are generally considered less severe than truncating variants. There remain a large number of variants of undetermined significance. Studies have attempted to correlate the location of variants with impact on protein structure and overall severity of the PJS phenotype. The results from these cohort studies have consistently found a non-random distribution of variants. Nevertheless, a consensus on phenotype severity based on variant location is yet to be established. A centralised database that collates all known variants would facilitate the interpretation of these variants, best under the governance of an international disease-specific organisation (InSiGHT). In particular, it could help explore the significance of variants based on their type or location. Understanding the genotype-phenotype link between STK11 variants and PJS could allow more personalised care for PJS patients and their families via appropriate risk stratification and personalised and targeted cancer screening.

http://ift.tt/2feT7cz