Effect of retirement on cognitive function: the Whitehall II cohort study

Abstract

According to the 'use it or lose it' hypothesis, a lack of mentally challenging activities might exacerbate the loss of cognitive function. On this basis, retirement has been suggested to increase the risk of cognitive decline, but evidence from studies with long follow-up is lacking. We tested this hypothesis in a cohort of 3433 civil servants who participated in the Whitehall II Study, including repeated measurements of cognitive functioning up to 14 years before and 14 years after retirement. Piecewise models, centred at the year of retirement, were used to compare trajectories of verbal memory, abstract reasoning, phonemic verbal fluency, and semantic verbal fluency before and after retirement. We found that all domains of cognition declined over time. Declines in verbal memory were 38% faster after retirement compared to before, after taking account of age-related decline. In analyses stratified by employment grade, higher employment grade was protective against verbal memory decline while people were still working, but this 'protective effect' was lost when individuals retired, resulting in a similar rate of decline post-retirement across employment grades. We did not find a significant impact of retirement on the other cognitive domains. In conclusion, these findings are consistent with the hypothesis that retirement accelerates the decline in verbal memory function. This study points to the benefits of cognitively stimulating activities associated with employment that could benefit older people's memory.

from Cancer via ola Kala on Inoreader http://ift.tt/2BC5SY0
via IFTTT

Induction of autophagy and autophagy-dependent apoptosis in diffuse large B-cell lymphoma by a new antimalarial artemisinin derivative, SM1044

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma. R-CHOP is currently the standard therapy for DLBCL, but the prognosis of refractory or recurrent patients remains poor. In this study, we synthesized a new water-soluble antimalarial drug artemisinin derivative, SM1044. The treatment of DLBCL cell lines with SM1044 induces autophagy-dependent apoptosis, which is directed by an accelerated degradation of the antiapoptosis protein Survivin, via its acetylation-dependent interaction with the autophagy-related protein LC3-II. Additionally, SM1044 also stimulates the de novo synthesis of ceramide, which in turn activates the CaMKK2–AMPK–ULK1 axis, leading to the initiation of autophagy. Our findings not only elucidate the mechanism of autophagy-dependent apoptosis in DLBCL cells, but also suggest that SM1044 is a promising therapeutic molecule for the treatment of DLBCL, along with R-CHOP regimen.

Our research reported an artemisinin derivative, SM1044, induces autophagy-dependent apoptosis which is triggered by an increased acetylation of Survivin, a modification which induces its interaction with LC3-II and its degradation. We also unraveled that the activation of CaMKK2–AMPK–ULK1 axis was molecular basis of SM1044-dependent stimulation of autophagy. These investigations not only point to SM1044 as a promising molecule in fighting diffuse large B-cell lymphoma (DLBCL), but also unravel important information of the molecular pathways involved in the oncogenesis of DLBCL.

http://ift.tt/2C9AFPc

Effects of Th17 cells and IL-17 in the progression of cervical carcinogenesis with high-risk human papillomavirus infection

Abstract

The existence of Th17 cells and IL-17 was recently shown in several types of infectious diseases, but their distribution and functions in cervical lesions with high-risk human papillomavirus (HPV) infection have not been fully elucidated. In this study, the frequency of Th17 cells in peripheral blood samples obtained from 28 cervical squamous cell carcinoma patients, 26 CIN1 patients, 30 CIN2 patients, 29 CIN3 patients, 25 high-risk HPV-infected women with normal cervical cytology, and 30 healthy controls was determined by flow cytometry. Besides, the levels of IL-17 in peripheral blood samples as well as in supernatant of cervical tissue homogenate were assessed by enzyme-linked immunosorbent assay (ELISA) simultaneously. We found that during the disease progression of cervical lesions, the proportion of Th17 cells in the total CD4⁺ cells showed a gradually increased tendency compared with the controls (P < 0.05). Moreover, levels of IL-17 in serum and supernatant of cervical tissue homogenate showed the same tendency as the proportion of Th17 cells (P < 0.05). When compared in pairs, the levels of IL-17 in supernatant differed significantly among the study groups and the control group (P < 0.05), but no significant difference was observed in serum (P > 0.05). In conclusions, the results indicate that Th17 cells and IL-17 may play a role of immune enhancement in the infection of high-risk HPV especially in the cervical microenvironment, which contribute to the disease progression of its associated cervical lesions.

In this work, we evaluated the frequency of Th17 cells in peripheral blood samples obtained from cervical squamous cell carcinoma patients, CIN1 patients, CIN2 patients, CIN3 patients, high-risk HPV-infected women with normal cervical cytology, and healthy controls,as well as the levels of IL-17 in peripheral blood samples and in supernatant of cervical tissue homogenate. So we had come to the conclusion that Th17 cells and IL-17 may play a role of immune enhancement in the infection of high-risk HPV, which contribute to the disease progression of its associated cervical lesions.

http://ift.tt/2BEjFxb

Personality and breast cancer screening in women of the GAZEL cohort study

Abstract

The potential benefit of breast cancer screening is mitigated by the risk of false positives and overdiagnosis, thus advocating for a more personalized approach, based on the individual benefit-harm balance. Since personality might influence the women's appraisal of this balance, this prospective observational cohort study examined whether it could influence mammography use. A total of 2691 postmenopausal women of the GAZEL Cohort Study completed the Bortner Type A Rating Scale and the Buss and Durkee Hostility Inventory in 1993. Associations between personality scores and subsequent mammography use, self-reported through up to five triennial follow-up questionnaires, were estimated with Odds Ratio (OR) and 95% confidence interval (CI) with logistic mixed model regressions, adjusting for age, occupational grade, marital status, family history of breast cancer, age at menarche, age at first delivery, gynecological follow-up, hormone therapy use, and depressive symptoms. Individual propensity scores were used to weight the analyses to control for potential selection biases. More than 90% of the participants completed at least two follow-up questionnaires. Type A personality, but not hostility, was associated with mammography use in both univariate (crude OR [95% CI]: 1.62 [1.24–2.11], P < 0.001) and multivariate analyses (OR [95% CI]: 1.46 [1.13–1.90], P < 0.01). Type A personality traits (i.e., sense of time urgency, high job involvement, competitiveness) independently predicted mammography use among postmenopausal women. While paying more attention to the adherence of women with low levels of these traits, clinicians may help those with higher levels to better consider the risks of false positives and overdiagnosis.

Type A personality traits (i.e., sense of time urgency, high job involvement, competitiveness) independently predicted mammography use among 2691 postmenopausal women of the GAZEL Cohort Study (adjusted Odds Ratio [95% confidence interval]: 1.46: [1.13–1.90], P < 0.01). While paying more attention to the adherence of women with low levels of these traits, clinicians may help those with higher levels to better consider the risks of false positives and overdiagnosis.

http://ift.tt/2C9AW4U

Induction of autophagy and autophagy-dependent apoptosis in diffuse large B-cell lymphoma by a new antimalarial artemisinin derivative, SM1044

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma. R-CHOP is currently the standard therapy for DLBCL, but the prognosis of refractory or recurrent patients remains poor. In this study, we synthesized a new water-soluble antimalarial drug artemisinin derivative, SM1044. The treatment of DLBCL cell lines with SM1044 induces autophagy-dependent apoptosis, which is directed by an accelerated degradation of the antiapoptosis protein Survivin, via its acetylation-dependent interaction with the autophagy-related protein LC3-II. Additionally, SM1044 also stimulates the de novo synthesis of ceramide, which in turn activates the CaMKK2–AMPK–ULK1 axis, leading to the initiation of autophagy. Our findings not only elucidate the mechanism of autophagy-dependent apoptosis in DLBCL cells, but also suggest that SM1044 is a promising therapeutic molecule for the treatment of DLBCL, along with R-CHOP regimen.

Our research reported an artemisinin derivative, SM1044, induces autophagy-dependent apoptosis which is triggered by an increased acetylation of Survivin, a modification which induces its interaction with LC3-II and its degradation. We also unraveled that the activation of CaMKK2–AMPK–ULK1 axis was molecular basis of SM1044-dependent stimulation of autophagy. These investigations not only point to SM1044 as a promising molecule in fighting diffuse large B-cell lymphoma (DLBCL), but also unravel important information of the molecular pathways involved in the oncogenesis of DLBCL.

from Cancer via ola Kala on Inoreader http://ift.tt/2C9AFPc
via IFTTT

Effects of Th17 cells and IL-17 in the progression of cervical carcinogenesis with high-risk human papillomavirus infection

Abstract

The existence of Th17 cells and IL-17 was recently shown in several types of infectious diseases, but their distribution and functions in cervical lesions with high-risk human papillomavirus (HPV) infection have not been fully elucidated. In this study, the frequency of Th17 cells in peripheral blood samples obtained from 28 cervical squamous cell carcinoma patients, 26 CIN1 patients, 30 CIN2 patients, 29 CIN3 patients, 25 high-risk HPV-infected women with normal cervical cytology, and 30 healthy controls was determined by flow cytometry. Besides, the levels of IL-17 in peripheral blood samples as well as in supernatant of cervical tissue homogenate were assessed by enzyme-linked immunosorbent assay (ELISA) simultaneously. We found that during the disease progression of cervical lesions, the proportion of Th17 cells in the total CD4⁺ cells showed a gradually increased tendency compared with the controls (P < 0.05). Moreover, levels of IL-17 in serum and supernatant of cervical tissue homogenate showed the same tendency as the proportion of Th17 cells (P < 0.05). When compared in pairs, the levels of IL-17 in supernatant differed significantly among the study groups and the control group (P < 0.05), but no significant difference was observed in serum (P > 0.05). In conclusions, the results indicate that Th17 cells and IL-17 may play a role of immune enhancement in the infection of high-risk HPV especially in the cervical microenvironment, which contribute to the disease progression of its associated cervical lesions.

In this work, we evaluated the frequency of Th17 cells in peripheral blood samples obtained from cervical squamous cell carcinoma patients, CIN1 patients, CIN2 patients, CIN3 patients, high-risk HPV-infected women with normal cervical cytology, and healthy controls,as well as the levels of IL-17 in peripheral blood samples and in supernatant of cervical tissue homogenate. So we had come to the conclusion that Th17 cells and IL-17 may play a role of immune enhancement in the infection of high-risk HPV, which contribute to the disease progression of its associated cervical lesions.

from Cancer via ola Kala on Inoreader http://ift.tt/2BEjFxb
via IFTTT

Personality and breast cancer screening in women of the GAZEL cohort study

Abstract

The potential benefit of breast cancer screening is mitigated by the risk of false positives and overdiagnosis, thus advocating for a more personalized approach, based on the individual benefit-harm balance. Since personality might influence the women's appraisal of this balance, this prospective observational cohort study examined whether it could influence mammography use. A total of 2691 postmenopausal women of the GAZEL Cohort Study completed the Bortner Type A Rating Scale and the Buss and Durkee Hostility Inventory in 1993. Associations between personality scores and subsequent mammography use, self-reported through up to five triennial follow-up questionnaires, were estimated with Odds Ratio (OR) and 95% confidence interval (CI) with logistic mixed model regressions, adjusting for age, occupational grade, marital status, family history of breast cancer, age at menarche, age at first delivery, gynecological follow-up, hormone therapy use, and depressive symptoms. Individual propensity scores were used to weight the analyses to control for potential selection biases. More than 90% of the participants completed at least two follow-up questionnaires. Type A personality, but not hostility, was associated with mammography use in both univariate (crude OR [95% CI]: 1.62 [1.24–2.11], P < 0.001) and multivariate analyses (OR [95% CI]: 1.46 [1.13–1.90], P < 0.01). Type A personality traits (i.e., sense of time urgency, high job involvement, competitiveness) independently predicted mammography use among postmenopausal women. While paying more attention to the adherence of women with low levels of these traits, clinicians may help those with higher levels to better consider the risks of false positives and overdiagnosis.

Type A personality traits (i.e., sense of time urgency, high job involvement, competitiveness) independently predicted mammography use among 2691 postmenopausal women of the GAZEL Cohort Study (adjusted Odds Ratio [95% confidence interval]: 1.46: [1.13–1.90], P < 0.01). While paying more attention to the adherence of women with low levels of these traits, clinicians may help those with higher levels to better consider the risks of false positives and overdiagnosis.

from Cancer via ola Kala on Inoreader http://ift.tt/2C9AW4U
via IFTTT

Extrahepatic cholangiocarcinoma with prolonged survival: a case report

Cholangiocarcinoma has poor prognosis and short term-survival. Here, we report the case of a patient with unusually prolonged survival.

http://ift.tt/2zsz169

PTCH1 Germline Mutations and the Basaloid Follicular Hamartoma Values in the Tumor Spectrum of Basal Cell Carcinoma Syndrome (NBCCS)

Background/Aim: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominantly inherited disorder characterized by multiple basal cell carcinomas (BCC), odontogenic tumors and various skeletal anomalies. Basaloid follicular hamartomas (BFHs) constitute rare neoplasms that can be detected in sporadic and familial settings as in the Basaloid Follicular Hamartoma Syndrome (BFHS). Although BFHS shares clinical, histopathological and genetic overlapping with the NBCCS, they are still considered two distinctive entities. The aim of our single-institution study was the analysis of a cohort of PTCH1-mutated patients in order to define clinical and biomolecular relationship between NBCCS and BFHs. Materials and Methods: In our study we evaluated PTCH1 gene-carrier probands affected by NBCCS to detect the incidence of BFHs and their correlation with this rare syndrome. Results: Among probands we recognized 4 patients with BFHs. We found 15 germline PTCH1 mutations, uniformly distributed across the PTCH1 gene. Six of them had familial history of NBCCS, two of them were novel and have not been described previously. Conclusion: NBCCS and BFHS may be the same genetic entity and not two distinctive syndromes. The inclusion of BFH in the NBCCS cutaneous tumor spectrum might be useful for the recognition of misdiagnosed NBCCS cases that could benefit from tailored surveillance strategies.

http://ift.tt/2l5vNAa

Cancer Progenitor Cells: The Result of an Epigenetic Event?

The concept of cancer stem cells was proposed in the late 1990s. Although initially the idea seemed controversial, the existence of cancer stem cells is now well established. However, the process leading to the formation of cancer stem cells is still not clear and thus requires further research. This article discusses epigenetic events that possibly produce cancer progenitor cells from predisposed cells by the influence of their environment. Every somatic cell possesses an epigenetic signature in terms of histone modifications and DNA methylation, which are obtained during lineage-specific differentiation of pluripotent stem cells, which is specific to that particular tissue. We call this signature an epigenetic switch. The epigenetic switch is not fixed. Our epigenome alters with aging. However, depending on the predisposition of the cells of a particular tissue and their microenvironment, the balance of the switch (histone modifications and the DNA methylation) may be tilted to immortality in a few cells, which generates cancer progenitor cells.

http://ift.tt/2kTX7C9

The Role of Prophylactic Cranial Irradiation for Non-small Cell Lung Cancer

Background: The use of prophylactic cranial irradiation (PCI) to treat brain metastases (BM) in non-small cell lung cancer (NSCLC) is restricted due to the potential associated toxicity and lack of survival benefit. BM can have a negative impact on neurocognitive function (NF) and quality of life (QOL). The aim of this review was to assess the impact of PCI on disease-specific and NF and QOL outcomes. Materials and Methods: An electronic database literature search was completed to identify relevant studies. Results: Fourteen published articles were included. PCI significantly reduced the incidence of BM, but no significant survival advantage was found. NF decline was reported in one trial. No significant difference in QOL with PCI was reported. PCI was well tolerated by the majority of patients with NSCLC and associated with a relatively low toxicity. Conclusion: PCI reduces the incidence of BM without any significant survival advantage. PCI has the potential to be beneficial in practice for certain patients with locally advanced NSCLC, based on disease factors and patient preference.

http://ift.tt/2l84wgE

The Efficacy of Wide Resection for Musculoskeletal Metastatic Lesions of Renal Cell Carcinoma

Background/Aim: This study evaluated the outcome of wide resection for metastatic renal cell carcinoma (RCC) to the bone or soft tissue. Patients and Methods: Thirty patients who underwent surgery for bone or soft tissue metastatic lesions of RCC were retrospectively evaluated. The surgical procedures were wide resection in 14 patients (group 1) and intralesional resection in 16 (group 2). Results: The 3-, 5-, 10-, and 15-year overall survival (OS) was 76%, 48%, 35%, and 23%, respectively, and OS was significantly favorable in group 1. In addition, recurrence-free survival rate was significantly higher in group 1. In the multivariate analysis, intralesional resection was an independent risk factor for poor prognosis. There was no significant difference in surgical time, though intraoperative hemorrhage was significantly larger in group 2. Conclusion: The wide resection of bone and soft tissue metastatic lesions of RCC is a favorable option for controlling local metastasis and improving prognosis.

http://ift.tt/2kVHE4r

Regimens of Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis from Colorectal Cancer

Although systemic chemotherapy has been improved, peritoneal carcinomatosis remains a factor of poor prognosis in patients with colorectal cancer. In order to achieve a higher drug concentration in the peritoneal cavity, intraperitoneal chemotherapy has been performed. However, the optimal regimen for intraperitoneal chemotherapy has not been determined. In this review of intraperitoneal chemotherapy for colorectal cancer, we summarize regimens of hyperthermic intraperitoneal chemotherapy (HIPEC) and other intraperitoneal chemotherapy modalities, such as early postoperative intraperitoneal chemotherapy (EPIC) and sequential postoperative intraperitoneal chemotherapy (SPIC). Mitomycin C and oxaliplatin are the most common chemotherapeutic agents used for HIPEC. Some combination therapies such as those involving bevacizumab, H₂O₂, and amifostine have potential to increase HIPEC efficacy. 5-Fluorouracil is used mainly for EPIC and SPIC. Some new agents such as paclitaxel, melphalan, and various nanoparticles have been developed. These novel chemotherapeutic agents may achieve clinical implementation in the future.

http://ift.tt/2l8kffx

Computed Tomography Density Change in the Thyroid Gland Before and After Radiation Therapy

Background/Aim: Hypothyroidism is an established adverse effect of radiation therapy for head and neck cancer, and computed tomography (CT) density of the thyroid gland is lower in hypothyroid than euthyroid individuals. No previous studies have evaluated changes in CT densities of the thyroid gland caused by radiation therapy. The aim was to investigate the relationship between the change in CT density of the thyroid gland before and after radiation therapy for head and neck cancer and hypothyroidism. Materials and Methods: This retrospective study analyzed data of 24 patients treated by radiation therapy for head and neck cancers. After dosimetric analysis of received radiation therapy, a Picture Archiving and Communication System was used to manually contour the thyroid on pre-treatment CT images to enable determination of mean thyroid gland CT densities and received radiation doses. Pre- and post-treatment thyroid function was assessed on the basis of serum TSH concentrations. Multivariate and univariate analyses were used to determine what clinical factors are associated with post-radiation therapy decrease in CT density of the thyroid and Pearson's ² test was used to assess correlations between these densities and TSH concentrations. Results: Mean CT densities of the thyroid gland decreased from before to after radiation therapy in 73.9% of our patients (median decrease 16.8 HU). Serum TSH concentrations were significantly higher in patients with greater then median decreases in CT density than in those with lesser or no decreases. Conclusion: Post-radiation therapy hypothyroidism may be predicted by significant decreases in CT density of the thyroid gland.

http://ift.tt/2kUIIFR

Should Adjuvant Radiation Therapy Be Systematically Proposed for Male Breast Cancer? A Systematic Review

Background: Guidelines for radiotherapy in male breast cancer (MBC) are lacking. Some extrapolate the results from female breast cancer trials, while others advocate systematic adjuvant irradiation. We evaluated clinical practices and outcomes with respect to radiation therapy in MBC treated with locoregional irradiation in the adjuvant setting using a systematic literature review. Material and Methods: We included studies with data about adjuvant radiotherapy published between 1984 and 2017 and including at least 40 patients. Results: We found 29 retrospective series, 10,065 men were diagnosed with breast cancer; 3-100% (mean=54%) received adjuvant radiotherapy. Tumor size and nodal involvement were the strongest prognostic factors. Approximatively half of all cases had nodal metastases. Radiation therapy improved locoregional control in six series, overall survival in three and distant metastasis-free survival in one. Conclusion: MBC is diagnosed at a highly advanced stage and may be linked with poorer outcomes. Adjuvant radiation therapy must, at least, be proposed to men with positive nodes. Despite the large number of cases gathered here, arguments for radiotherapy in other prognostic subgroups (especially in pN0) may exist but are not well supported.

http://ift.tt/2l82KMu

Hepatic Resection Followed by Hepatic Arterial Infusion Chemotherapy for Hepatocellular Carcinoma with Intrahepatic Dissemination

Background/Aim: To investigate the utility of adjuvant hepatic arterial infusion chemotherapy (HAIC) following hepatectomy for patients with hepatocellular carcinoma (HCC) with intrahepatic dissemination (IHD) after local ablation therapy. Patients and Methods: Twelve patients with HCC with IHD were divided into two groups: HAIC group (n=6) underwent hepatectomy followed by HAIC; and the non-HAIC group (n=6) underwent hepatectomy alone. HAIC with cisplatin and 5-fluorouracil was started within a month and was continued for a month: Results: At the first local ablation, tumors close to the major portal vein and insufficient ablation were recognized in eight (67.7%) and six (58.3%) of the patients, respectively. In the HAIC group, the 1-, 3-, and 5-year disease-free and overall survival rates were 50.0%, 16.7%, and 16.7%, and 83.3%, 83.3% and 62.5%, respectively. Three patients in the HAIC group remain alive after 10 years of follow-up. Conclusion: Hepatic resection with short-term postoperative HAIC may provide excellent outcomes in patients with HCC and IHD.

http://ift.tt/2kTcPgU

Managing Focal Nodular Hyperplasia of the Liver: Surgery or Minimally-invasive Approaches? A Review of the Preferable Treatment Options

Background/Aim: Focal nodular hyperplasia (FNH) is the second most common benign tumor of the liver. As of 2017, many clinical, radiological and surgical features have been largely documented. On the other hand, little is still known about the correlation of FNH with hepatocellular carcinoma, nor the preferable modality of treatment. Our aim was to elucidate the latter topic. Materials and Methods: We investigated the pertinent literature available as of 2017 through four popular search engines (PubMed, Science Direct, Scopus and Google Scholar). Four main approaches were selected: conservative treatment, surgery, radiofrequency ablation (RFA) and transarterial embolization (TAE). Results: We found most works to be on conservative and surgical approaches. On the contrary, only one article has been published for RFA to date. Seventeen articles dealt with TAE. Conclusion: TAE currently represents the most cogent and successful alternative to surgery.

http://ift.tt/2l7C4LG

Molecular Basis for Mitochondrial Signaling

http://ift.tt/2kU3NQF

Histone Deacetylase Inhibitors as a Novel Targeted Therapy Against Non-small Cell Lung Cancer: Where Are We Now and What Should We Expect?

Non-small cell lung cancer constitutes the most common type of lung cancer, accounting for 85-90% of lung cancer, and is a leading cause of cancer-related death. Despite the progress during the past years, poor prognosis remains a challenge and requires further research and development of novel antitumor treatment. Recently, the role of histone deacetylases in gene expression has emerged showing their regulation of the acetylation of histone proteins and other non-histone protein targets and their role in chromatin organization, while their inhibitors, the histone deacetylase inhibitors, have been proposed to have a potential therapeutic role in diverse malignancies, including non-small cell lung cancer. This review article focuses on the role of histone deacetylase inhibitors in the treatment of non-small cell lung cancer and the major molecular mechanisms underlying their antitumor activity recognized so far.

http://ift.tt/2l8xQDq

Long-term Outcomes of a Dose-reduction Trial to Decrease Late Gastrointestinal Toxicity in Patients with Prostate Cancer Receiving Soft Tissue-matched Image-guided Intensity-modulated Radiotherapy

Background/Aim: We experienced an unexpected high incidence of gastrointestinal (GI) toxicity in patients undergoing image-guided intensity-modulated radiotherapy (IG-IMRT) using helical tomotherapy in our initial 2.2 Gy/fraction schedule for prostate cancer; hence, a dose-reduction trial from 2.2 Gy to 2 Gy/fraction was conducted using modified planning target volume (PTV) contouring. Patients and Methods: We compared 130 patients treated using 2.2 Gy/fraction (Group A) and 144 treated using the 2 Gy/fraction (Group B) with modified PTV (excluding rectal volume) with a median follow-up period of 62 months. Prescribed dose was 72.6-74.8 Gy in 33-34 fractions (Group A) and 72-74 Gy in 36-37 fractions (Group B). Results: Patients in Group B had a reduced rectal and bladder V10-V70 and were irradiated at the maximal dose. Their cumulative incidence of grade ≤2 GI toxicity at 5 years improved from 10.1% [95% confidence interval (CI), 4.9-15.3%] to 1.4% (0-3.3%). Grade 2≤ urinary toxicity also decreased from 5.5% (1.5-9.4%) in Group A to 1.4% (0-3.3%, p=0.0167) in Group B. The biochemical failure-free 5-year survival rate was 89.1% (95%CI=83.6-95.4%) and 87.5% (82.0-92.9%, p=0.75) in groups A and B, respectively. Conclusion: The reduced dose fraction schedule decreased the incidence of late GI toxicity without compromising prostate-specific antigen control. Careful target volume definition and fraction size are important even for IG-IMRT.

http://ift.tt/2kUF5jn

Our ACE in the HOLE: Justifying the Use of Angiotensin-converting Enzyme Inhibitors as Adjuvants to Standard Chemotherapy

Angiotensin-I-converting enzyme (ACE) inhibitors have been very effective in treating cardiac hypertension since their clinical inception over four decades ago. Since then, it has been established that angiotensin II, the product of ACE, has oncogenic and pro-proliferative qualities, which begs the question as to whether ACE inhibitors may have oncolytic characteristics. In fact, scattered reports suggest that ACE inhibitors are oncolytic and oncopreventive, but the available literature has yet to be thoroughly examined. In the present review, we examine the available literature and determine that ACE inhibitors would have great utility in the prevention and treatment of cancer. At the same time, they would augment the efficacy of chemo- and radiotherapy as well as mitigating damage to healthy tissue by standard chemotherapeutic regimens. We review some of the mounting clinical evidence and show that ACE inhibitors have oncolytic activity in multiple types of cancer and discuss the ability of ACE inhibitors to prevent cardiotoxicity of multiple chemotherapies. Our analysis demonstrates that the actions of ACE inhibitors converge on vascular endolthelial growth factor to reduce its levels in tumors and prevent construction of blood vessels to masses, leaving them nutrient-depleted and subsequently hindering their growth. Given that ACE inhibitors are approved by the Federal Drug Administration and the therapeutic dose for hypertension treatment also slows the growth of multiple cancers types, ACE inhibitors are in a perfect position to be repurposed as oncolytic agents, that would widely increase their utility in the clinic.

http://ift.tt/2l9sHuX

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in Elderly Patients: Complete Cytoreduction Is Feasible and Crucial for Improved Survival Despite High Carcinomatosis Index

Background: We aimed to study the surgical outcomes of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in elderly patients, and investigate whether the pursuit of complete cytoreduction implies a survival benefit despite a high peritoneal carcinomatosis index (PCI). Patients and Methods: All CRS and HIPEC procedures performed for patients with peritoneal surface malignancy (PSM) ≥65 years old between 2005-2017 were included. A control group comprising patients 60-64 years old who underwent CRS and HIPEC over the same period was also selected for comparison of characteristics and outcomes. Results: A total of 54 elderly patients and 27 control patients were included. Increasing age did not result in any difference in demographics, perioperative characteristics, or surgical outcomes. Elderly patients who achieved completeness of cytoreduction (CC) 0/1 were compared to those with CC2/3, and were found to have a higher body mass index, lower peritoneal cancer index, higher rate of inpatient mortality, and a significantly longer median survival (43 vs. 15 months; p=0.020). Cox multivariate regression identified Charlson score ≥2, the occurrence of major morbidities, colorectal and sarcoma primary tumor, and CC2/3 as significant predictors of poor survival. Conclusion: CRS and HIPEC are feasible in elderly patients without a significant effect of increasing age on the surgical outcomes. CC0/1 carries higher postoperative mortality rate, but yields a longer overall survival. Baseline comorbidities, postoperative complications, certain histologies, and CC2/3 are predictors of poor prognosis in this population. PCI is a predictor of CC, but not of survival when CC0/1 is achieved.

http://ift.tt/2kUNAe9

Pacifastin-derived Peptides Target Tumors for Use in In Vivo Imaging

Background/Aim: Developments in imaging have improved cancer diagnosis, but identification of malignant cells during surgical resection remains a challenge. The aim of this study was to investigate the pacifastin family of peptides for novel activity targeting tumor cells and the delivery of either imaging or therapeutic agents. Materials and Methods: Variants of pacifastin family peptides were generated, chemically modified and tested in human tumor xenografts. Results: A tumor-homing peptide-dye conjugate (THP1) accumulated in tumors in vivo and was internalized into cells. Examination of related peptides revealed residues critical for accumulation and allowed the engineering of improved tumor-targeting variants. A THP1-drug conjugate carrying the microtubule inhibitor, MMAE, showed limited activity in vitro and no difference compared to vehicle control in vivo. Conclusion: Although there are some obstacles to developing pacifastin-derived peptides for therapeutic activity, these optimized peptides have great promise for cancer imaging.

http://ift.tt/2l8Joqv

The Outcome of Sorafenib Therapy on Unresectable Hepatocellular Carcinoma: Experience of Conversion and Salvage Hepatectomy

Background/Aim: We report the outcomes of sorafenib therapy for advanced hepatocellular carcinoma (HCC) in our Department. Patients and Methods: Thirty-eight patients with unresectable HCC who were administrated sorafenib from 2009 to 2015 were investigated retrospectively. Results: The 1-year overall survival rate was 59.3%. The macroscopic vascular invasion and response rate were independent prognostic factors of survival. Surgical resection after sorafenib achieved long-term survival in two cases. Case 1: A patient with locally unresectable HCC showed significant response induced by sorafenib, which allowed complete surgical resection. This tumor tested positive for FGF4. Case 2: A patient with a history of hepatectomy for HCC had multiple distant metastases. Most lesions were reduced in size after sorafenib therapy and new lesions in the remnant liver and residual lung metastases were resected. The sorafenib-resistant lesions were negative for FGF4. Conclusion: Sorafenib combined with surgical resection is a feasible option in advanced HCC patients, if sorafenib has been effective.

http://ift.tt/2kS1IF1

In Vitro Evaluation of Humanized/De-immunized Anti-PSMA Immunotoxins for the Treatment of Prostate Cancer

Background: We generated humanized/de-immunized immunotoxins targeting the prostate-specific membrane antigen (PSMA) and tested their cytotoxic activity against prostate cancer cells in vitro. Materials and Methods: The humanized/de-immunized version of our murine anti-PSMA single-chain antibody fragment (scFv) D7, termed hD7-1(VL-VH), was ligated to the 40-kDa toxin domain of Pseudomonas aeruginosa exotoxin A (PE40), and to the deimmunized 24-kDa toxin domains PE24 or PE24mut. The immunotoxins designated as hD7-1(VL-VH)-PE40, hD7-1(VL-VH)-PE24 and hD7-1(VL-VH)-PE24mut were bacterially expressed and purified by affinity chromatography. Binding and cytotoxicity were examined by flow cytometry and viability assay, respectively. Results: All immunotoxins revealed strong binding to prostate cancer cells expressing PSMA and specific cytotoxicity, with half-maximal inhibitory concentration values in the picomolar range. Conclusion: We successfully created powerful anti-PSMA immunotoxins with reduced immunogenicity for further clinical development and application against advanced prostate cancer.

http://ift.tt/2lbayNA

Clinical Significance of PD-L1 Expression in Brain Metastases from Non-small Cell Lung Cancer

Aim: To investigate the association between positivity for programmed cell death-ligand 1 (PD-L1) in brain metastases (BM) and the prognosis or clinical factors in patients with non-small cell lung cancer (NSCLC). Materials and Methods: Thirty-two patients with surgically resected brain-metastatic NSCLC were enrolled. The PD-L1 expression in BM was analyzed using the antibody against human PD-L1 (clone SP142). The PD-L1 positivity was defined as PD-L1 expression on brain-metastatic tumor cells of ≥5%. Results: Seven (21.9%) out of 32 patients showed PD-L1 positivity in BM. The PD-L1-positive BM group had a significantly shorter brain-specific disease-free survival than the PD-L1-negative BM group (p<0.05). PD-L1 positivity in BM was significantly associated with a heavy smoking history and the administration of radiotherapy for BM before surgery (p<0.05 and p<0.05, respectively). Conclusion: The PD-L1 expression in BM from NSCLC may be associated with local recurrence following surgery, and the smoking- or radiotherapy-derived effects.

http://ift.tt/2kUWUi3

Sphingosine Induces Apoptosis and Down-regulation of MYCN in PAX3-FOXO1-positive Alveolar Rhabdomyosarcoma Cells Irrespective of TP53 Mutation

Background/Aim: Rhabdomyosarcoma is the most common type of pediatric soft-tissue sarcoma. Among the subsets of this disease, alveolar rhabdomyosarcoma (ARMS) expressing paired box 3 (PAX3) and forkhead box O1 (PAX3–FOXO1) fusion oncoprotein has the worst prognosis. The goal of this study was to investigate the chemotherapeutic effects of sphingosine on PAX3–FOXO1-positive ARMS cells [tumor protein p53 (TP53)-mutated RH30 and TP53 wild-type RH18 cells]. Materials and Methods: The proliferation, cell death, apoptosis, cell cycle, and MYCN proto-oncogene (MYCN) expression of RH30 and RH18 cells were determined. Results: Sphingosine inhibited the growth and caused cell death in a dose-dependent manner in both cell lines. Sphingosine triggered cell death by inducing apoptosis without affecting the cell cycle. MYCN expression was down-regulated within 2 and 4 h of sphingosine treatment in both RH30 and RH18 cells. Conclusion: Sphingosine exerts antiproliferative and pro-apoptotic effects via MYCN down-regulation independently of TP53 mutation status in PAX3–FOXO1-positive ARMS cells.

http://ift.tt/2l7ts81

Chordomas and Chondrosarcomas of the Skull Base and Spine. 2nd Edition

http://ift.tt/2kUPKdU

PTCH1 Germline Mutations and the Basaloid Follicular Hamartoma Values in the Tumor Spectrum of Basal Cell Carcinoma Syndrome (NBCCS)

Background/Aim: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominantly inherited disorder characterized by multiple basal cell carcinomas (BCC), odontogenic tumors and various skeletal anomalies. Basaloid follicular hamartomas (BFHs) constitute rare neoplasms that can be detected in sporadic and familial settings as in the Basaloid Follicular Hamartoma Syndrome (BFHS). Although BFHS shares clinical, histopathological and genetic overlapping with the NBCCS, they are still considered two distinctive entities. The aim of our single-institution study was the analysis of a cohort of PTCH1-mutated patients in order to define clinical and biomolecular relationship between NBCCS and BFHs. Materials and Methods: In our study we evaluated PTCH1 gene-carrier probands affected by NBCCS to detect the incidence of BFHs and their correlation with this rare syndrome. Results: Among probands we recognized 4 patients with BFHs. We found 15 germline PTCH1 mutations, uniformly distributed across the PTCH1 gene. Six of them had familial history of NBCCS, two of them were novel and have not been described previously. Conclusion: NBCCS and BFHS may be the same genetic entity and not two distinctive syndromes. The inclusion of BFH in the NBCCS cutaneous tumor spectrum might be useful for the recognition of misdiagnosed NBCCS cases that could benefit from tailored surveillance strategies.

from Cancer via ola Kala on Inoreader http://ift.tt/2l5vNAa
via IFTTT

Cancer Progenitor Cells: The Result of an Epigenetic Event?

The concept of cancer stem cells was proposed in the late 1990s. Although initially the idea seemed controversial, the existence of cancer stem cells is now well established. However, the process leading to the formation of cancer stem cells is still not clear and thus requires further research. This article discusses epigenetic events that possibly produce cancer progenitor cells from predisposed cells by the influence of their environment. Every somatic cell possesses an epigenetic signature in terms of histone modifications and DNA methylation, which are obtained during lineage-specific differentiation of pluripotent stem cells, which is specific to that particular tissue. We call this signature an epigenetic switch. The epigenetic switch is not fixed. Our epigenome alters with aging. However, depending on the predisposition of the cells of a particular tissue and their microenvironment, the balance of the switch (histone modifications and the DNA methylation) may be tilted to immortality in a few cells, which generates cancer progenitor cells.

from Cancer via ola Kala on Inoreader http://ift.tt/2kTX7C9
via IFTTT

The Role of Prophylactic Cranial Irradiation for Non-small Cell Lung Cancer

Background: The use of prophylactic cranial irradiation (PCI) to treat brain metastases (BM) in non-small cell lung cancer (NSCLC) is restricted due to the potential associated toxicity and lack of survival benefit. BM can have a negative impact on neurocognitive function (NF) and quality of life (QOL). The aim of this review was to assess the impact of PCI on disease-specific and NF and QOL outcomes. Materials and Methods: An electronic database literature search was completed to identify relevant studies. Results: Fourteen published articles were included. PCI significantly reduced the incidence of BM, but no significant survival advantage was found. NF decline was reported in one trial. No significant difference in QOL with PCI was reported. PCI was well tolerated by the majority of patients with NSCLC and associated with a relatively low toxicity. Conclusion: PCI reduces the incidence of BM without any significant survival advantage. PCI has the potential to be beneficial in practice for certain patients with locally advanced NSCLC, based on disease factors and patient preference.

from Cancer via ola Kala on Inoreader http://ift.tt/2l84wgE
via IFTTT

The Efficacy of Wide Resection for Musculoskeletal Metastatic Lesions of Renal Cell Carcinoma

Background/Aim: This study evaluated the outcome of wide resection for metastatic renal cell carcinoma (RCC) to the bone or soft tissue. Patients and Methods: Thirty patients who underwent surgery for bone or soft tissue metastatic lesions of RCC were retrospectively evaluated. The surgical procedures were wide resection in 14 patients (group 1) and intralesional resection in 16 (group 2). Results: The 3-, 5-, 10-, and 15-year overall survival (OS) was 76%, 48%, 35%, and 23%, respectively, and OS was significantly favorable in group 1. In addition, recurrence-free survival rate was significantly higher in group 1. In the multivariate analysis, intralesional resection was an independent risk factor for poor prognosis. There was no significant difference in surgical time, though intraoperative hemorrhage was significantly larger in group 2. Conclusion: The wide resection of bone and soft tissue metastatic lesions of RCC is a favorable option for controlling local metastasis and improving prognosis.

from Cancer via ola Kala on Inoreader http://ift.tt/2kVHE4r
via IFTTT

Regimens of Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis from Colorectal Cancer

Although systemic chemotherapy has been improved, peritoneal carcinomatosis remains a factor of poor prognosis in patients with colorectal cancer. In order to achieve a higher drug concentration in the peritoneal cavity, intraperitoneal chemotherapy has been performed. However, the optimal regimen for intraperitoneal chemotherapy has not been determined. In this review of intraperitoneal chemotherapy for colorectal cancer, we summarize regimens of hyperthermic intraperitoneal chemotherapy (HIPEC) and other intraperitoneal chemotherapy modalities, such as early postoperative intraperitoneal chemotherapy (EPIC) and sequential postoperative intraperitoneal chemotherapy (SPIC). Mitomycin C and oxaliplatin are the most common chemotherapeutic agents used for HIPEC. Some combination therapies such as those involving bevacizumab, H₂O₂, and amifostine have potential to increase HIPEC efficacy. 5-Fluorouracil is used mainly for EPIC and SPIC. Some new agents such as paclitaxel, melphalan, and various nanoparticles have been developed. These novel chemotherapeutic agents may achieve clinical implementation in the future.

from Cancer via ola Kala on Inoreader http://ift.tt/2l8kffx
via IFTTT

Computed Tomography Density Change in the Thyroid Gland Before and After Radiation Therapy

Background/Aim: Hypothyroidism is an established adverse effect of radiation therapy for head and neck cancer, and computed tomography (CT) density of the thyroid gland is lower in hypothyroid than euthyroid individuals. No previous studies have evaluated changes in CT densities of the thyroid gland caused by radiation therapy. The aim was to investigate the relationship between the change in CT density of the thyroid gland before and after radiation therapy for head and neck cancer and hypothyroidism. Materials and Methods: This retrospective study analyzed data of 24 patients treated by radiation therapy for head and neck cancers. After dosimetric analysis of received radiation therapy, a Picture Archiving and Communication System was used to manually contour the thyroid on pre-treatment CT images to enable determination of mean thyroid gland CT densities and received radiation doses. Pre- and post-treatment thyroid function was assessed on the basis of serum TSH concentrations. Multivariate and univariate analyses were used to determine what clinical factors are associated with post-radiation therapy decrease in CT density of the thyroid and Pearson's ² test was used to assess correlations between these densities and TSH concentrations. Results: Mean CT densities of the thyroid gland decreased from before to after radiation therapy in 73.9% of our patients (median decrease 16.8 HU). Serum TSH concentrations were significantly higher in patients with greater then median decreases in CT density than in those with lesser or no decreases. Conclusion: Post-radiation therapy hypothyroidism may be predicted by significant decreases in CT density of the thyroid gland.

from Cancer via ola Kala on Inoreader http://ift.tt/2kUIIFR
via IFTTT

Should Adjuvant Radiation Therapy Be Systematically Proposed for Male Breast Cancer? A Systematic Review

Background: Guidelines for radiotherapy in male breast cancer (MBC) are lacking. Some extrapolate the results from female breast cancer trials, while others advocate systematic adjuvant irradiation. We evaluated clinical practices and outcomes with respect to radiation therapy in MBC treated with locoregional irradiation in the adjuvant setting using a systematic literature review. Material and Methods: We included studies with data about adjuvant radiotherapy published between 1984 and 2017 and including at least 40 patients. Results: We found 29 retrospective series, 10,065 men were diagnosed with breast cancer; 3-100% (mean=54%) received adjuvant radiotherapy. Tumor size and nodal involvement were the strongest prognostic factors. Approximatively half of all cases had nodal metastases. Radiation therapy improved locoregional control in six series, overall survival in three and distant metastasis-free survival in one. Conclusion: MBC is diagnosed at a highly advanced stage and may be linked with poorer outcomes. Adjuvant radiation therapy must, at least, be proposed to men with positive nodes. Despite the large number of cases gathered here, arguments for radiotherapy in other prognostic subgroups (especially in pN0) may exist but are not well supported.

from Cancer via ola Kala on Inoreader http://ift.tt/2l82KMu
via IFTTT

Hepatic Resection Followed by Hepatic Arterial Infusion Chemotherapy for Hepatocellular Carcinoma with Intrahepatic Dissemination

Background/Aim: To investigate the utility of adjuvant hepatic arterial infusion chemotherapy (HAIC) following hepatectomy for patients with hepatocellular carcinoma (HCC) with intrahepatic dissemination (IHD) after local ablation therapy. Patients and Methods: Twelve patients with HCC with IHD were divided into two groups: HAIC group (n=6) underwent hepatectomy followed by HAIC; and the non-HAIC group (n=6) underwent hepatectomy alone. HAIC with cisplatin and 5-fluorouracil was started within a month and was continued for a month: Results: At the first local ablation, tumors close to the major portal vein and insufficient ablation were recognized in eight (67.7%) and six (58.3%) of the patients, respectively. In the HAIC group, the 1-, 3-, and 5-year disease-free and overall survival rates were 50.0%, 16.7%, and 16.7%, and 83.3%, 83.3% and 62.5%, respectively. Three patients in the HAIC group remain alive after 10 years of follow-up. Conclusion: Hepatic resection with short-term postoperative HAIC may provide excellent outcomes in patients with HCC and IHD.

from Cancer via ola Kala on Inoreader http://ift.tt/2kTcPgU
via IFTTT

Managing Focal Nodular Hyperplasia of the Liver: Surgery or Minimally-invasive Approaches? A Review of the Preferable Treatment Options

Background/Aim: Focal nodular hyperplasia (FNH) is the second most common benign tumor of the liver. As of 2017, many clinical, radiological and surgical features have been largely documented. On the other hand, little is still known about the correlation of FNH with hepatocellular carcinoma, nor the preferable modality of treatment. Our aim was to elucidate the latter topic. Materials and Methods: We investigated the pertinent literature available as of 2017 through four popular search engines (PubMed, Science Direct, Scopus and Google Scholar). Four main approaches were selected: conservative treatment, surgery, radiofrequency ablation (RFA) and transarterial embolization (TAE). Results: We found most works to be on conservative and surgical approaches. On the contrary, only one article has been published for RFA to date. Seventeen articles dealt with TAE. Conclusion: TAE currently represents the most cogent and successful alternative to surgery.

from Cancer via ola Kala on Inoreader http://ift.tt/2l7C4LG
via IFTTT

Molecular Basis for Mitochondrial Signaling

from Cancer via ola Kala on Inoreader http://ift.tt/2kU3NQF
via IFTTT

Histone Deacetylase Inhibitors as a Novel Targeted Therapy Against Non-small Cell Lung Cancer: Where Are We Now and What Should We Expect?

Non-small cell lung cancer constitutes the most common type of lung cancer, accounting for 85-90% of lung cancer, and is a leading cause of cancer-related death. Despite the progress during the past years, poor prognosis remains a challenge and requires further research and development of novel antitumor treatment. Recently, the role of histone deacetylases in gene expression has emerged showing their regulation of the acetylation of histone proteins and other non-histone protein targets and their role in chromatin organization, while their inhibitors, the histone deacetylase inhibitors, have been proposed to have a potential therapeutic role in diverse malignancies, including non-small cell lung cancer. This review article focuses on the role of histone deacetylase inhibitors in the treatment of non-small cell lung cancer and the major molecular mechanisms underlying their antitumor activity recognized so far.

from Cancer via ola Kala on Inoreader http://ift.tt/2l8xQDq
via IFTTT

Long-term Outcomes of a Dose-reduction Trial to Decrease Late Gastrointestinal Toxicity in Patients with Prostate Cancer Receiving Soft Tissue-matched Image-guided Intensity-modulated Radiotherapy

Background/Aim: We experienced an unexpected high incidence of gastrointestinal (GI) toxicity in patients undergoing image-guided intensity-modulated radiotherapy (IG-IMRT) using helical tomotherapy in our initial 2.2 Gy/fraction schedule for prostate cancer; hence, a dose-reduction trial from 2.2 Gy to 2 Gy/fraction was conducted using modified planning target volume (PTV) contouring. Patients and Methods: We compared 130 patients treated using 2.2 Gy/fraction (Group A) and 144 treated using the 2 Gy/fraction (Group B) with modified PTV (excluding rectal volume) with a median follow-up period of 62 months. Prescribed dose was 72.6-74.8 Gy in 33-34 fractions (Group A) and 72-74 Gy in 36-37 fractions (Group B). Results: Patients in Group B had a reduced rectal and bladder V10-V70 and were irradiated at the maximal dose. Their cumulative incidence of grade ≤2 GI toxicity at 5 years improved from 10.1% [95% confidence interval (CI), 4.9-15.3%] to 1.4% (0-3.3%). Grade 2≤ urinary toxicity also decreased from 5.5% (1.5-9.4%) in Group A to 1.4% (0-3.3%, p=0.0167) in Group B. The biochemical failure-free 5-year survival rate was 89.1% (95%CI=83.6-95.4%) and 87.5% (82.0-92.9%, p=0.75) in groups A and B, respectively. Conclusion: The reduced dose fraction schedule decreased the incidence of late GI toxicity without compromising prostate-specific antigen control. Careful target volume definition and fraction size are important even for IG-IMRT.

from Cancer via ola Kala on Inoreader http://ift.tt/2kUF5jn
via IFTTT

Our ACE in the HOLE: Justifying the Use of Angiotensin-converting Enzyme Inhibitors as Adjuvants to Standard Chemotherapy

Angiotensin-I-converting enzyme (ACE) inhibitors have been very effective in treating cardiac hypertension since their clinical inception over four decades ago. Since then, it has been established that angiotensin II, the product of ACE, has oncogenic and pro-proliferative qualities, which begs the question as to whether ACE inhibitors may have oncolytic characteristics. In fact, scattered reports suggest that ACE inhibitors are oncolytic and oncopreventive, but the available literature has yet to be thoroughly examined. In the present review, we examine the available literature and determine that ACE inhibitors would have great utility in the prevention and treatment of cancer. At the same time, they would augment the efficacy of chemo- and radiotherapy as well as mitigating damage to healthy tissue by standard chemotherapeutic regimens. We review some of the mounting clinical evidence and show that ACE inhibitors have oncolytic activity in multiple types of cancer and discuss the ability of ACE inhibitors to prevent cardiotoxicity of multiple chemotherapies. Our analysis demonstrates that the actions of ACE inhibitors converge on vascular endolthelial growth factor to reduce its levels in tumors and prevent construction of blood vessels to masses, leaving them nutrient-depleted and subsequently hindering their growth. Given that ACE inhibitors are approved by the Federal Drug Administration and the therapeutic dose for hypertension treatment also slows the growth of multiple cancers types, ACE inhibitors are in a perfect position to be repurposed as oncolytic agents, that would widely increase their utility in the clinic.

from Cancer via ola Kala on Inoreader http://ift.tt/2l9sHuX
via IFTTT

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in Elderly Patients: Complete Cytoreduction Is Feasible and Crucial for Improved Survival Despite High Carcinomatosis Index

Background: We aimed to study the surgical outcomes of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in elderly patients, and investigate whether the pursuit of complete cytoreduction implies a survival benefit despite a high peritoneal carcinomatosis index (PCI). Patients and Methods: All CRS and HIPEC procedures performed for patients with peritoneal surface malignancy (PSM) ≥65 years old between 2005-2017 were included. A control group comprising patients 60-64 years old who underwent CRS and HIPEC over the same period was also selected for comparison of characteristics and outcomes. Results: A total of 54 elderly patients and 27 control patients were included. Increasing age did not result in any difference in demographics, perioperative characteristics, or surgical outcomes. Elderly patients who achieved completeness of cytoreduction (CC) 0/1 were compared to those with CC2/3, and were found to have a higher body mass index, lower peritoneal cancer index, higher rate of inpatient mortality, and a significantly longer median survival (43 vs. 15 months; p=0.020). Cox multivariate regression identified Charlson score ≥2, the occurrence of major morbidities, colorectal and sarcoma primary tumor, and CC2/3 as significant predictors of poor survival. Conclusion: CRS and HIPEC are feasible in elderly patients without a significant effect of increasing age on the surgical outcomes. CC0/1 carries higher postoperative mortality rate, but yields a longer overall survival. Baseline comorbidities, postoperative complications, certain histologies, and CC2/3 are predictors of poor prognosis in this population. PCI is a predictor of CC, but not of survival when CC0/1 is achieved.

from Cancer via ola Kala on Inoreader http://ift.tt/2kUNAe9
via IFTTT

Pacifastin-derived Peptides Target Tumors for Use in In Vivo Imaging

Background/Aim: Developments in imaging have improved cancer diagnosis, but identification of malignant cells during surgical resection remains a challenge. The aim of this study was to investigate the pacifastin family of peptides for novel activity targeting tumor cells and the delivery of either imaging or therapeutic agents. Materials and Methods: Variants of pacifastin family peptides were generated, chemically modified and tested in human tumor xenografts. Results: A tumor-homing peptide-dye conjugate (THP1) accumulated in tumors in vivo and was internalized into cells. Examination of related peptides revealed residues critical for accumulation and allowed the engineering of improved tumor-targeting variants. A THP1-drug conjugate carrying the microtubule inhibitor, MMAE, showed limited activity in vitro and no difference compared to vehicle control in vivo. Conclusion: Although there are some obstacles to developing pacifastin-derived peptides for therapeutic activity, these optimized peptides have great promise for cancer imaging.

from Cancer via ola Kala on Inoreader http://ift.tt/2l8Joqv
via IFTTT

The Outcome of Sorafenib Therapy on Unresectable Hepatocellular Carcinoma: Experience of Conversion and Salvage Hepatectomy

Background/Aim: We report the outcomes of sorafenib therapy for advanced hepatocellular carcinoma (HCC) in our Department. Patients and Methods: Thirty-eight patients with unresectable HCC who were administrated sorafenib from 2009 to 2015 were investigated retrospectively. Results: The 1-year overall survival rate was 59.3%. The macroscopic vascular invasion and response rate were independent prognostic factors of survival. Surgical resection after sorafenib achieved long-term survival in two cases. Case 1: A patient with locally unresectable HCC showed significant response induced by sorafenib, which allowed complete surgical resection. This tumor tested positive for FGF4. Case 2: A patient with a history of hepatectomy for HCC had multiple distant metastases. Most lesions were reduced in size after sorafenib therapy and new lesions in the remnant liver and residual lung metastases were resected. The sorafenib-resistant lesions were negative for FGF4. Conclusion: Sorafenib combined with surgical resection is a feasible option in advanced HCC patients, if sorafenib has been effective.

from Cancer via ola Kala on Inoreader http://ift.tt/2kS1IF1
via IFTTT

In Vitro Evaluation of Humanized/De-immunized Anti-PSMA Immunotoxins for the Treatment of Prostate Cancer

Background: We generated humanized/de-immunized immunotoxins targeting the prostate-specific membrane antigen (PSMA) and tested their cytotoxic activity against prostate cancer cells in vitro. Materials and Methods: The humanized/de-immunized version of our murine anti-PSMA single-chain antibody fragment (scFv) D7, termed hD7-1(VL-VH), was ligated to the 40-kDa toxin domain of Pseudomonas aeruginosa exotoxin A (PE40), and to the deimmunized 24-kDa toxin domains PE24 or PE24mut. The immunotoxins designated as hD7-1(VL-VH)-PE40, hD7-1(VL-VH)-PE24 and hD7-1(VL-VH)-PE24mut were bacterially expressed and purified by affinity chromatography. Binding and cytotoxicity were examined by flow cytometry and viability assay, respectively. Results: All immunotoxins revealed strong binding to prostate cancer cells expressing PSMA and specific cytotoxicity, with half-maximal inhibitory concentration values in the picomolar range. Conclusion: We successfully created powerful anti-PSMA immunotoxins with reduced immunogenicity for further clinical development and application against advanced prostate cancer.

from Cancer via ola Kala on Inoreader http://ift.tt/2lbayNA
via IFTTT

Clinical Significance of PD-L1 Expression in Brain Metastases from Non-small Cell Lung Cancer

Aim: To investigate the association between positivity for programmed cell death-ligand 1 (PD-L1) in brain metastases (BM) and the prognosis or clinical factors in patients with non-small cell lung cancer (NSCLC). Materials and Methods: Thirty-two patients with surgically resected brain-metastatic NSCLC were enrolled. The PD-L1 expression in BM was analyzed using the antibody against human PD-L1 (clone SP142). The PD-L1 positivity was defined as PD-L1 expression on brain-metastatic tumor cells of ≥5%. Results: Seven (21.9%) out of 32 patients showed PD-L1 positivity in BM. The PD-L1-positive BM group had a significantly shorter brain-specific disease-free survival than the PD-L1-negative BM group (p<0.05). PD-L1 positivity in BM was significantly associated with a heavy smoking history and the administration of radiotherapy for BM before surgery (p<0.05 and p<0.05, respectively). Conclusion: The PD-L1 expression in BM from NSCLC may be associated with local recurrence following surgery, and the smoking- or radiotherapy-derived effects.

from Cancer via ola Kala on Inoreader http://ift.tt/2kUWUi3
via IFTTT

Sphingosine Induces Apoptosis and Down-regulation of MYCN in PAX3-FOXO1-positive Alveolar Rhabdomyosarcoma Cells Irrespective of TP53 Mutation

Background/Aim: Rhabdomyosarcoma is the most common type of pediatric soft-tissue sarcoma. Among the subsets of this disease, alveolar rhabdomyosarcoma (ARMS) expressing paired box 3 (PAX3) and forkhead box O1 (PAX3–FOXO1) fusion oncoprotein has the worst prognosis. The goal of this study was to investigate the chemotherapeutic effects of sphingosine on PAX3–FOXO1-positive ARMS cells [tumor protein p53 (TP53)-mutated RH30 and TP53 wild-type RH18 cells]. Materials and Methods: The proliferation, cell death, apoptosis, cell cycle, and MYCN proto-oncogene (MYCN) expression of RH30 and RH18 cells were determined. Results: Sphingosine inhibited the growth and caused cell death in a dose-dependent manner in both cell lines. Sphingosine triggered cell death by inducing apoptosis without affecting the cell cycle. MYCN expression was down-regulated within 2 and 4 h of sphingosine treatment in both RH30 and RH18 cells. Conclusion: Sphingosine exerts antiproliferative and pro-apoptotic effects via MYCN down-regulation independently of TP53 mutation status in PAX3–FOXO1-positive ARMS cells.

from Cancer via ola Kala on Inoreader http://ift.tt/2l7ts81
via IFTTT

Chordomas and Chondrosarcomas of the Skull Base and Spine. 2nd Edition

from Cancer via ola Kala on Inoreader http://ift.tt/2kUPKdU
via IFTTT