Cancers, Vol. 10, Pages 144: Temozolomide Enhances Triple-Negative Breast Cancer Virotherapy In Vitro

Cancers, Vol. 10, Pages 144: Temozolomide Enhances Triple-Negative Breast Cancer Virotherapy In Vitro

Cancers doi: 10.3390/cancers10050144

Authors: Rodolfo Garza-Morales Roxana Gonzalez-Ramos Akiko Chiba Roberto Montes de Oca-Luna Lacey R. McNally Kelly M. McMasters Jorge G. Gomez-Gutierrez

Triple-negative breast cancer (TNBC) is one of the most aggressive types of cancer, and treatment is limited to chemotherapy and radiation. Oncolytic virotherapy may be a promising approach to treat TNBC. However, oncolytic adenovirus (OAd)-based mono-therapeutic clinical trials have resulted in modest outcomes. The OAd potency could be increased by chemotherapy-induced autophagy, an intracellular degradation system that delivers cytoplasmic constituents to the lysosome. In this study, the ability of alkylating agent temozolomide (TMZ)-induced autophagy to increase OAd replication and oncolysis in TNBC cells was evaluated. Human TNBC MDA-MB-231 and HCC1937 cells and mouse 4T1 cells were infected with an OAd expressing the red fluorescent protein mCherry on the virus capsid (OAdmCherry) alone or in combination with TMZ. TNBC cells treated with OAdmCherry/TMZ displayed greater mCherry and adenovirus (Ad) early region 1A (E1A) expression and enhanced cancer-cell killing compared to OAdmCherry or TMZ alone. The combined therapy-mediated cell death was associated with virus replication and accumulation of the autophagy marker light chain 3 (LC3)-II. Overall, this study provides experimental evidence of TMZ’s ability to increase oncolytic virotherapy in both human and murine TNBC cells.

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The investigation of the survival time after recurrence in patients with pancreatic ductal adenocarcinoma for individualization of adjuvant chemotherapy

Abstract

Purpose

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease; however, the frequency of recurrence can be reduced if curative surgery following adjuvant chemotherapy is applied. At present, adjuvant chemotherapy is uniformly performed in all patients, as it is unclear which tumor types are controlled best or worst. We investigated patients with recurrence to establish the optimum treatment strategy.

Methods

Of 138 patients who underwent curative surgery for PDAC, 85 developed recurrence. Comprehensive clinicopathological factors were investigated for their association with the survival time after recurrence (SAR).

Results

The median SAR was 12.6 months. Treatments for recurrence included best supportive care, GEM-based therapy and S-1. The performance status [hazard ratio (HR) 0.12, P < 0.001], histological invasion of lymph vessels (HR 0.27, P < 0.001), kind of treatment for recurrence (HR 5.0, P < 0.001) and initial recurrence site (HR 2.9, P < 0.001) were independent significant risk factors for the SAR. The initial recurrence sites were the liver (n = 21, median SAR 8.8 months), lung (n = 10, 14.9 months), peritoneum (n = 6, 1.7 months), lymph nodes (n = 6, 14.7 months), local site (n = 17, 13.9 months) and multiple sites (n = 25, 10.1 months). A shorter recurrence-free survival (< 1 year) and higher postoperative CA19-9 level were significantly associated with critical recurrence (peritoneal/liver).

Conclusions

Several risk factors for SAR were detected in this study. Further investigations are needed to individualize the adjuvant chemotherapy for each patient with PDAC.

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Quality of life and patients’ expectations in soft tissue sarcoma

Future Oncology, Volume 14, Issue 10s, Page 51-62, May 2018.


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Options for treating different soft tissue sarcoma subtypes

Future Oncology, Volume 14, Issue 10s, Page 25-49, May 2018.


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The key role of pathology, surgery and radiotherapy in the initial management of soft tissue sarcoma

Future Oncology, Volume 14, Issue 10s, Page 15-23, May 2018.


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Foreword

Future Oncology, Volume 14, Issue 10s, Page 1-2, May 2018.


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Getting up-to-date in the management of soft tissue sarcoma

Future Oncology, Volume 14, Issue 10s, Page 3-13, May 2018.


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Orally bioavailable and blood-brain-barrier penetrating ATM inhibitor (AZ32) radiosensitizes intracranial gliomas in mice.

Inhibition of ataxia-telangiectasia mutated (ATM) during radiotherapy of glioblastoma multiforme (GBM) may improve tumor control by short-circuiting the response to radiation-induced DNA damage. A major impediment for clinical implementation is that current inhibitors have limited CNS bioavailability, thus, the goal was to identify ATM inhibitors (ATMi) with improved CNS penetration. Drug screens and refinement of lead compounds identified AZ31 and AZ32. The compounds were then tested in vivo for efficacy and impact on tumor and healthy brain. Both AZ31 and AZ32 blocked the DNA damage response (DDR) and radiosensitized GBM cells in vitro. AZ32, with enhanced blood-brain barrier (BBB) penetration, was highly efficient in vivo as radiosensitizer in syngeneic and human, orthotopic mouse glioma model compared with AZ31. Furthermore, human glioma cell lines expressing mutant p53 or having checkpoint-defective mutations were particularly sensitive to ATMi radiosensitization. The mechanism for this p53 effect involves a propensity to undergo mitotic catastrophe relative to cells with wild-type p53. In vivo, apoptosis was >6-fold higher in tumor relative to healthy brain after exposure to AZ32 and low dose radiation. AZ32 is the first ATMi with oral bioavailability shown to radiosensitize glioma and improve survival in orthotopic mouse models. These findings support the development of a clinical-grade, BBB-penetrating ATMi for the treatment of GBM. Importantly, since many GBMs have defective p53 signalling, the use of an ATMi concurrent with standard radiotherapy is expected to be cancer-specific, increase the therapeutic ratio, and maintain full therapeutic effect at lower radiation doses.

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The clinical significance of platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) in gastric cancer: A systematic review and meta-analysis

Publication date: July 2018
Source:Critical Reviews in Oncology/Hematology, Volume 127
Author(s): Hai Qian, Kwaku Appiah-Kubi, Ying Wang, Min Wu, Yan Tao, Yan Wu, Yongchang Chen
BackgroundThe overexpression and mutation of platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) are widespread in cancers and have been recognized as attractive oncologic targets with diverse therapeutic targets. Reports of the overexpression of genes, proteins and mutations of PDGFs/PDGFRs in gastric cancer and their associations with clinicopathological features, Western and Asian patients, as well as prognostic role have shown variable outcomes. This study sought to employ meta-analysis to evaluate PDGFs/PDGFRs status prognostic significance and their association with clinicopathological features of gastric cancer.MethodA comprehensive search of PubMed database for studies that investigated the overexpression of mRNA/Protein and mutation of PDGFs/PDGFRs in gastric cancer of Western and Asian patients, their prognostic significance and association with clinicopathological characteristics in May, 2017 or earlier was carried out by two reviewers independently. Pooled odd ratios and hazard ratios at 95% confidence intervals were estimated and summarized using fixed-effect and random-effect Mantel-Haenszel models and Inverse Variance models in Review Manager software version 5.3.ResultsFourteen studies with 16 datasets of 1178 patients were included in meta-analysis. Fourteen studies of 1178 patients with 1446 cases and 7 studies of 1076 patients with 1280 cases were included in meta-analysis of clinicopathological and prognostic significance of high or positive PDGF/PDGFR status respectively. Odd ratio at 95% confidence intervals for different groups of analysis are as follows: males versus females(OR = 1.38, 95% CI: 1.04–1.83, POR = 0.03); ≥T2 stage versus T1 stage(OR = 2.06, 95% CI: 1.22–3.49, POR = 0.007); nodal metastasis versus no nodal metastasis(OR = 2.78, 95% CI: 1.48–5.22, POR = 0.002); TNM stage ≥II versus TNM stage I(OR = 3.55, 95% CI: 1.89–6.69, POR<0.0001). Subgroup analysis of the association of PDGF/PDGFR among Western patients(OR = 0.24 95% CI: 0.10–0.58, POR = 0.002) and association of PDGFs/PDGFRs gene mutation among gastric cancer patients(OR = 0.15, 95% CI: 0.05–0.45, POR = 0.0008) were significant. The association of PDGFs/PDGFRs in young and middle age versus elderly aged, undifferentiated versus well differentiated tumors, large tumor size group(>6 cm) versus small tumor size group(≤6 cm) were insignificant. Subgroup analysis of the association of PDGFs/PDGFRs among Western Asian patients; PDGF/PDGFR mRNA expression and protein expression among gastric cancer patients were insignificant. In addition, PDGF/PDGFR status among gastric cancer patients was insignificant in overall effect analysis PDGF/PDGFR status has shown to predict reduced overall survival(HR = 1.25, 95% CI: 0.49–3.22, PHR = 0.64) and relapse free survival(HR = 0.93, 95% CI: 0.36–2.41, PHR = 0.88) insignificantly. Also, overall prognostic effect analysis(HR = 1.07, 95% CI: 0.58–1.96, PHR = 0.84) was insignificant.ConclusionPDGFs/PDGFRs status amongst gastric cancer patients plays a key role in clinical variables and nodal metastasis. These insights might be helpful in providing guidelines for diagnosis, molecular target therapy, and prognosis of gastric cancer.



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In vitro priming of adoptively transferred T cells with a ROR{gamma} agonist confers durable memory and stemness in vivo

Adoptive T cell transfer therapy is an FDA-approved treatment for leukemia that relies on the ex vivo expansion and re-infusion of a patient's immune cells, which can be engineered with a chimeric antigen receptor (CAR) for more efficient tumor recognition. Type 17 T cells, controlled transcriptionally by RORγ, have been reported to mediate potent anti-tumor effects superior to those observed with conventionally expanded T cells. Here we demonstrate that addition of a synthetic, small molecule RORγ agonist during ex vivo expansion potentiates the anti-tumor activity of human Th17 and Tc17 cells redirected with a CAR. Likewise, ex vivo use of this agonist bolstered the anti-tumor properties of murine tumor-specific CD4+ and CD8+ T cells. Expansion in the presence of the RORγ agonist enhanced IL-17A production without compromising IFN-γ secretion in vitro. In vivo, cytokine neutralization studies revealed that IFN-γ and IL-17A were required to regress murine melanoma tumors. The enhanced anti-tumor effect of RORγ agonist treatment was associated with recovery of more donor T cells in the tumor and spleen; these cells produced elevated levels of cytokines months after infusion and expressed markers of long-lived stem and central memory cells such as Tcf7 and CD62L. Conversely, untreated cells mainly exhibited effector phenotypes in the tumor. Cured mice previously treated with agonist-primed T cells were protected from tumor re-challenge. Collectively, our work reveals that in vitro treatment with a RORγ agonist generates potent anti-tumor Type 17 effector cells that persist as long-lived memory cells in vivo.

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Long chain n-3 fatty acids attenuate oncogenic KRas-driven proliferation by altering plasma membrane nanoscale proteolipid composition

Ras signaling originates from transient nanoscale compartmentalized regions of the plasma membrane composed of specific proteins and lipids. The highly specific lipid composition of these nanodomains, termed nanoclusters, facilitates effector recruitment and therefore influences signal transduction. This suggests that Ras nanocluster proteolipid composition could represent a novel target for future chemoprevention interventions. There is evidence that consumption of fish oil containing long-chain n-3 polyunsaturated fatty acids (n-3 PUFA) such as eicosapentaenoic acid (EPA, 20:5Δ5,8,11,14,17) and docosahexaenoic acid (DHA, 22:6Δ4,7,10,13,16,19) may reduce colon cancer risk in humans, yet the mechanism underlying this effect is unknown. Here we demonstrate that dietary n-3 PUFA reduce the lateral segregation of cholesterol-dependent and -independent nanoclusters, suppressing phosphatidic acid-dependent oncogenic KRas effector interactions, via their physical incorporation into plasma membrane phospholipids. This results in attenuation of oncogenic Ras-driven colonic hyperproliferation in both Drosophila and murine models. These findings demonstrate the unique properties of dietary n-3 PUFA in the shaping of Ras nanoscale proteolipid complexes and support the emerging role of plasma membrane-targeted therapies.

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Metabolic Imaging of the Human Brain with Hyperpolarized 13C Pyruvate Demonstrates 13C Lactate Production in Brain Tumor Patients

Hyperpolarized (HP) magnetic resonance imaging using [1-13C] pyruvate is a novel method that can characterize energy metabolism in the human brain and brain tumors. Here we present the first dynamically acquired human brain HP 13C metabolic spectra and spatial metabolite maps in cases of both untreated and recurrent tumors. In vivo production of HP lactate from HP pyruvate by tumors was indicative of altered cancer metabolism, while production of HP lactate in the entire brain was likely due to baseline metabolism. We correlated our results with standard clinical brain MRI, MRI DCE perfusion, and in one case FDG PET/CT. Our results suggest that HP 13C pyruvate-to-lactate conversion may be a viable metabolic biomarker for assessing tumor response.

https://ift.tt/2L6B0E7

Mathematical modeling predicts response to chemotherapy and drug combinations in ovarian cancer

Platinum-based chemotherapy constitutes the backbone of clinical care in advanced solid cancers such as high-grade serous ovarian cancer (HGSOC) and has prolonged survival of millions of cancer patients. Most of these patients, however, become resistant to chemotherapy, which generally leads to a fatal refractory disease. We present a comprehensive stochastic mathematical model and simulator approach to describe platinum resistance and standard-of-care (SOC) therapy in HGSOC. We used pre- and post-treatment clinical data, including 18F-FDG-PET/CT images, to reliably estimate the model parameters and simulate "virtual HGSOC patients." Treatment responses of the virtual patients generated by our mathematical model were indistinguishable from real-life HGSOC patients. We demonstrated the utility of our approach by evaluating the survival benefit of combination therapies that contain up to six drugs targeting platinum resistance mechanisms. Several resistance mechanisms were already active at diagnosis, but combining SOC with a drug that targets the most dominant resistance subpopulation resulted in a significant survival benefit. This work provides a theoretical basis for a cancer treatment paradigm in which maximizing platinum's killing effect on cancer cells requires overcoming resistance mechanisms with targeted drugs. This freely available mathematical model and simulation framework enable rapid and rigorous evaluation of the benefit of a targeted drug or combination therapy in virtual patients before clinical trials, which facilitates translating preclinical findings into clinical practice.

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Cancer-associated fibroblasts drive glycolysis in a targetable signaling loop implicated in head and neck squamous cell carcinoma progression

Despite aggressive therapies, head and neck squamous cell carcinoma (HNSCC) is associated with a less than 50% 5-year survival rate. Late stage HNSCC frequently consists of up to 80% cancer-associated fibroblasts (CAF). We previously reported that CAF-secreted hepatocyte growth factor (HGF) facilitates HNSCC progression, however very little is known about the role of CAFs in HNSCC metabolism. Here we demonstrate that CAF-secreted HGF increases extracellular lactate levels in HNSCC via upregulation of glycolysis. CAF-secreted HGF induced basic fibroblast growth factor (bFGF) secretion from HNSCC. CAFs were more efficient than HNSCC in using lactate as a carbon source. HNSCC-secreted bFGF increased mitochondrial oxidative phosphorylation (OXPHOS) and HGF secretion from CAFs. Combined inhibition of c-Met and FGFR significantly inhibited CAF-induced HNSCC growth in vitro and in vivo (p<0.001). Our cumulative findings underscore reciprocal signaling between CAF and HNSCC involving bFGF and HGF. This contributes to metabolic symbiosis and a targetable therapeutic axis involving c-Met and FGFR.

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An in vivo screen identifies PYGO2 as a driver for metastatic prostate cancer

Advanced prostate cancer displays conspicuous chromosomal instability and rampant copy number aberrations, yet the identity of functional drivers resident in many amplicons remain elusive. Here, we implemented a functional genomics approach to identify new oncogenes involved in prostate cancer progression. Through integrated analyses of focal amplicons in large prostate cancer genomic and transcriptomic datasets as well as genes upregulated in metastasis, 276 putative oncogenes were enlisted into an in vivo gain-of-function tumorigenesis screen. Among the top positive hits, we conducted an in-depth functional analysis on Pygopus family PHD finger 2 (PYGO2), located in the amplicon at 1q21.3. PYGO2 overexpression enhances primary tumor growth and local invasion to draining lymph nodes. Conversely, PYGO2 depletion inhibits prostate cancer cell invasion in vitro and progression of primary tumor and metastasis in vivo. In clinical samples, PYGO2 upregulation associated with higher Gleason score and metastasis to lymph nodes and bone. Silencing PYGO2 expression in patient-derived xenograft models impairs tumor progression. Lastly, PYGO2 is necessary to enhance the transcriptional activation in response to ligand-induced Wnt/β-catenin signaling. Together, our results indicate that PYGO2 functions as a driver oncogene in the 1q21.3 amplicon and may serve as a potential prognostic biomarker and therapeutic target for metastatic prostate cancer.

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Osteocyte-Driven Downregulation of Snail Restrains Effects of Drd2 Inhibitors on Mammary Tumor Cells

While bone is a frequent target of breast cancer-associated metastasis, little is known about the effects of tumor-bone interactions on the efficacy of tumor-suppressing agents. Here we examined the effect of two FDA-approved dopamine modulators, Fluphenazine (FP) and Trifluoperazine (TFP), on mammary tumor cells, osteoclasts, osteoblasts, and osteocytes. These agents suppressed proliferation and migration of mammary tumor cells chiefly by antagonizing dopamine receptor D2 and reduced bone resorption by downregulating nuclear factor of activated T-cells, cytoplasmic 1 (Nfatc1). Three-dimensional spheroid formation assays revealed that tumor cells have high affinity to osteocytes and type I collagen, and interactions with osteocytes as well as administration of FP and TFP downregulated Snail and suppressed migratory behaviors. Unlike the inhibitory action of FP and TFP on tumor growth, tumor-osteocyte interactions stimulated tumor proliferation by upregulating NFκB and Akt. In the bone microenvironment, osteocytes downregulated Snail and acted as an attractant as well as a stimulant to mammary tumor cells. These results demonstrate that tumor-osteocyte interactions strengthen dopamine receptor-mediated suppression of tumor migration but weaken its inhibition of tumor proliferation in the osteocyte-rich bone microenvironment.

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Estrogen receptor-negative progesterone receptor-positive breast cancer – “Nobody's land“ or just an artifact?

Publication date: June 2018
Source:Cancer Treatment Reviews, Volume 67
Author(s): Michał Kunc, Wojciech Biernat, Elżbieta Senkus-Konefka
The estrogen receptor α (ER) and the progesterone receptor (PgR) are one of the most important prognostic and predictive immunohistochemical markers in breast cancer. Breast cancers may express various profiles of hormone receptors: ER(+)/PgR(+), ER(−)/PgR(−), ER(+)/PgR(−) and ER(−)/PgR(+). The existence of the latter profile is a matter of controversy since PgR expressions is induced by ER-dependent pathways in breast cancer cells. One of the most extensively propagated hypotheses trying to explain the origin of ER(−)/PgR(+) breast cancers claims that they are technical artifacts dependent on the immunohistochemical procedure. On the other hand, in recent years there is a growing body of evidence, suggesting that such cancers create a unique group with distinct molecular and clinical features. In the following review, we present background theories on the ER(−)/PgR(+) breast cancer origin and their epidemiological and clinicopathological characteristics, including the predictive and prognostic significance of these rare tumors.



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Burnout in Oncologists is a serious issue: What can we do about it?

Publication date: Available online 16 May 2018
Source:Cancer Treatment Reviews
Author(s): Krithika Murali, Susana Banerjee
The cancer burden is rising globally with an increasing need for oncologists. The significant demands associated with caring for cancer patients within a rapidly evolving scientific field, poses manifold challenges, including the risk of work-related burnout. Surveys have already shown that the prevalence of burnout in oncologists worldwide is significant. There is growing concern that burnout has a detrimental impact on the wellbeing of oncologists and their patients. In this review article, we provide an oncologist's perspective on this important and topical issue. We have summarised the literature with regard to the consequences of physician burnout, its associated risk factors and previously evaluated solutions. We conclude by suggesting further strategies for addressing this problem.



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25. Unexpected favorable outcome in a patient with high grade B-cell lymphoma with abnormalities of MYC, BCL6 and BCL2 loci

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Hussam Al-Kateb, Thomas Adams, Deborah Fuchs, Patricia K Shadoan, Laurel Johnstone, Branden M Lau, Lee McGhan, Faiz Anwer




https://ift.tt/2L4eLyy

41. Feasibility of integrated testing for sequence and structural variants in the clinical setting

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Soheil Shams, Shalini Verma, Gordana Raca




https://ift.tt/2GpcHxI

33. SNP microarray autozygosity-directed mutation assessment of children and families with heritable retinal dystrophies in Costa Rica; identification of autosomal recessive mutations and one copy number variant

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Daynna J. Wolff, Iya Znoyko, W. Bailey Glen, Joaquin Martinez Arguedas, Rames Badilla Porras, Mae Millicent Peterseim




https://ift.tt/2Iq0deU

21. Clinical utility of comprehensive genomic profiling in pediatric acute leukemias

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Gordana Raca, Jianling Ji, Matthew Oberley, Deepa Bhojwani, Jaclyn Biegel, Matthew Hiemenz




https://ift.tt/2Gticvm

29. Development and validation of 15-min FISH hybridization technology for interphase and metaphase cytogenetic samples

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Ramesh Babu, Daniel L. Van Dyke, Stephen L. Papa, Ernesto Fuentes, Sarah Fuentes, Srikanthi Kopuri, Cynthia Williamson, Mingya Liu, Vaithilingam G. Dev, Jim Tepperberg, Stuart Schwartz, Peter Papenhausen, Prasad Koduru




https://ift.tt/2L6qn47

37. Microdeletions Including the RYR2 Gene Are Not Associated with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) in Four Unrelated Families

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Matthew Thomas, George McDaniel, Kaitlyn Amos, Eli Williams




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Editorial Board

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225





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5. Modeling Synovial Sarcoma from initiation through metastasis

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Mario Capecchi




https://ift.tt/2GoImPT

1. Detection of mosaicism and chimerism using SNP arrays in pediatric clinical testing: 10 year experience

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Laura K. Conlin, Brooke Weckselblatt, Jinbo Fan, Elaine Zackai, Matthew C. Dulik, Nancy B. Spinner, Minjie Luo




https://ift.tt/2GoLZ8g

23. Prevalence of KANK1-NTRK3 fusion in renal metanephric adenomas that lack BRAF mutations

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Aida Catic, Amina Kurtovic-Kozaric, Ardis Sophian, Lech Mazur, Faruk Skenderi, Ondrej Hes, Stephen Rohan, Dinesh Rakheja, Jillene Kogan, Michael R Pins




https://ift.tt/2L6yn5h

2. Two patients demonstrating the rare phenomenon of rod/ring mosaicism

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Natasha T. Strande, Melissa A. Hayden, Alexis F. Poss, Christie M. Turcott, Arti Pandya, Arthur S. Aylsworth, Kathleen W. Rao, Kathleen Kaiser-Rogers




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27. Treating patients with lymphoma as a paradigm for “personalized medicine”

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): James Armitage




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3. Unusual case of mosaic Robertsonian Down syndrome with three cell lines and review of history of Robertsonian translocations at Greenwood Genetic Center

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Barbara DuPont, Frank Bartel, Alka Chaubey




https://ift.tt/2GqzuJo

31. Assessing telomere length and chromosome aberrations in twin and unrelated astronauts

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Susan M. Bailey, Miles J. McKenna, Lynn Taylor, Kerry A. George




https://ift.tt/2L5jO1G

4. Non-invasive prenatal screening: Understanding the underlying mechanisms for discordance

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Rupa Udani, Kim Oxendine, Jennifer Laffin, Vanessa Horner




https://ift.tt/2IneRDJ

35. Runs of homozygosity (ROH) reveal that segmental-UPD is associated with the repair of genomic imbalance

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Andrea Penton, Peter Papenhausen, Stuart Schwartz, James Tepperberg




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39. Lessons learned from supplementary testing in constitutional and hematologic cases

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Teresa A. Smolarek, Kristen Sund, Nicki Smith, Deema Aljeaid, Priscila Badia Alonso, Brenton Francisco, Pamela Long, Jeremy Rubinstein, Robert Lorsbach, John Perentesis, Christine Phillips, K. Nicole Weaver, Lisa Dyer




https://ift.tt/2Imy2gQ

6. An algorithm to maximize detection of double/triple hit diffuse large B-cell lymphomas while reducing workload for the cytogenetic laboratory

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Hana Aviv, Ivana Maxwell, Lauri Goodell, James Van Gurp




https://ift.tt/2Gppi3G

43. Using directional genomic hybridization to discover and detect structural variation

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Miles McKenna, Erin Robinson, Susan Bailey, F. Andrew Ray, Michael Cornforth, Joel Bedford, Ed Goodwin




https://ift.tt/2L8pQyr

7. Clinical implications of cytogenetic heterogeneities in BCR-ABL1 fusion positive adult B cell acute lymphoblastic leukemia

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Xinyan Lu




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Infusion of alloanergized donor lymphocytes after CD34-selected haploidentical myeloablative hematopoietic stem cell transplantation

Purpose: Allogeneic haematopoietic stem-cell transplantation (HSCT) is a curative treatment for many haematologic cancers. Use of haploidentical (mismatched) donors increases HSCT availability but is limited by severe graft-versus-host disease (GvHD) and delayed immune reconstitution. Alloanergization of donor T-cells is a simple approach to rebuild immunity whilst limiting GvHD after haploidentical HSCT but the optimal T-cell dose and impact on immune reconstitution remain unknown.  Experimental Design: We performed a multicentre Phase 1 trial of alloanergized donor lymphocyte infusion (aDLI) after CD34-selected myeloablative haploidentical HSCT. The primary aim was feasibility and safety with secondary aims of assessing the less frequently addressed issue of impact on immune reconstitution. Results: Nineteen high-risk acute leukemia or myelodysplasia patients were enrolled. Engraftment occurred in 18/19 patients (95%). Pre-aDLI, twelve patients (63%) had bacteremia, 9/17 at-risk patients (53%) reactivated CMV and one developed acute GvHD. Sixteen patients received aDLI at dose-levels 1 (10³ T-cells/kg, n=4), 2 (10⁴, n=8), and 3 (10⁵, n=4). Post-aDLI, 5 patients developed clinically significant acute GvHD and 4/14 at-risk patients (29%) reactivated CMV. T-cell recovery was significantly greater and functional virus- and tumor-associated antigen-specific T-cells were detectable earlier in patients receiving dose-level 2 or 3 vs dose-level 1/no aDLI. Alloanergization of donor cells expanded the CD4⁺ T-regulatory cell frequency within aDLI which increased further in vivo without impeding expansion of virus- and tumor-associated antigen-specific T-cells. Conclusions: These data demonstrate safety and a potential role for aDLI in contributing to immune reconstitution and expanding tolerogenic regulatory T-cells in vivo after CD34-selected myeloablative haploidentical HSCT.

https://ift.tt/2IorGd2

Mitigating SOX2-potentiated immune escape of Head and Neck Squamous Cell Carcinoma with a STING-inducing nanosatellite vaccine

Purpose: The response rates of Head and Neck Squamous Cell Carcinoma (HNSCC) to checkpoint blockade are below 20%. We aim to develop a mechanism-based vaccine to prevent HNSCC immune escape. Experimental Design: We performed RNA-Seq of sensitive and resistant HNSCC cells to discover central pathways promoting resistance to immune killing. Using biochemistry, animal models, HNSCC microarray and immune cell deconvolution, we assessed the role of SOX2 in inhibiting STING-type I interferon (IFN-I) signaling-mediated anti-tumor immunity. To bypass SOX2-potentiated STING suppression, we engineered a novel tumor antigen-targeted nanosatellite vehicle to enhance the efficacy of STING agonist and sensitize SOX2-expressing HNSCC to checkpoint blockade. Results: The DNA-sensing defense response is the most suppressed pathway in immune-resistant HNSCC cells. We identified SOX2 as a novel inhibitor of STING. SOX2 facilitates autophagy-dependent degradation of STING and inhibits IFN-I signaling. SOX2 potentiates an immunosuppressive microenvironment and promotes HNSCC growth in vivo in an IFN-I-dependent fashion. Our unique nanosatellite vehicle significantly enhances the efficacy of STING agonist. We show that the E6/E7-targeted nanosatellite vaccine expands the tumor-specific CD8⁺ T-cells by over 12-fold in the tumor microenvironment and reduces tumor burden. A combination of nanosatellite vaccine with anti-PD-L1 significantly expands tumor-specific CTL and limits the populations expressing markers for exhaustion, resulting in more effective tumor control and improved survival. Conclusion: SOX2 dampens the immunogenicity of HNSCC by targeting the STING pathway for degradation. The nanosatellite vaccine offers a novel and effective approach to enhance the adjuvant potential of STING agonist and break cancer tolerance to immunotherapy.

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Time-to-event Bayesian Optimal Interval Design to Accelerate Phase I Trials

Late-onset toxicity is common for novel molecularly targeted agents and immunotherapy. It causes major logistic difficulty for existing adaptive phase I trial designs, which require the observance of toxicity early enough to apply dose escalation rules for new patients. The same logistic difficulty arises when the accrual is rapid. We propose the time-to-event Bayesian optimal interval (TITE-BOIN) design to accelerate phase I trials by allowing for real-time dose assignment decisions for new patients while some enrolled patients' toxicity data are still pending. Similar to the rolling six design, the TITE-BOIN dose escalation/de-escalation rule can be tabulated before the trial begins, making it transparent and simple to implement, but is more flexible in choosing the target DLT rate and has higher accuracy to identify the MTD. Compared to the more complicated model-based time-to-event continuous reassessment method (TITE-CRM), the TITE-BOIN has comparable accuracy to identify the MTD, but is simpler to implement with substantially better overdose control. As the TITE-CRM is more aggressive, it is less likely to underdose patients. A numerical study shows that the TITE-BOIN design supports continuous accrual, without sacrificing patient safety nor the accuracy of identifying the MTD, and therefore has great potential to accelerate early phase drug development.

https://ift.tt/2Iprr1i

Playing the melanoma endgame

Treatments for melanoma are of two main types: targeted therapies and immune checkpoint inhibitors. However, both are only effective in a subset of patients and are limited by acquired resistance.  Here, the authors present the preclinical basis to broadly target different forms of therapy-resistant melanoma.

https://ift.tt/2k5B9vc

Targeting the IDH2 Pathway in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis. A large percentage of patients succumb to this disease, in spite of aggressive treatments with chemotherapy. Recent advances with mutational analysis led to the discovery of isocitrate dehydrogenase (IDH) mutations in AML. IDH2 is an enzyme that catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate; its mutated version leads to the accumulation of the oncometabolite (R)-2 hydroxyglutarate, which disrupts several cell processes and leads to a blockage in differentiation. Targeting IDH2 is compelling, as it is an early and stable mutation in AML. Enasidenib, a specific small molecule inhibitor of IDH2, recently gained FDA approval for the treatment of patients with relapsed/refractory IDH2-mutated AML. In this review, we will focus on the indications and efficacy of enasidenib in the treatment of IDH2-mutated AML patients.

https://ift.tt/2Ip2EKJ

Comment on 'Domestic light at night and breast cancer risk: a prospective analysis of 105 000 UK women in the Generations Study'

Comment on 'Domestic light at night and breast cancer risk: a prospective analysis of 105 000 UK women in the Generations Study'

Comment on 'Domestic light at night and breast cancer risk: a prospective analysis of 105 000 UK women in the Generations Study', Published online: 17 May 2018; doi:10.1038/s41416-018-0060-7

Comment on 'Domestic light at night and breast cancer risk: a prospective analysis of 105 000 UK women in the Generations Study'

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Reply to ‘Comment on ‘Domestic light at night and breast cancer risk: a prospective analysis of 105 000 UK women in the Generations Study”

Reply to 'Comment on 'Domestic light at night and breast cancer risk: a prospective analysis of 105 000 UK women in the Generations Study"

Reply to 'Comment on 'Domestic light at night and breast cancer risk: a prospective analysis of 105 000 UK women in the Generations Study", Published online: 17 May 2018; doi:10.1038/s41416-018-0092-z

Reply to 'Comment on 'Domestic light at night and breast cancer risk: a prospective analysis of 105 000 UK women in the Generations Study"

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A systematic review of physical activity-based behaviour change interventions reaching men with prostate cancer

Abstract

Purpose

Men who are survivors of prostate cancer report a variety of psychological and physical factors contributing to a lower quality of life, and physical activity can assist to mitigate these issues. This review aims to provide a summary of physical activity behaviour change trials targeting prostate cancer survivors, assess the feasibility of these interventions and, if possible, identify intervention and study characteristics associated with significant intervention effects.

Method

Four databases (PubMed, CINAHL, PsycINFO and EMBASE) were systematically searched for randomised controlled trials containing at least one behavioural outcome relating to physical activity published up until July 2016. Forward and backwards, hand, key author citation searching and known research were also considered.

Results

From a total of 13, 828 titles, the search resulted in 12 studies (6 prostate cancer only and 6 mixed cancer interventions), eight of which found positive results most often related immediately to post-intervention aerobic activity. Factors relating to efficacy were not conclusive due to the heterogeneity of studies and lack of cancer-specific data in mixed cancer trials. Future research focusing on intervention reach, maintenance of intervention effects and resistance training outcomes is needed.

Conclusion

There is preliminary evidence to suggest that a variety of physical activity behaviour change interventions targeting men with a history of prostate cancer can be efficacious, at least in the short term. Experimental studies are required to identify key intervention features.

Implications for Cancer Survivors

Physical activity interventions can assist prostate cancer survivors in relation to short-term lifestyle change, though more evidence is required to improve the clarity of factors related to efficacy.

https://ift.tt/2wMub7A

The relationship between physical impairments, quality of life and disability of the neck and upper limb in patients following neck dissection

Abstract

Purpose

The purpose of this study was to examine the relationship between physical impairments, quality of life and disability in patients following neck dissection, with consideration of patient and clinical characteristics.

Methods

Cross-sectional study of patients < 5 years after neck dissection for head and neck cancer. Quality of life and self-reported disability were measured with the Neck Dissection Impairment Index, Quick Disabilities of the Arm, Shoulder and Hand, and Neck Disability Index. Active neck and shoulder range of motion and isometric muscle strength were also assessed. Generalised linear modelling was used to explore relationships between variables.

Results

Eighty-four participants (68% male, median age 61 years) demonstrated reduced quality of life (median (interquartile range) score = 76 (49, 93) from 0 (worst) to 100 (best)), and mild levels of upper limb (14 (2, 32)) and neck disability (14 (6, 28)) (from 0 (best) to 100 (worst)). Bilateral neck dissection was associated with reduced quality of life (coeff (95% CI) = − 12.49 (− 24.69, − 0.29)). Post-operative chemoradiation therapy was associated with reduced quality of life (− 21.46 (− 37.57, − 5.35)) and neck disability (0.71 (0.10, 1.32)). Measures of shoulder flexibility or strength were associated with quality of life and self-reported disability.

Conclusions

Quality of life and musculoskeletal disability after neck dissection are associated with factors from multiple domains including physical motor function and treatment modality.

Implications for Cancer Survivors

Having reduced shoulder flexibility or strength is related to functional deficits and quality of life after neck dissection for head and neck cancer.

https://ift.tt/2rHFucf

Weight-Loss Cognitive-Behavioural Treatment and Essential Amino Acid Supplementation in a Patient with Spinal Muscular Atrophy and Obesity

Spinal muscular atrophy is a genetic neuromuscular disease characterised by muscle atrophy, hypotonia, weakness, and progressive paralysis. Usually, these patients display increased fat mass deposition and reductions in fat-free mass and resting energy expenditure—an unfavourable condition that facilitates the development of obesity. However, weight management of these patients remains poorly described. Hence, the aim of this case report was to describe the clinical presentation and weight management of a 31-year-old male patient with spinal muscular atrophy type III, class I obesity, and metabolic syndrome treated for 1 year by means of a personalised multistep cognitive-behavioural treatment for obesity. The treatment produced a weight loss of 7.2 kg (7.1%), which was associated with a marked improvement in both the patient's self-reported general conditions and obesity-related cardiometabolic profile, and no adverse effects in terms of spinal muscular atrophy (i.e., reductions in fat-free mass or resting energy expenditure).

https://ift.tt/2rMbcVL

Comment on 'Domestic light at night and breast cancer risk: a prospective analysis of 105 000 UK women in the Generations Study'

https://ift.tt/2wMok27

Reply to ‘Comment on ‘Domestic light at night and breast cancer risk: a prospective analysis of 105 000 UK women in the Generations Study”

https://ift.tt/2rM2lmZ

Sarcomatoid Carcinoma of Urinary Bladder: a Case Report

Abstract

Sarcomatoid carcinoma is an extremely rare aggressive tumor variant comprising about 0.3% of all primary tumors of the urinary bladder and carries an overall dismal prognosis. Diagnosis is important and is sometimes difficult. Immunohistochemistry plays an important role in establishing diagnosis. We report a case with sarcomatoid variant of bladder urothelial carcinoma and review the pathologic features. A 65-year-old male on evaluation of long standing obstructive voiding symptoms and intermittent hematuria found to have a bladder mass. Magnetic resonance urography revealed a 35 × 45 mm mass at dome of urinary bladder with perivesical fat infiltration. He underwent transurethral resection and histopathology revealed pT1 high-grade malignant spindle cell tumor. He underwent radical cystoprostatectomy with bilateral extended pelvic lymphadenectomy with EPLND with ileal conduit urine diversion. Histopathology revealed high-grade muscle invasive spindle cell tumor. The diagnosis was uncertain and two differential diagnosis were kept, sarcomatoid carcinoma and pleomorphic sarcoma. Finally, IHC confirmed the final diagnosis of sarcomatoid carcinoma as it was positive for cytokeratin, CK – 8/18, GATA 3. All lymph nodes were negative for metastasis (pT2, N0, Mx). Recognition of the rare variants of the urinary bladder urothelial tumors is imperative as it is affects the overall management and hence prognosis. Immunohistochemistry plays a paramount role in establishing the diagnosis.

https://ift.tt/2Iq2McQ

Depressive Symptoms and Quality of Life Among Adolescent and Young Adult Cancer Survivors: Impact of Gender and Latino Culture

Journal of Adolescent and Young Adult Oncology, Ahead of Print.


https://ift.tt/2k1cDv6

Esophageal Metallic-Stent Migration: a Rare Cause of Anal Pain in a Patient with Gastric Cancer

Abstract

Stents are a great development for esophageal fistula treatment; however, stent migration is a frequent complication. A stent migration that caused anal pain is presented. A 79-year-old man with poorly differentiated gastric carcinoma was submitted to a total gastrectomy with a Roux-en-Y esophagojejunostomy. The patient developed an anastomosis leakage 3 months after surgery; a fixed metallic stent was used as treatment with good evolution. Five months after the stent (and 8 months after gastrectomy), the patient returned to the emergency department with acute incapacitating anal pain; the pain was caused by the migrated stent. Esophageal stent migration is frequent; however, rarely, metallic stent migration may cause anal pain.

https://ift.tt/2L7LPpd

Malignant Peripheral Nerve Sheath Tumor of the Parotid Gland

Abstract

Malignant peripheral nerve sheath tumor (MPNST) refers to spindle cell sarcomas arising from or separating in the direction of cells of peripheral nerve sheath. The MPNST of the parotid gland is an extremely rare tumor, accounts for < 5% of all soft tissue sarcomas, and carries a poor prognosis. In this article, we report a case of MPNST of parotid gland in a 45-year-old male and review its diagnostic and therapeutic challenges. A 45-year-old male presented with right parotid swelling for 2 years with rapid increase in size over the last 3 months. He underwent right total conservative parotidectomy with selective neck dissection. Reconstruction was done with microvascular anterolateral thigh flap. On immunohistochemistry, the tumor cells expressed CD 56 diffusely and S 100 focally. Tumor was immunonegative for CK, Desmin, SOX – 10, and SMA consistent with MPNST. The MPNSTs arising as parotid mass are very rare and aggressive tumors. The role of IHC is paramount in establishing the diagnosis. Multimodal management including wide surgical resection, neck dissection, and adjuvant chemoradiotherapy is the choice of treatment.

https://ift.tt/2rObsTl

Multiple Gastrointestinal Cancers in a Single Patient—a Rare Clinical Entity

Abstract

Multiple gastrointestinal cancers in a single patient is a rare entity. In our study, we are showing the clinical presentation and management of these patients. A fifty-nine-year-old asthenic male (already treated case of metachronous colorectal cancer in 2008 and 2011) presented with complaints of generalized weakness and fatigue. Strong family history was present with two of his first-degree relatives having diagnosed with gastrointestinal cancer at the age < 50 years with one of them having stomach carcinoma and another with GEJ tumors. On evaluation, upper GI endoscopy revealed growth at cardia and endoscopic biopsy revealed adenocarcinoma. Radiological evaluation with PET-CT scan revealed proximal stomach growth with regional lymphadenopathy. Patient was optimized for surgery and underwent D2 total gastrectomy, distal pancreatectomy and splenectomy with Roux-en-Y oesophago-jejunal anastomosis. Pathological stage revealed pT4N2M0, moderately differentiated adenocarcinoma of proximal stomach, both distal and proximal cut margins negative for tumor, LVI present with no perineural invasion, and 5/18 lymph nodes dissected were positive for malignancy. Genetic testing needs to be considered in this patient (modified Bethesda guidelines and IGCLC criteria). Familial gastric cancer are of two types: (a) hereditary diffuse gastric cancer syndrome, (b) familial intestinal type gastric cancer. Approximately 5% of patients have germ-line mutations—AD LYNCH syndrome, hereditary breast-ovarian cancer, and polyposis and non-polyposis syndrome. Once diagnosed in localized advanced stage, the best treatment is R0 resection though overall prognosis in these patients is very poor. So it is rationale to find such families with elevated risk and to do active surveillance for early diagnosis and providing prophylactic gastrectomies to them as it has proven to be beneficial in hereditary form of gastric cancer.

https://ift.tt/2Ipbegw

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC): Initial Experience from Indian Centers and a Review of Literature

Abstract

Cytoreductive surgery and HIPEC is a therapeutic option that benefits only selected patients with peritoneal metastases (PM). New treatments like pressurized intraperitoneal aerosol chemotherapy (PIPAC) have been developed to overcome some limitations of intraperitoneal chemotherapy and treat patients who are not eligible for a curative approach. The safety and feasibility of the procedure in the first few Indian patients treated with PIPAC, and the technique and the set-up required for PIPAC are described here. From May 2017 to August 2017, data was collected prospectively for all patients undergoing PIPAC at three Indian centers. The patients' characteristic, operative findings, and perioperative outcomes were recorded. Seventeen procedures were performed in 16 patients with peritoneal metastases from various primary sites using standard drug regimens developed for the procedure. The median hospital stay was 1 day, minor and major complications were seen in two patients each (11.7%), and there was one post-operative death. Of the six patients who completed at least 6 weeks of follow-up, there was disease progression in two, unrelated problems in two patients, and a second procedure was performed in one patient. One patient underwent subsequent CRS and HIPEC. Our results show the feasibility and safety of PIPAC in Indian patients with a low morbidity and mortality and short hospital stay. While clinical trials will determine its role in addition to systemic chemotherapy, it can be used in patients who have progressed on one or more lines of systemic chemotherapy and those who have chemotherapy-resistant ascites.

https://ift.tt/2rObkTR

Improving the safety of high‐dose methotrexate for children with hematologic cancers in settings without access to MTX levels using extended hydration and additional leucovorin

Pediatric Blood &Cancer, EarlyView.


https://ift.tt/2IPkLx3

Differentiated thyroid cancer in children: Heterogeneity of predictive risk factors

Pediatric Blood &Cancer, EarlyView.


https://ift.tt/2wHKen0

LAPTM4B gene copy number gain is associated with inferior response to anthracycline-based chemotherapy in hormone receptor negative breast carcinomas

Abstract

Purpose

To determine the associations between lysosomal-associated transmembrane protein 4b (LAPTM4B) gene copy number and response to different chemotherapy regimens in hormone receptor negative (HR-) primary breast carcinomas.

Patients and methods

Two cohorts were analyzed: (1) 69 core biopsies from HR-breast carcinomas treated with neoadjuvant chemotherapy (anthracycline based in 72.5% of patients and non-anthracycline based in 27.5% of patients). (2) Tissue microarray (TMA) of 74 HR-breast carcinomas treated with adjuvant therapy (77.0% of the patients received anthracycline, 17.6% of the patients non-anthracycline-based therapy, and in 5.4% of the cases, no treatment data are available). Interphase FISH technique was applied on pretreatment core biopsies (cohort I) and on TMAs (cohort II) using custom-made dual-labelled FISH probes (LAPTM4B/CEN8q FISH probe Abnova Corp.).

Results

In the neoadjuvant cohort in the anthracycline-treated group, we observed a significant difference (p = 0.029) of average LAPTM4B copy number between the non-responder and pathological complete responder groups (4.1 ± 1.1 vs. 2.6 ± 0.1). In the adjuvant setting, the anthracycline-treated group of metastatic breast carcinomas was characterized by higher LAPTM4B copy number comparing to the non-metastatic ones (p = 0.046). In contrast, in the non-anthracycline-treated group of patients, we did not find any LAPTM4B gene copy number differences between responder vs. non-responder groups or between metastatic vs. non-metastatic groups.

Conclusion

Our results confirm the possible role of the LAPTM4B gene in anthracycline resistance in HR− breast cancer. Analyzing LAPTM4B copy number pattern may support future treatment decision.

https://ift.tt/2God5wo

Constitutive Interferon Pathway Activation in Tumors as an Efficacy Determinant Following Oncolytic Virotherapy

Abstract

Background

Attenuated measles virus (MV) strains are promising agents currently being tested against solid tumors or hematologic malignancies in ongoing phase I and II clinical trials; factors determining oncolytic virotherapy success remain poorly understood, however.

Methods

We performed RNA sequencing and gene set enrichment analysis to identify pathways differentially activated in MV-resistant (n = 3) and -permissive (n = 2) tumors derived from resected human glioblastoma (GBM) specimens and propagated as xenografts (PDX). Using a unique gene signature we identified, we generated a diagonal linear discriminant analysis (DLDA) classification algorithm to predict MV responders and nonresponders, which was validated in additional randomly selected GBM and ovarian cancer PDX and 10 GBM patients treated with MV in a phase I trial. GBM PDX lines were also treated with the US Food and Drug Administration–approved JAK inhibitor, ruxolitinib, for 48 hours prior to MV infection and virus production, STAT1/3 signaling and interferon stimulated gene expression was assessed. All statistical tests were two-sided.

Results

Constitutive interferon pathway activation, as reflected in the DLDA algorithm, was identified as the key determinant for MV replication, independent of virus receptor expression, in MV-permissive and -resistant GBM PDXs. Using these lines as the training data for the DLDA algorithm, we confirmed the accuracy of our algorithm in predicting MV response in randomly selected GBM PDX ovarian cancer PDXs. Using the DLDA prediction algorithm, we demonstrate that virus replication in patient tumors is inversely correlated with expression of this resistance gene signature (ρ = –0.717, P = .03). In vitro inhibition of the interferon response pathway with the JAK inhibitor ruxolitinib was able to overcome resistance and increase virus production (1000-fold, P = .03) in GBM PDX lines.

Conclusions

These findings document a key mechanism of tumor resistance to oncolytic MV therapy and describe for the first time the development of a prediction algorithm to preselect for oncolytic treatment or combinatorial strategies.

https://ift.tt/2Io4krM

Activated prothrombin complex concentrate to reverse the factor Xa inhibitor (apixaban) effect before emergency surgery: a case series

The lack of an antidote against factor Xa inhibitors in case of major bleeding or need for urgent surgery is a concern to clinicians. Guidelines on managing major bleeding in patients under anticoagulation wit...

https://ift.tt/2Iq0v1c

Acute blindness as a presenting sign of childhood endemic Burkitt’s lymphoma in Cameroon: a case report

Endemic Burkitt's lymphoma is found predominantly in malaria holoendemic zones, typically in the tropical rain forest of Africa. It usually presents as an extra-nodal tumour in children and young adults with p...

https://ift.tt/2k39H1a

Contemporary enteral and parenteral nutrition before surgery for gastrointestinal cancers: a literature review

Abstract

Background

Gastrointestinal cancers are among the most recognised oncological diseases in well-developed countries. Tumours located in the digestive tract may cause the fast occurrence of malnutrition.

Main text

The perioperative period is a special time for systemic metabolism. Thanks to published guidelines, early universal control nutritional status before treatment, patients may have a chance to get suitable nutritional intervention. Although the first line of the intervention—nutritional consultation as well as the fortification of a diet and oral nutritional support (ONS)—is not debatable, in a case of inability of undergoing an oral feeding, the choice of the way of administration in patients before a surgery may represent a serious clinical obstacle.

Conclusions

Although there is broad agreement in the staging, classification, and role of surgery and nutritional status for outcomes of treatment of gastrointestinal cancers, there the way of nutritional intervention in patients with gastrointestinal cancer are still discussed.

https://ift.tt/2k2IwTW

The clinical features of radiation cataract in patients with ocular adnexal mucosa-associated lymphoid tissue lymphoma

To examine the clinical features of radiation cataract in patients with ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma.

https://ift.tt/2wIOZwQ

Clinical outcome of elderly patients (≥ 70 years) with esophageal cancer undergoing definitive or neoadjuvant radio(chemo)therapy: a retrospective single center analysis

To analyse the outcome of elderly patients (≥70 years) with esophageal cancer treated with curative intent radio(chemo)therapy.

https://ift.tt/2jZeD70

A new strategy for volumetric-modulated arc therapy planning using AutoPlanning based multicriteria optimization for nasopharyngeal carcinoma

A new strategy for making the appropriate choice of the representative optimization parameters in planning processes and accurate selection criteria during Pareto surface navigation for general multicriteria o...

https://ift.tt/2KvXVYr

The alfa and beta of tumours: a review of parameters of the linear-quadratic model, derived from clinical radiotherapy studies

Prediction of radiobiological response is a major challenge in radiotherapy. Of several radiobiological models, the linear-quadratic (LQ) model has been best validated by experimental and clinical data. Clinic...

https://ift.tt/2k59B93

A new strategy for volumetric-modulated arc therapy planning using AutoPlanning based multicriteria optimization for nasopharyngeal carcinoma

Abstract

Background

A new strategy for making the appropriate choice of the representative optimization parameters in planning processes and accurate selection criteria during Pareto surface navigation for general multicriteria optimization (MCO) was recommended in the study. The purpose was to combine both benefits of AutoPlanning optimization and MCO (APMCO) for achieving an individual volumetric-modulated arc therapy (VMAT) plan according to the clinically achieved patient-specific tradeoff among conflicting priorities. The preclinical investigation of this optimization approach for nasopharyngeal carcinoma (NPC) radiotherapy was performed and compared to general MCO VMAT.

Methods

A total of 60 NPC patients with various stages were enrolled in this study. General MCO and APMCO plans were generated for each patient on the treatment planning system. The differences between two planning schemes were evaluated and compared.

Results

All plans were capable of achieving the prescription requirement. The planning target volume coverage and conformation number were remarkably similar between general MCO and APMCO plans. There were no significant differences in most of organs at risk (OARs) sparing. However, in APMCO plans, relatively remarkable decreases were observed in the mean dose (D_mean) to the glottic larynx and pharyngeal constrictor muscles. The reductions of average D_mean to the two OARs were 10.5% (p < 0.0001) and 8.4% (p < 0.0001), respectively. APMCO technique was found to increase the planning time for an average of approximately 5 h and did not lead to a significant increase of monitor units compared to general MCO.

Conclusions

The potential of the APMCO strategy is best realized with a clinical implementation that exploits individual generation of Pareto surface representations without manual interaction. It also assists physicians to ensure navigation in a more efficient and straightforward manner.

https://ift.tt/2Ikw0Ot

The alfa and beta of tumours: a review of parameters of the linear-quadratic model, derived from clinical radiotherapy studies

Abstract

Background

Prediction of radiobiological response is a major challenge in radiotherapy. Of several radiobiological models, the linear-quadratic (LQ) model has been best validated by experimental and clinical data. Clinically, the LQ model is mainly used to estimate equivalent radiotherapy schedules (e.g. calculate the equivalent dose in 2 Gy fractions, EQD₂), but increasingly also to predict tumour control probability (TCP) and normal tissue complication probability (NTCP) using logistic models. The selection of accurate LQ parameters α, β and α/β is pivotal for a reliable estimate of radiation response. The aim of this review is to provide an overview of published values for the LQ parameters of human tumours as a guideline for radiation oncologists and radiation researchers to select appropriate radiobiological parameter values for LQ modelling in clinical radiotherapy.

Methods and materials

We performed a systematic literature search and found sixty-four clinical studies reporting α, β and α/β for tumours. Tumour site, histology, stage, number of patients, type of LQ model, radiation type, TCP model, clinical endpoint and radiobiological parameter estimates were extracted. Next, we stratified by tumour site and by tumour histology. Study heterogeneity was expressed by the I² statistic, i.e. the percentage of variance in reported values not explained by chance.

Results

A large heterogeneity in LQ parameters was found within and between studies (I² > 75%). For the same tumour site, differences in histology partially explain differences in the LQ parameters: epithelial tumours have higher α/β values than adenocarcinomas. For tumour sites with different histologies, such as in oesophageal cancer, the α/β estimates correlate well with histology. However, many other factors contribute to the study heterogeneity of LQ parameters, e.g. tumour stage, type of LQ model, TCP model and clinical endpoint (i.e. survival, tumour control and biochemical control).

Conclusions

The value of LQ parameters for tumours as published in clinical radiotherapy studies depends on many clinical and methodological factors. Therefore, for clinical use of the LQ model, LQ parameters for tumour should be selected carefully, based on tumour site, histology and the applied LQ model. To account for uncertainties in LQ parameter estimates, exploring a range of values is recommended.

https://ift.tt/2rMSDzN

The clinical features of radiation cataract in patients with ocular adnexal mucosa-associated lymphoid tissue lymphoma

Abstract

Background

To examine the clinical features of radiation cataract in patients with ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma.

Methods

Twenty-one patients with 26 eyes diagnosed with ocular adnexal MALT lymphoma (26 eyes), who were treated in Hokkaido University Hospital, were retrospectively reviewed based on medical records.

Results

Out of the 21 patients, 16 patients (21 eyes) received radiation therapy (RT) with a total dose of 30 Gy. All cases eventually achieved complete remission. Eight of these patients (11 eyes: 52.3%) required cataract surgery after RT. The mean age at surgery was 56.8 (40–70) years. The mean latency between RT and the indication for surgery was 43.3 months. The percentage of females was significantly higher in patients who required surgery (P < 0.01), compared with those without surgery. The eyes of patients who received bolus technique on radiation treatment developed cataract more frequently (P < 0.05). In contrast, none of the patients without RT required cataract surgery.

Conclusions

Patients with ocular adnexal MALT lymphoma who underwent surgery for radiation cataract were seen more often in relatively young, female patients, and surgery was required about 3 years after RT. A long-term observation may be needed for patients after RT for a tumor. A female sex and the bolus technique may be risk factors for radiation cataract.

https://ift.tt/2L5apr1

Clinical outcome of elderly patients (≥ 70 years) with esophageal cancer undergoing definitive or neoadjuvant radio(chemo)therapy: a retrospective single center analysis

Abstract

Background

To analyse the outcome of elderly patients (≥70 years) with esophageal cancer treated with curative intent radio(chemo)therapy.

Methods

Fifty five patients (median 75 years) receiving curative intent radio(chemo)therapy for esophageal cancer from 1999 to 2015 were retrospectively analyzed. Most patients showed locally advanced disease (T3/4:78%, N+:58%) with squamous cell histology (74%). Charlson comorbidity score was > 1 in 27%. 48 patients (87%) received definitive treatment while 7 patients were treated neoadjuvantly. RT was carried out as 3D-conformal treatment or IMRT. Concurrent chemotherapy was applied in 85%, mainly cisplatin/5-FU or mitomycin/5-FU. ¹⁸FDG-PET/CT staging was used in 65%.

Results

Median follow-up was 11 months (1–68) and 21 months in survivors. 1- and 2-year rates of LRC, DC, FFTF and OS were 60%/45, 81%/72, 55%/41 and 46%/26% for the entire cohort. In univariate analysis, addition of surgery was associated with improved LRC and FFTF, nodal involvement with improved DC and lower T stage, lower Charlson score and use of PET-CT with improved OS. In multivariate analysis, lower T stage and lower Charlson score remained significant for OS. Patients treated after 2008 showed a significantly improved FFTF (1-year FFTF 64% vs 35%) and OS (1-year OS 66% vs 24%). Maximum (chemo)radiation related grade3+ toxicity was observed in 80% including 7 deaths (13%). Grade5 toxicity was significantly associated with Charlson score (CS > 1:33% vs CS ≤ 1:5%) and treatment period (24% before vs 3% after 2008). The patients treated after 2008 included significantly more SCCs, less T4 stages, had a higher percentage of PET-CT staging and were treated with smaller field lengths. Trends were also observed for lower Charlson scores and increased use of IMRT.

Conclusion

Curative intent (chemo)radiation of elderly patients with esophageal cancer may result in considerable toxicity and unfavorable outcome. However, a clear improvement over time was observed in our cohort, probably based on improved patient selection. In patients with less advanced stages and lower comorbidity similar results as in younger cohorts seem achievable with modern staging and treatment approaches. Age per se should not be a decisive factor, but careful attention should be paid regarding patient selection including a structured and tight follow-up strategy.

https://ift.tt/2rMTmAZ

Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC)

Abstract

Immunotherapy is among the most rapidly evolving treatment strategies in oncology. The therapeutic potential of immune-checkpoint inhibitors is exemplified by the recent hail of Food and Drug Administration (FDA) approvals for their use in various malignancies. Continued efforts to enhance outcomes with immunotherapy agents have led to the formulation of advanced treatment strategies. Recent evidence from pre-clinical studies evaluating immune-checkpoint inhibitors in various cancer cell-lines has suggested that combinatorial approaches may have superior survival outcomes compared to single-agent immunotherapy regimens. Preliminary trials assessing combination therapy with anti-PD-1/PD-L1 plus anti-CTLA-4 immune-checkpoint inhibitors have documented considerable advantages in survival indices over single-agent immunotherapy. The therapeutic potential of combinatorial approaches is highlighted by the recent FDA approval of nivolumab plus ipilimumab for patients with advanced melanoma. Presently, dual-immune checkpoint inhibition with anti-programmed death receptor-1/programmed cell death receptor- ligand-1 (anti-PD-1/PD-L1) plus anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) monoclonal antibodies (MoAbs) is being evaluated for a wide range of tumor histologies. Furthermore, several ongoing clinical trials are investigating combination checkpoint inhibition in association with traditional treatment modalities such as chemotherapy, surgery, and radiation. In this review, we summarize the current landscape of combination therapy with anti-PD-1/PD-L1 plus anti-CTLA-4 MoAbs for patients with melanoma and non-small cell lung cancer (NSCLC). We present a synopsis of the prospects for expanding the indications of dual immune-checkpoint inhibition therapy to a more diverse set of tumor histologies.

https://ift.tt/2Im66de

γ-Tocotrienol induces apoptosis in pancreatic cancer cells by upregulation of ceramide synthesis and modulation of sphingolipid transport

Abstract

Background

Ceramide synthesis and metabolism is a promising target in cancer drug development. γ-tocotrienol (GT3), a member of the vitamin E family, orchestrates multiple effects that ensure the induction of apoptosis in both, wild-type and RAS-mutated pancreatic cancer cells. Here, we investigated whether these effects involve changes in ceramide synthesis and transport.

Methods

The effects of GT3 on the synthesis of ceramide via the de novo pathway, and the hydrolysis of sphingomyelin were analyzed by the expression levels of the enzymes serine palmitoyl transferase, ceramide synthase-6, and dihydroceramide desaturase, and acid sphingomyelinase in wild-type RAS BxPC3, and RAS-mutated MIA PaCa-2 and Panc 1 pancreatic cancer cells. Quantitative changes in ceramides, dihydroceramides, and sphingomyelin at the cell membrane were detected by LCMS. Modulation of ceramide transport by GT3 was studied by immunochemistry of CERT and ARV-1, and the subsequent effects at the cell membrane was analyzed via immunofluorescence of ceramide, caveolin, and DR5.

Results

GT3 favors the upregulation of ceramide by stimulating synthesis at the ER and the plasma membrane. Additionally, the conversion of newly synthesized ceramide to sphingomyelin and glucosylceramide at the Golgi is prevented by the inhibition of CERT. Modulation ARV1 and previously observed inhibition of the HMG-CoA pathway, contribute to changes in membrane structure and signaling functions, allows the clustering of DR5, effectively initiating apoptosis.

Conclusions

Our results suggest that GT3 targets ceramide synthesis and transport, and that the upregulation of ceramide and modulation of transporters CERT and ARV1 are important contributors to the apoptotic properties demonstrated by GT3 in pancreatic cancer cells.

https://ift.tt/2KwfGH3

Patterns of care for anal cancer in the United States - a comparison between academic and community cancer centers

Abstract

Background

Management of squamous cell carcinoma of the anus (SCCA) is becoming more relevant, as its incidence increases. The purpose of this study was to investigate possible differences in patient population and care delivery for SCCA between academic and community cancer programs in the United States.

Methods

A review of available data from the American College of Surgeons Committee on Cancer National Cancer DataBase focused on gender, age, race, type of health insurance, comorbidity score, distance traveled for care, stage at diagnosis, and therapy utilization (surgery, chemotherapy, and radiation therapy) as first course of treatment (FCT). The analysis included 38,766 patients treated for SCCA. Of them, 14,422 patients received treatment at Academic Cancer Programs (ACPs), while 24,344 were treated at Community Cancer Programs (CCPs) between the years 2003 and 2013.

Results

Over the 11-year study period, ACPs had significantly more male patients, of younger age, a greater non-white race population, with more Medicaid or no insurance coverage, who traveled farther for cancer center care (p < 0.001). There was no difference between ACPs and CCPs with respect to Charlson co-morbidity score and stage of SCCA at diagnosis. For stage 0 patients, use of chemotherapy was 8% for ACPs, 9% for CCPs, and use of radiotherapy was 10% for ACPs and 14% for CCPs. The incidence of stage unknown was identical at both ACPs and CCPs (11.5%). CCPs had a greater overall utilization of radiation therapy as FCT for stage 0, I, II and IV patients (p < 0.001).

Conclusions

Our study indicates that gender, demographic and socio-economic differences exist in the patient population with SCCA accessing different cancer programs in the US. The high incidence of stage unknown patients reflects ongoing challenges in the pre-treatment phase. A significant percentage of stage 0 patients received systemic chemotherapy and/or radiotherapy, rather than surgery alone. Despite comparable stage at diagnosis and comorbidity scores between ACPs and CCPs, there appear to be variations in treatment choices, especially with the use of radiotherapy, with associated cost and toxicity risks. Further analysis and monitoring of SCCA management in the US may lead to improved compliance with NCCN guidelines.

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BioPro-RCMI-1505 trial: multicenter study evaluating the use of a biodegradable balloon for the treatment of intermediate risk prostate cancer by intensity modulated radiotherapy; study protocol

Abstract

Background

Prospective trials have demonstrated the advantage of dose-escalated radiotherapy for the biochemical and clinical control of intermediate risk prostate cancer. Dose escalation improves outcomes but increases risks of urinary and bowel toxicity. Recently the contribution of "spacers" positioned in the septum between the rectum and the prostate could improve the functional results of intensity modulated radiation therapy (IMRT). To date most of the evaluated devices were polyethylen glycol (PEG) and hyaluronic acid (HA). Men on the Spacer arm had decreased bowel toxicity and less decline in both urinary and bowel quality of life as compared to Control men in a randomized trial.

Methods

This is an interventional, multi-center study to evaluate the use of biodegradable inflatable balloon for patients with intermediate risk prostate cancer treated by IMRT (74 to 80 Gy, 2 Gy/fraction) with daily image guided radiotherapy.

Discussion

This multicenter prospective study will yield new data regarding dosimetric gain and implantation stages of Bioprotect balloon. Acute and late toxicities and quality of life will be registered too.

Trial registration

NCT02478112, date of registration: 15/06/2015.

https://ift.tt/2Kq3GGX

Knowledge towards cervical cancer prevention and screening practices among women who attended reproductive and child health clinic at Magu district hospital, Lake Zone Tanzania: a cross-sectional study

Abstract

Background

Cervical cancer is a global leading cause of morbidity and mortality, attributable to the death of approximately 266,000 women every year. Majority (87%) of cervical cancer deaths occur in developing countries including Tanzania. Though knowledge of cervical cancer is an important determinant of women's participation in prevention and screening for cervical cancer, little is known about this topic in Tanzania. This study aimed to determine the knowledge of cervical cancer prevention services and screening practices among women who attended Reproductive Child Health clinic at a district hospital in Lake Zone, Tanzania. This information is important to help designing appropriate interventions and scaling up cervical cancer control programs, hence accelerate the achievement towards Sustainable Development Goals.

Methods

A cross-sectional study was conducted from March to June 2017, involving 307 women attending reproductive and child health clinic at Magu district hospital. A questionnaire adopted from the validated Cervical Cancer Awareness Measure was used to collect data from the study participants. Data was analysed using SPSS version 20. Descriptive statistics were summarized using frequencies and percentages for categorical variables while mean and standard deviation was used for continuous variables. Multivariable logistic regressions model was used to estimate Adjusted Odds ratio with 95% CI for factors associated with knowledge.

Results

Knowledge of cervical cancer was low, where 82.7% of the women scored less than 50%. Majority (82.4%) were aware about cervical cancer. Secondary education or higher (OR = 7.77, 95% CI: 1.70-35.48) and "knowing someone who has ever had cervical cancer" (OR = 2.19, 95% CI: 1.16-4.13) were significantly associated with higher knowledge. Only 14.3% of participants practiced cervical cancer screening.

Conclusions

Majority of women lack comprehensive knowledge of cervical cancer and only few utilize screening services. Strategies for awareness creation about cervical cancer may help to improve knowledge and utilization of cancer screening practices.

https://ift.tt/2Ij4ZL8

Advances on chimeric antigen receptor-modified T-cell therapy for oncotherapy

Abstract

Tumor treatment is still complicated in the field of medicine. Tumor immunotherapy has been the most interesting research field in cancer therapy. Application of chimeric antigen receptor T (CAR-T) cell therapy has recently achieved excellent clinical outcome in patients, especially those with CD19-positive hematologic malignancies. This phenomenon has induced intense interest to develop CAR-T cell therapy for cancer, especially for solid tumors. However, the performance of CAR-T cell treatment in solid tumor is not as satisfactory as that in hematologic disease. Clinical studies on some neoplasms, such as glioblastoma, ovarian cancer, and cholangiocarcinoma, have achieved desirable outcome. This review describes the history and evolution of CAR-T, generalizes the structure and preparation of CAR-T, and summarizes the latest advances on CAR-T cell therapy in different tumor types. The last section presents the current challenges and prospects of CAR-T application to provide guidance for subsequent research.

https://ift.tt/2L6bnU2

Access to quality gynecologic oncology care: A work in progress

Cancer, EarlyView.


https://ift.tt/2k2vype

Access to gynecologic oncology care and the network adequacy standard

Cancer, EarlyView.


https://ift.tt/2KuRaGi

68 Ga-PSMA-PET/CT for the evaluation of pulmonary metastases and opacities in patients with prostate cancer

Abstract

Background

The purpose of this study was to investigate the imaging properties of pulmonary metastases and benign opacities in ⁶⁸Ga-PSMA positron emission tomography (PET) in patients with prostate cancer (PC).

Methods

⁶⁸Ga-PSMA-PET/CT scans of 739 PC patients available in our database were evaluated retrospectively for lung metastases and non-solid focal pulmonary opacities. Maximum standardized uptake values (SUV_max) were assessed by two- and three-dimensional regions of interest (2D/3D ROI). Additionally CT features of the lesions, such as location, morphology and size were identified.

Results

Ninety-one pulmonary metastases and fourteen opacities were identified in 34 PC patients. In total, 66 PSMA-positive (72.5%) and 25 PSMA-negative (27.5%) metastases were identified. The mean SUV_max of pulmonary opacities was 2.2±0.7 in 2D ROI and 2.4±0.8 in 3D ROI. The mean SUV_max of PSMA-positive pulmonary metastases was 4.5±2.7 in 2D ROI and in 4.7±2.9 in 3D ROI; this was significantly higher than the SUV_max of pulmonary opacities in both 2D and 3D ROI (p<0.001). The mean SUV_max of PSMA-negative metastases was 1.0±0.5 in 2D ROI and 1.0±0.4 in 3D ROI, and significantly lower than that of the pulmonary opacities (p<0.001). A significant (p<0.05) weak linear correlation between size and 3D SUV_max in lung metastases (ρ_Spearman=0.207) was found.

Conclusion

Based on the SUV_max in ⁶⁸Ga-PSMA-PET alone, it was not possible to differentiate between pulmonary metastases and pulmonary opacities. The majority of lung metastases highly overexpressed PSMA, while a relevant number of metastases were PSMA-negative. Pulmonary opacities demonstrated a moderate tracer uptake, significantly lower than PSMA-positive lung metastases, yet significantly higher than PSMA-negative metastases.

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Animal models for studying tumor microenvironment (TME) and resistance to lymphocytic infiltration

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https://ift.tt/2KwaeE5

Effectiveness of adjunct psychotherapy for cancer treatment: a review

Future Oncology, Ahead of Print.


https://ift.tt/2wL0eET

After TCGA: Building Clinical Genomic Resources

The Center for Cancer Genomics (CCG) continues to build genomic resources with a special focus on clinical features and patient outcome. A new wave of cancer characterization projects will generate data relevant for precision medicine and build on the legacy left by The Cancer Genome Atlas, which officially concluded in April 2018.

https://ift.tt/2IprTfT

Dying to communicate: apoptotic functions of Eph/Ephrin proteins

Abstract

The Erythropoietin-producing human hepatocellular carcinoma (Eph) receptors constitute the largest family of receptor tyrosine kinases and interact with a group of ligands called Ephrins. An essential feature of the Eph receptors and Ephrin ligands is that both are membrane-bound and, upon cell–cell interaction, initiate a bidirectional signaling involving both the receptor (forward signaling) and the ligand (reverse signaling). They regulate a large set of pleiotropic functions in virtually every tissue and physiological system. In vitro as well as in vivo data support a role for Eph and Ephrin molecules in cellular processes such as proliferation, cell–cell attraction and repulsion, motility and sorting. An increasing amount of evidence supports a role for these molecules in apoptosis and, although this function in cell death has been barely examined, the available information warrants a global consideration, to identify unmet needs and potential research avenues. Here we propose a comprehensive analysis of the data available regarding the importance of Ephs and Ephrins in cell death mechanisms throughout a large array of physiological systems.

https://ift.tt/2IkXLq5

Unusual cystic lung metastasis

Description 

A 35-year-old woman was recently diagnosed with cervical cancer, confirmed by histology to be squamous cell cancer. A CT of the chest performed as a part of her initial workup did not show any clear evidence of metastasis (figure 1). She underwent chemoradiotherapy with external beam radiotherapy and cisplatin. A positron-emission tomography (PET)-CT of the chest 12 weeks later demonstrated multiple 18F-Fluorodeoxyglucose  (FDG)-avid lung nodules suggestive of disease progression (figure 2). She subsequently received palliative therapy with carboplatin and paclitaxel. A follow-up CT chest 4 months later showed multiple bilateral randomly distributed cystic lesions of different sizes (largest measuring 29 mm) that were not seen on prior imaging (figure 3). These have been diagnosed as metastatic cystic lung disease.

Figure 1

Normal initial CT scan.

Figure 2

Multiple FDG-avid lung nodules on positron - emission tomography-CT.

...

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Metabolic acidosis in short bowel syndrome: think D-lactic acid acidosis

Short bowel syndrome (SBS) is a condition when a person's gastrointestinal function is insufficient to supply the body with essential nutrients and hydration. Patients with SBS suffer from diarrhoea and symptoms of malabsorption such as weight loss, electrolyte disturbances and vitamin deficiencies. Long-term management of this condition can be complicated by the underlying disease, the abnormal bowel function and issues related to treatment like administration of parenteral nutrition and the use of a central venous catheter. Here, we describe a case of D-lactic acid acidosis, a rarer complication of SBS, presenting with generalised weakness and severe metabolic acidosis.

https://ift.tt/2Ir1puG

Use of CSF infusion studies to unblock occluded hydrocephalus ventricular shunt catheters: a preliminary report of two patients

Two patients with ventriculoperitoneal shunts presented with symptoms of raised intracranial pressure indicative of possible shunt malfunction. During investigation, to eliminate this possibility, cerebral spinal fluid infusion studies were performed, which indicated proximal occlusion of the shunts in both cases. Retrograde flush of the ventricular catheter was performed during temporary compression of the siphon-control device, a manoeuvre which blocks distal flow. After the use of this technique, both patients' symptoms improved and they have remained symptom-free for over 2 years. This case report validates the role that infusion studies can play in clearing a blocked ventricular catheter shunt.

https://ift.tt/2IHymGn

Pyopericardium progressing to tamponade in a patient with immune thrombocytopenia

Pericardial effusion can develop during any stage of pericarditis, and small effusions that appear rapidly can cause cardiac tamponade. Pyopericardium is a rare aetiology for tamponade. This is a case of an elderly diabetic lady, on steroid therapy for immune thrombocytopenia, who presented with fever and acute dyspnoea. She developed cardiac tamponade due to pyopericardium with Staphylococcus as the causative organism. Staphylococcus pyopericardium, in the absence of a primary focus of infection, progressing to tamponade is an uncommon scenario.

https://ift.tt/2Ir1miu

Intraoperative intraluminal injection of N-acetylcysteine allowing treatment of distal intestinal obstruction syndrome without the need for enterotomy

We describe a case of an 18-year-old man who suffers from cystic fibrosis and developed distal intestinal obstruction syndrome while being treated as an inpatient. Following failed medical management, we proceeded to laparotomy where the small bowel was decompressed with retrograde milking into the stomach, leaving a section of impacted stool in the distal ileum. N-acetylcysteine was injected into the bowel lumen proximal to the obstruction. This resulted in dissolution of the stool without the need for enterotomy and is, to our knowledge, the first successful example of this technique in the literature.

https://ift.tt/2IKThZa

Pneumoperitoneum in a neonate weighing less than 500 g. What do we really know about it?

Pneumoperitoneum in preterm infants is a surgical emergency as it is usually indicative of intestinal perforation. Rare cases of idiopathic pneumoperitoneum have been described in the literature, the underlying causes and pathophysiology of which remain uncertain. We present a case of pneumoperitoneum in an extremely preterm infant with severe growth restriction. This occurred while she was receiving high frequency oscillatory ventilation. She had respiratory distress syndrome with pulmonary interstitial emphysema. The pneumoperitoneum occurred in isolation. Despite the insertion of two surgical drains and two exploratory laparotomies in which no obvious intestinal perforation was noted, the free air in the abdomen reaccumulated. A decision was made to manage it conservatively. She was successfully extubated on the fourth week of life and the pneumoperitoneum resolved spontaneously. She was discharged home on day 136 of life. This case highlights our limited understanding of the intricate physiology of extremely low birthweight preterm neonates.

https://ift.tt/2Ir1eQ2

Sturge-Weber syndrome-associated glaucoma and intraocular osseous metaplasia: a unique complicated case

A 30-year-old European man was admitted to our centre complaining about severe pain of the right eye (OD) and right part of the face, redness and no vision of the OD. He had an 18-year history of secondary to Sturge-Weber syndrome glaucoma, 6-month history of red eye and 1-week history of pain in OD. The best-corrected visual acuity was no light perception OD and 20/20 OS. Intraocular pressure was 36 mm Hg OD. Examination revealed endophthalmitis, Sturge-Weber syndrome-associated glaucoma and complicated cataract of OD.

Unfortunately, no prescribed treatment helped this patient, so evisceration of OD was performed. During the evisceration, a subretinal 20 mm in width and 22 mm in length osseous tissue, partially vascularised, was removed surgically and was sent to the histological laboratory. Histopathologically, there were data of active inflammatory process, retinal detachment due to huge subretinal osseous metaplasia, gliosis and retinal pigment epithelial hyperplasia, and druses with ossification.

https://ift.tt/2INM6Qc

Unusual case of iron overload with cancer-mimicking abdominal splenosis

A 48-year-old man, former alcohol abuser and drug addicted, was referred to our tertiary referral centre for iron disorders because of marked hyperferritinaemia. His clinical history revealed chronic hepatitis C, ß-thalassaemia trait and post-traumatic splenectomy at age of 22. MRI-estimated liver iron content was markedly elevated, while first-line genetic test for haemochromatosis was negative. Alpha-fetoprotein was increased but liver ultrasonography did not reveal focal liver lesions. Multiphasic contrast-enhanced CT confirmed this result but showed two abdominal masses (diameter of 9 cm and 7 cm, respectively) among bowel loops, strongly suspicious for cancer. However, biopsy of one of the masses led to the final diagnosis of abdominal splenosis.

https://ift.tt/2IngAF3

Unique presentation of a ruptured Meckels diverticulum after blunt trauma

Description 

A 25-year-old man with no significant medical or surgical history presented with a complaint of thick, dark drainage from a periumbilical wound for 1 month (figure 1). He reported first noticing the drainage several days after bumping into the corner of a machine at work. He was seen by his primary care physician and prescribed oral antibiotics for persistent drainage and erythema; however, his symptoms failed to improve.

Figure 1

Chronic umbilical wound sustained after blunt abdominal trauma, with drainage of a thick, dark fluid for 1 month.

On presentation to the emergency department, the patient was afebrile and haemodynamically stable. Lab work was within normal limits. An abdominal CT scan demonstrated a loculated periumbilical fluid collection, with extension intraperitoneally into a portion of thickened small bowel with suspicion of an enterocutaneous fistula (figure 2).

Figure...

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Impact of targeting transforming growth factor β-2 with antisense OT-101 on the cytokine and chemokine profile in patients with advanced pancreatic cancer

https://ift.tt/2rNEByP

Long noncoding RNA GAPLINC promotes gastric cancer cell proliferation by acting as a molecular sponge of miR-378 to modulate MAPK1 expression

https://ift.tt/2GoWh8j

Current state of surgical training using cadavers in Japan compared with Western countries

Abstract

Surgical skill training using cadavers is important for surgeons to gain an understanding of anatomical approaches. However, the laws and guidelines stipulating surgical technique training using corpses differ in each country. We discuss the new guidelines and the current situation in Japan in comparison with that in Western Europe and the United States.

https://ift.tt/2rMhwfc

Neonatal mitochondrial leukoencephalopathy with brain and spinal involvement and high lactate: expanding the phenotype of ISCA2 gene mutations

Abstract

A homoallelic missense founder mutation of the iron-sulfur cluster assembly 2 (ISCA2) gene has been recently reported in six cases affected by an autosomal recessive infantile neurodegenerative mitochondrial disorder. We documented a case of a 2-month-old girl presenting with severe hypotonia and nystagmus, who rapidly deteriorated and died at the age of three months. Increased cerebral spinal fluid level of lactate, documented also at the brain spectroscopy, involvement of the cortex, restricted diffusion of white and gray matter abnormalities, sparing of the corpus callosum and extensive involvement of the spinal cord were observed. Her clinical presenting features and course as well as some neuroradiological findings mimicked those of early-onset leukoencephalopathy with brainstem and spinal cord involvement and high brain lactate (LBSL). The analysis of the mitochondrial respiratory chain function showed a reduced activity of complexes II and IV. The girl harboured two heterozygous mutations in the ISCA2 gene. A comprehensive review of the literature and a comparison with the cases of early onset LBSL enabled us to highlight significant differences in the clinical, biochemical and neuroradiological phenotype between the two conditions, which also emerged from the comparison with the other 6 reported cases of ISCA2 gene mutation previously reported. In summary, this represents the second report ever published associating ISCA2 gene mutation with a mitochondrial leukoencephalopathy, with a different genetic mechanism to the previous cases. Molecular analysis of ISCA2 should be included in the genetic panel for the diagnosis of early onset mitochondrial leukoencephalopathies.

https://ift.tt/2GmEG0N

Late-onset cobalamin C deficiency Chinese sibling patients with neuropsychiatric presentations

Abstract

The Cobalamin C deficiency (cblC), characterized with elevated methylmalonic acidemia and homocystinuria in plasma, is an inborn error of cobalamin metabolism. The late-onset cblC siblings patients were rarely reported. In this study, we analyzed the clinical presentations and treatment outcomes of late-onset cblC in Chinese sibling patients with neuropsychiatric presentations. The clinical data of four pairs of Chinese patients were retrospectively analyzed. Serum homocysteine, urine organic acids measurements, neuroimaging exams and gene analysis were carried out in all patents. Patients were reevaluated after treatments with cobalamin, folate, betaine, L-carnitine and compound vitamin B. The mean age at disease onset was 13.7 (range 2–19) years. The neuropsychiatric disturbances including cognitive decline (3/8), psychiatric disturbances (4/8), gait instability (2/8), lower extremity weakness and numbness (3/8) and thromboembolic events (1/8). Two patients suffered nephropathy. The mean serum homocysteine when patients were diagnosed was 109.4 (range 69.5–138) μM/L. The abnormal radioimaging included scoliosis by X-ray (5/6), cerebral atrophy (4/6) and spinal cord atrophy (3/6) by MRI scan. Three pairs of siblings showed heterozygous mutations of MMACHC gene including c.482G > A (4/6), c.354G > C (2/6), c.570insT (2/6), c.445_446del (2/6) and c.656_4658del (2/6). The other two siblings showed homozygous mutation with c.452A > G in MMACHC gene. After treatments, the psychiatric symptoms were obviously relieved in all the patients. In Chinese siblings with late-onset cblC, the main clinic manifestation and abnormal radioimaging were cognitive decline and cerebral atrophy respectively. The most common gene mutation was c.482G > A of MMACHC gene. The patients responded well to the treatments.

https://ift.tt/2rJ4m3i

Comments on: insomnia, postpartum depression and estradiol in women after delivery

https://ift.tt/2Gl3mXC

Vanillic acid attenuates cerebral hyperemia, blood-brain barrier disruption and anxiety-like behaviors in rats following transient bilateral common carotid occlusion and reperfusion

Abstract

Transient bilateral common carotid artery occlusion (tBCCAO), followed by reperfusion, is a model of transient global hypoperfusion. In the present study we aimed to investigate the probable effects of Vanillic acid (VA) on some physiological parameters including cerebral hyperemia, blood-brain barrier (BBB) disruption, anxiety behaviors and neurological deficits induced by bilateral occlusion of the common carotid arteries and reperfusion (BCCAO/R) in rats. Rats were randomly divided into four groups; Sham, BCCAO/R, VA and VA+ BCCAO/R. Chronic cerebral hypoperfusion was induced after 2 weeks of pretreatment by VA. Subsequently, sensorimotor scores, elevated plus maze tests, cerebral hyperemia, and BBB disruption were evaluated 72 h after 30 min of BCCAO. Pretreatment of rats by VA improved sensory motor signs, anxiolytic behavior in BCCAO/R rats compared with untreated rats (p < 0.05). Further, VA attenuated reactive hyperemia and BBB disruption in BCCAO/R rats compared with untreated rats (p < 0.01). To our knowledge, this study is the first to reveal VA could attenuate reactive hyperemia and improve BBB disruption following BCCAO/R, and could improve neurological scores and anxiety like behaviors in this model of cerebral hypoperfusion. These results suggest that VA could be a promising pretreatment agent in cerebral hypoperfusion.

https://ift.tt/2k1ySkJ

Neuroprotective effect of p-coumaric acid in mice with cerebral ischemia reperfusion injuries

Abstract

Cerebral ischemia reperfusion (IR) is associated with neuronal death, which leads to disability and cognitive decline. The pathomechanism occurs because ischemia is exacerbated during the reperfusion period. Neuronal damage susceptibility depends on the affected brain areas and the duration of ischemia. Prevention and supplementation to neurons may help them endure during IR and further benefit them in rehabilitation. We investigated the protective effect of p-coumaric acid (PC) on cerebral IR injuries in mice. We randomly divided 30 male ICR mice into 3 groups of Sham (received vehicle and not induced IR), Control-IR (received vehicle and induced IR) and PC-IR (received 100 mg/kg PC and induced IR). We orally administered vehicle or 100 mg/kg of p-coumaric acid for 2 weeks before inducing the cerebral IR injuries by using 30 min of a bilateral common carotid artery occlusion followed by a 45-min reperfusion. We induced the IR condition in the Control-IR and PC-IR groups but not the Sham group, and only the PC-IR group received p-coumaric acid. After IR induction, we sacrificed all the mice and collected their brain tissues to evaluate their oxidative statuses, whole brain infarctions and vulnerable neuronal deaths. We studied the whole-brain infarction volume by 2, 3, 5-triethyltetrazoliumchloride staining of sections. We performed a histological investigation of the vulnerable neuronal population in the dorsal hippocampus by staining brain sections with 0.1% cresyl violet. The results indicated that IR caused significant increases in calcium and malondialdehyde (MDA) levels, whole brain infarction volume and hippocampal neuronal death. Pretreatment with p-coumaric acid significantly reduced MDA levels, whole-brain infarction volume and hippocampal neuronal death together and increased catalase and superoxide dismutase activities. We conclude here that pretreating animals with p-coumaric acid can prevent IR-induced brain oxidative stress, infarction size and neuronal vulnerability to death in cerebral IR injuries.

https://ift.tt/2IrNR1M

Neuronal loss and gliosis in the rat striatum subjected to 15 and 30 minutes of middle cerebral artery occlusion

Abstract

Selective neuronal death or loss in certain brain regions has been well characterized in animal models of transient global cerebral ischemia. However, selective neuronal death in transient focal cerebral ischemia needs more investigation. Therefore, in this study, we studied selective neuronal death in the striatum (caudate putamen) of rats subjected to 15 or 30 min middle cerebral artery occlusion (MCAO). Neuronal death occurred in the dorsolateral field, not in the medial field in 30 min, not 15 min, MCAO-operated rats 5 days after MCAO using neuronal nuclear antigen immunohistochemistry and Fluoro-Jade B histofluorescence staining. In this group, immunoreactivity of glial fibrillary acidic protein in astrocytes was hardly shown in the dorsolateral field, although the immunoreactivity increased in the medial field. In addition, immunoreactivity of ionized calcium binding adapter molecule 1 in microglia was dramatically increased in the dorsolateral, not in the medial, field only in 30 min MCAO-operated rats. Briefly, these results show that at least 30 min of MCAO can evoke selective neuronal death, astrocytic dysfunction and microglial activation in the dorsolateral field of the rat striatum and suggest that a rat model of 30 min MCAO can be used to investigate mechanisms of neuronal death and gliosis following brief transient focal cerebral ischemic events for acute transient ischemic attack.

https://ift.tt/2IooRsg

Turkish case of ethylmalonic encephalopathy misdiagnosed as short chain acyl-CoA dehydrogenase deficiency

Abstract

Ethylmalonic encephalopathy is a very rare autosomal recessively inherited inborn error of metabolism; characterized by encephalopathy, recurrent petechiae without bleeding diathesis, chronic diarrhea, and orthostatic acrocyanosis. Here, we describe a case of ethylmalonic encephalopathy with late onset neurologic symptoms and a confusing family history of two deceased brothers with the wrong suspicion of short chain acyl-CoA dehydrogenase deficiency.

https://ift.tt/2k1yGlv

Hibiscus rosa sinensis mediate anxiolytic effect via modulation of ionotropic GABA-A receptors: possible mechanism of action

Abstract

The current study was designed with the aim to investigate anti-anxiety potential of Hibiscus rosa sinensis roots and its possible mechanism of action. For this purpose hole board test, elevated plus maze test and light/dark exploration test were employed. The ethanol extract of plant was administered orally at two different doses i.e. 100 and 500 mg/kg for consecutive 14 days. The results of present investigation indicate that plant extract significantly (p < 0.05) increased the number of head dips and rearings as compared to control on respective days of observation. The extract increased the time of permanence in open arms and the number of head dips in elevated plus maze. In light/dark test, our study indicate that Hibiscus rosa sinensis significantly (p < 0.05) increased the time spent in light compartment and number of entries as compared to control. In addition the anxiolytic effects of HRS at highest tested dose were blocked by flumazenil, a GABA-A receptor antagonist that indicate that Hibiscus rosa sinensis potentiated the GABAergic actions. The results propose that the ethanol extract of Hibiscus rosa sinensis has prospective anxiolytic effect in mice via inhibition of ionotropic GABA receptors, using different behavioral paradigms.

https://ift.tt/2ImJKE5

Predictive value of excision repair cross-complementing group 2 gene Lys751Gln and Asp312Asn polymorphisms in melanoma risk

Epidemiological studies have assessed the association between excision repair cross-complementing group 2 (ERCC2) Lys751Gln and Asp312Asn polymorphisms and melanoma risk with conflicting results. Relevant articles were searched from PubMed, Embase, and Web of Science with a time limit of 3 September 2016. Pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of the association. We performed this meta-analysis with 12 studies including 6157 cases and 8873 controls for Lys751Gln and nine studies including 5037 cases and 7542 controls for Asp312Asn polymorphism. Overall, no significant associations were found under all the models for Lys751Gln polymorphism, and significant associations were found for Asp312Asn polymorphism for AA versus GG (OR=1.12, 95% CI=1.00–1.26) and for the recessive model (OR=1.11, 95% CI=1.00–1.24). In the stratification analyses by source of control: for Lys751Gln polymorphism, significant associations were found for CC versus AA (OR=1.19, 95% CI=1.04–1.36) and the recessive model (OR=1.15, 95% CI=1.02–1.30); for Asp312Asn polymorphism, significant associations were found for AA versus GG (OR=1.31, 95% CI=1.11–1.53) and the recessive model (OR=1.29, 95% CI=1.11–1.50). This meta-analysis suggested that both the Lys751Gln and Asp312Asn polymorphisms were risk factors for melanoma risk in population-based subgroup. * Xue Zhou and Yong Zeng contributed equally to the writing of this article. Correspondence to Limei Xia, MSc, Department of Gynaecology, The Fourth People's Hospital of Shanghai, Shanghai 200081, China Tel: +86 215 666 3031; e-mail: limeixiadoc@163.com or Correspondence to Chuan Liu, MD, Department of Oncology, Shanghai General Hospital, 100 Haining Road, Shanghai 200080, China Tel: +86 216 324 0090; e-mail: chuanliu2005@163.com Received October 26, 2016 Accepted April 21, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2Kqr47g