Cancer by Sfakianakis Alexandros: 04/20/18

Παρασκευή 20 Απριλίου 2018

Cancers, Vol. 10, Pages 125: Selective Inhibition of Histone Deacetylation in Melanoma Increases Targeted Gene Delivery by a Bacteriophage Viral Vector

Cancers, Vol. 10, Pages 125: Selective Inhibition of Histone Deacetylation in Melanoma Increases Targeted Gene Delivery by a Bacteriophage Viral Vector

Cancers doi: 10.3390/cancers10040125

Authors: Samuel Campbell Keittisak Suwan Sajee Waramit Eric Ofori Aboagye Amin Hajitou

The previously developed adeno-associated virus/phage (AAVP) vector, a hybrid between M13 bacteriophage (phage) viruses that infect bacteria only and human Adeno-Associated Virus (AAV), is a promising tool in targeted gene therapy against cancer. AAVP can be administered systemically and made tissue specific through the use of ligand-directed targeting. Cancer cells and tumor-associated blood vessels overexpress the αν integrin receptors, which are involved in tumor angiogenesis and tumor invasion. AAVP is targeted to these integrins via a double cyclic RGD4C ligand displayed on the phage capsid. Nevertheless, there remain significant host-defense hurdles to the use of AAVP in targeted gene delivery and subsequently in gene therapy. We previously reported that histone deacetylation in cancer constitutes a barrier to AAVP. Herein, to improve AAVP-mediated gene delivery to cancer cells, we combined the vector with selective adjuvant chemicals that inhibit specific histone deacetylases (HDAC). We examined the effects of the HDAC inhibitor C1A that mainly targets HDAC6 and compared this to sodium butyrate, a pan-HDAC inhibitor with broad spectrum HDAC inhibition. We tested the effects on melanoma, known for HDAC6 up-regulation, and compared this side by side with a normal human kidney HEK293 cell line. Varying concentrations were tested to determine cytotoxic levels as well as effects on AAVP gene delivery. We report that the HDAC inhibitor C1A increased AAVP-mediated transgene expression by up to ~9-fold. These findings indicate that selective HDAC inhibition is a promising adjuvant treatment for increasing the therapeutic value of AAVP.

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Cancers, Vol. 10, Pages 125: Selective Inhibition of Histone Deacetylation in Melanoma Increases Targeted Gene Delivery by a Bacteriophage Viral Vector

Cancers, Vol. 10, Pages 125: Selective Inhibition of Histone Deacetylation in Melanoma Increases Targeted Gene Delivery by a Bacteriophage Viral Vector

Cancers doi: 10.3390/cancers10040125

Authors: Samuel Campbell Keittisak Suwan Sajee Waramit Eric Ofori Aboagye Amin Hajitou

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Diagnosis and Novel Approaches to the Treatment of Hypereosinophilic Syndromes

Abstract

Purpose of Review

Hypereosinophilic syndrome (HES) is characterized by persistent hypereosinophilia associated with end-organ damage. As our understanding of the pathogenesis of various forms of HES broadens, so does our ability to tailor steroid-sparing therapies for each subtype. The purpose of this review is to summarize recent literature related to the etiology, diagnosis, and management of HES.

Recent Findings

Mutations involved in subsets of HES can guide the choice of tyrosine kinase inhibitors beyond just imatinib. Several biologics that target interleukin-5 or its receptor have shown beneficial and selective eosinophil-reducing effects in clinical trials for asthma and other disorders including HES. Early clinical data with emerging therapies such as dexpramipexole and anti-Siglec-8 antibody show promise, but need to be confirmed in randomized trials.

Summary

Several new biologics and tyrosine kinase inhibitors have been shown to lower eosinophil numbers, but more randomized trials are needed to confirm efficacy in HES.

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Diagnosis and Novel Approaches to the Treatment of Hypereosinophilic Syndromes

Abstract

Purpose of Review

Recent Findings

Summary

Several new biologics and tyrosine kinase inhibitors have been shown to lower eosinophil numbers, but more randomized trials are needed to confirm efficacy in HES.

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Immunohistochemical Expression of Fatty Acid Synthase and Vascular Endothelial Growth Factor in Primary Colorectal Cancer: a Clinicopathological Study

Abstract

Background

Fatty acid synthase (FAS) is a valuable lipid enzyme involved in lipid biosynthesis and suggested to contribute in tumor carcinogenesis. Vascular endothelial growth factor (VEGF) is considered a serious angiogenic growth factor in the angiogenic pathway which is a very important in tumor growth and metastasis. Thus, inhibition of lipid biosynthesis and tumor angiogenesis can be new goals for colorectal cancer (CRC) treatment.

Aim of the Work

The assessment of the expression of FAS and VEGF protein and the relationship between them in CRC with the clinicopathological parameters.

Methods

The present retrospective study included 63 paraffin blocks previously diagnosed as primary cases of CRC. The slides were subjected to FAS and VEGF immunohistochemical staining using a streptavidin-biotin-peroxidase. The relationships among FAS and VEGF expression and clinicopathological parameters were statistically analyzed.

Results

The expression rate of FAS was 81% and VEGF was 84.1% in the studied cases. FAS expression was significantly associated with histopathological type (p = 0.02) and grade (p = 0.04), and highly associated with lymph node metastasis and stage (p < 0.001).VEGF was significantly associated with histopathological type (p = 0.01) and tumor depth (p = 0.02); highly associated with grade, lymph node metastasis, and stage (p < 0.001). There was a positive association between FAS and VEGF expression in CRC (p < 0.001).

Conclusion

FAS and VEGF showed a highly significant expression in the studied primary CRC cases. A significant association was observed between their expressions, suggesting the involvement of FAS in tumor angiogenesis. So they constitute potential targets in cancer prevention and treatment and make FAS an attractive antiangiogenic target.

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Immunohistochemical Expression of Fatty Acid Synthase and Vascular Endothelial Growth Factor in Primary Colorectal Cancer: a Clinicopathological Study

Abstract

Background

Aim of the Work

The assessment of the expression of FAS and VEGF protein and the relationship between them in CRC with the clinicopathological parameters.

Methods

Results

Conclusion

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In Response

No abstract available

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The Pros of Publishing Standalone Clinical Trial Protocols in Anesthesiology Journals

No abstract available

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Differential Effects of Anesthetics and Opioid Receptor Activation on Cardioprotection Elicited by Reactive Oxygen Species–Mediated Postconditioning in Sprague-Dawley Rat Hearts

BACKGROUND: Despite an array of cardioprotective interventions identified in preclinical models of ischemia–reperfusion (IR) injury, successful clinical translation has not been achieved. This study investigated whether drugs routinely used in clinical anesthesia influence cardioprotective effectiveness by reducing effects of reactive oxygen species (ROS), upstream triggers of cardioprotective signaling. Effects of propofol, sevoflurane, or remifentanil were compared on postischemic functional recovery induced by ROS-mediated postconditioning with Intralipid. METHODS: Recovery of left ventricular (LV) work, an index of IR injury, was measured in isolated Sprague-Dawley rat hearts subjected to global ischemia (20 minutes) and reperfusion (30 minutes). Hearts were either untreated or were treated with postconditioning with Intralipid (1%, throughout reperfusion). Propofol (10 μM), sevoflurane (2 vol%), remifentanil (3 nM), or combinations thereof were administered peri-ischemically (before and during IR). The effects of anesthetics on ROS production were measured in LV cardiac fibers by Amplex Red assay under phosphorylating and nonphosphorylating conditions. RESULTS: Recovery of LV work (expressed as percentage of the preischemic value ± standard deviation) in untreated hearts was poor (20% ± 7%) and was improved by Intralipid postconditioning (58% ± 8%, P = .001). In the absence of Intralipid postconditioning, recovery of LV work was enhanced by propofol (28% ± 9%, P = .049), sevoflurane (49% ± 5%, P

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A Pain in the Abs: Predicting Post-Cesarean Analgesia

No abstract available

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Delineating the Trajectory of Cognitive Recovery From General Anesthesia in Older Adults: Design and Rationale of the TORIE (Trajectory of Recovery in the Elderly) Project

BACKGROUND: Mechanistic aspects of cognitive recovery after anesthesia and surgery are not yet well characterized, but may be vital to distinguishing the contributions of anesthesia and surgery in cognitive complications common in the elderly such as delirium and postoperative cognitive dysfunction. This article describes the aims and methodological approach to the ongoing study, Trajectory of Recovery in the Elderly (TORIE), which focuses on the trajectory of cognitive recovery from general anesthesia. METHODS: The study design employs cognitive testing coupled with neuroimaging techniques such as functional magnetic resonance imaging, diffusion tensor imaging, and arterial spin labeling to characterize cognitive recovery from anesthesia and its biological correlates. Applying these techniques to a cohort of age-specified healthy volunteers 40–80 years of age, who are exposed to general anesthesia alone, in the absence of surgery, will assess cognitive and functional neural network recovery after anesthesia. Imaging data are acquired before, during, and immediately after anesthesia, as well as 1 and 7 days after. Detailed cognitive data are captured at the same time points as well as 30 days after anesthesia, and brief cognitive assessments are repeated at 6 and 12 months after anesthesia. RESULTS: The study is underway. Our primary hypothesis is that older adults may require significantly longer to achieve cognitive recovery, measured by Postoperative Quality of Recovery Scale cognitive domain, than younger adults in the immediate postanesthesia period, but all will fully recover to baseline levels within 30 days of anesthesia exposure. Imaging data will address systems neuroscience correlates of cognitive recovery from general anesthesia. CONCLUSIONS: The data acquired in this project will have both clinical and theoretical relevance regardless of the outcome by delineating the mechanism behind short-term recovery across the adult age lifespan, which will have major implications for our understanding of the effects of anesthetic drugs.

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Auditing Intraoperative Transfusions to Promote High-Value Perioperative Care

No abstract available

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Treatment of Chronic Pain Conditions: A Comprehensive Handbook

No abstract available

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Postoperative Troponin Elevation, Myocardial Injury, and Pulmonary Embolism

No abstract available

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In Response

No abstract available

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The American College of Surgeons Children’s Surgery Verification and Quality Improvement Program: Be Careful What You Wish For!

No abstract available

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Effect of Stellate Ganglion Block on the Regional Hemodynamics of the Upper Extremity: A Randomized Controlled Trial

BACKGROUND: The success of stellate ganglion block (SGB) is traditionally determined on the basis of findings such as Horner's syndrome, temperature rise in the face, hyperemia of the tympanic membrane, and nasal congestion. However, decreases in vascular resistance and increases in blood flow in the arm may be more meaningful findings. To date, the effect of SGB on the regional hemodynamics of the arm has not been evaluated using pulsed-wave Doppler ultrasound. METHODS: A total of 52 patients who were to undergo orthopedic surgery of the forearm were randomly assigned to either the mepivacaine group (SGB with 5 mL of 0.5% mepivacaine) or the saline group (SGB with 5 mL of normal saline). Before surgery, a single anesthesiologist performed a SGB under ultrasound guidance. The temperature of the upper extremity and the resistance index and blood flow in the brachial artery were measured before SGB, 15 and 30 minutes after SGB, and 1 hour after surgery. The severity of pain, requirement for rescue analgesics, and side effects of the local anesthetic agent were all documented. RESULTS: After SGB, the resistance index decreased significantly and the blood flow increased significantly in the brachial artery of members of the mepivacaine group (15 minutes: P = .004 and P

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Can Lung Ultrasound Be the First-Line Tool for Evaluation of Intraoperative Hypoxemia?

No abstract available

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Publishing Methods Without Results: A First That Hopefully Will Not Last

No abstract available

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Pain Medicine: An Essential Review

No abstract available

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The Eye: What You Don’t Know Can Hurt Your Patient

No abstract available

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Renal Interstitial Exhaustion and SGLT2 Blockers

No abstract available

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Looking Beyond the Pain: Can Effective Labor Analgesia Prevent the Development of Postpartum Depression?

No abstract available

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Perioperative Cardiac Arrest: Focus on Local Anesthetic Systemic Toxicity (LAST) Erratum

No abstract available

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Testing Times: Routine to Indicated!

No abstract available

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Teaching Medical Students Clinical Anesthesia

There are many reasons for evaluating our approach and improving our teaching of America's future doctors, whether they become anesthesiologists (recruitment) or participate in patient management in the perioperative period (general patient care). Teaching medical students the seminal aspects of any medical specialty is a continual challenge. Although no definitive curricula or single clinical approach has been defined, certain key features can be ascertained from clinical experience and the literature. A survey was conducted among US anesthesiology teaching programs regarding the teaching content and approaches currently used to teach US medical students clinical anesthesia. Using the Accreditation Council for Graduate Medical Education website that lists 133 accredited anesthesiology programs, residency directors were contacted via e-mail. Based on those responses and follow-up phone calls, teaching representatives from 125 anesthesiology departments were identified and asked via e-mail to complete a survey. The survey was returned by 85 programs, yielding a response rate of 68% of individuals contacted and 63% of all departments. Ninety-one percent of the responding departments teach medical students, most in the final 2 years of medical school. Medical student exposure to clinical anesthesia occurred as elective only at 42% of the institutions, was requirement only at 16% of responding institutions, and the remainder had both elective and required courses. Anesthesiology faculty at 43% of the responding institutions reported teaching in the preclinical years of medical school, primarily in the departments of pharmacology and physiology. Forty-five percent of programs reported interdisciplinary teaching with other departments teaching classes such as gross anatomy. There is little exposure of anesthesiology faculty to medical students in other general courses. Teaching in the operating room is the primary teaching method in the clinical years. Students are allowed full access to patient care, including performing history and physical examinations, participating in the insertion of IVs and airway management. Simulation-based teaching was used by 82% of programs during medical student anesthesia clerkships. Sixty-eight percent of respondents reported that they have no formal training for their anesthesiology faculty teachers, 51% stated that they do not receive nonclinical time to teach, and 38% of respondents stated that they received some form of remuneration for teaching medical students, primarily nonclinical time. This article presents a summary of these survey results, provides a historical review of previous evaluations of teaching medical students clinical anesthesia, and discusses the contributions of anesthesiologists to medical student education.

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Adjuvant therapy for colon cancer: genes, genes... and the patient in the center

Although molecular subtype-based stratification and genomic signatures of increasing complexity are becoming a new strategy to guide therapeutic decisions in stage II/III colon cancer, several prognostic factors that can be easily obtained from FFPE specimens should be considered in order to create combined models that better define individual patients needs

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Adjuvant therapy for colon cancer: genes, genes... and the patient in the center

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The EZH2 Inhibitor Tazemetostat Is Well Tolerated in a Phase I Trial [Research Watch]

Tazemetostat has antitumor activity in B-cell non-Hodgkin lymphoma and advanced solid tumors.

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Dual Targeting of MDMX and MDM2 Has Antileukemic Activity [Research Watch]

A p53-stapled peptide, ALRN-6924, blocks binding to MDMX and MDM2 to activate p53.

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From Pluripotent Stem to CAR T Cells [News in Brief]

Preclinical efficacy seen with FT819, a candidate off-the-shelf CAR T-cell therapy.

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A Cancer-Germline Antigen Signature Predicts Anti-CTLA4 Resistance [Research Watch]

High expression of the MAGE-A subcluster III is associated with anti-CTLA4 resistance in melanoma.

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Loss of p62 in Adipocytes Promotes Aggressive Prostate Cancer [Research Watch]

OPN released from p62-deficient adipocytes enhances fatty-acid oxidation in tumor cells.

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RE: Smoking, Sex, and Non–Small Cell Lung Cancer: Steroid Hormone Receptors in Tumor Tissue (S0424)

We write regarding the article by Cheng and colleagues recently published in the Journal (1). Using data from 813 women and men with non–small cell lung cancer, they examined the associations between smoking, sex, and multiple hormone receptors in lung cancer. They found that lung tumors in women had lower cytoplasmic estrogen receptor (ER)–α and nuclear ER-β expression when compared with those in men. Smoking was associated with lower total progesterone receptor (PR) expression, but with higher cytoplasmic ER-α and ER-β, which were subsequently found to be associated with mortality risk. One their conclusions was that lower expression of nuclear ER-β in women supports the estrogen hypothesis in lung cancer etiology. While we acknowledge that this study represents an important contribution to this line of research, we have some reservations about the results and their interpretation.

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Response to H. Nabi et al.

We agree with Nabi et al. that adiposity, as a main source of estrogen biosynthesis after menopause, can influence nuclear estrogen receptor (ER)–β expression in the lung. To approach this issue, in our data, we evaluated whether 1) adiposity measured by body mass index (BMI; self-reported weight in kilograms, divided by height in meters squared) was associated with nuclear ER-β expression and 2) the associations of sex and smoking with nuclear ER-β expression were altered after additionally adjusting for BMI. As shown here in Table 1, being overweight (BMI = 25 to 29.0 kg/m², P = .66) and obesity (BMI ≥ 30 kg/m², P = .86) were not associated with nuclear ER-β expression, compared with normal or underweight (BMI < 25 kg/m²) overall. Among female participants, there was indication that nuclear ER-β expression was higher among women with a higher BMI, although the differences were not statistically significant after adjustment for hormone therapy and other variables (β = 1.4, 95% CI = –17.2 to 20.1, for overweight; β = 3.7, 95% CI = –17.0 to 24.3, for obesity, compared with normal or underweight). The second analysis showed that, although the precision of estimates was affected, the associations of sex with nuclear ER-β were essentially the same after BMI was entered as a categorical variable (<25, 25–29.0, and ≥30 kg/m²) in the regression model. The regression coefficients (β) for sex, were –12.1 (95% CI = –24.3 to 0.03) for all participants, –13.0 (95% CI = –26.4 to 0.3) for ever smokers, and –14.7 (95% CI = –44.2 to 14.8) for never smokers, compared with β values before adjusting for BMI, presented in our article (–12.8, 95% CI = –24.7 to –0.9; –14.5, 95% CI = –27.6 to –1.5; and –14.0, 95% CI = –42.8 to 14.9, respectively). Additionally, the null association of smoking with nuclear ER-β expression was unchanged after adjustment for BMI. We are aware that BMI is an inaccurate measure of adiposity (1); other assessments of adiposity, including abdominal obesity, were unavailable in this study. A more accurate assessment of adiposity is warranted to determine whether obesity affects ER-β nuclear expression in lung cancer. Table 1.Association of BMI with nuclear ER-β protein expressionBMI, kg/m²Nuclear ER-βNo.H-score, meanβ (95% CI) in linear regressionP**All participants†723129.0 <25317126.4(Ref) 25–29.0244130.84.5 (–8.8 to 17.7).66 ≥30162130.71.3 (–13.6 to 16.2).86Males‡‡323134.7 <25113132.9(Ref) 25–29.0131136.85.3 (–14.3 to 24.8).60 ≥3079132.9–0.8 (–23.0 to 21.5).95Females‡‡,§400124.2 <25204122.8(Ref) 25–29.0113123.81.4 (–17.2 to 20.1).88 ≥3083128.63.7 (–17.0 to 24.3).73*P values were calculated using linear regression t test and were two-sided. BMI = body mass index; CI = confidence interval; ER = estrogen receptor.†Linear regression adjusting for age, race, sex, smoking.‡Linear regression adjusting for age, race, smoking.§Additionally adjusted for menopausal status and hormone therapy (HT) use (premenopausal, postmenopausal with never use of HT, postmenopausal with ever use of HT).

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A window into extreme longevity; the circulating metabolomic signature of the naked mole-rat, a mammal that shows negligible senescence

Abstract

Mouse-sized naked mole-rats (Heterocephalus glaber), unlike other mammals, do not conform to Gompertzian laws of age-related mortality; adults show no age-related change in mortality risk. Moreover, we observe negligible hallmarks of aging with well-maintained physiological and molecular functions, commonly altered with age in other species. We questioned whether naked mole-rats, living an order of magnitude longer than laboratory mice, exhibit different plasma metabolite profiles, which could then highlight novel mechanisms or targets involved in disease and longevity. Using a comprehensive, unbiased metabolomics screen, we observe striking inter-species differences in amino acid, peptide, and lipid metabolites. Low circulating levels of specific amino acids, particularly those linked to the methionine pathway, resemble those observed during the fasting period at late torpor in hibernating ground squirrels and those seen in longer-lived methionine-restricted rats. These data also concur with metabolome reports on long-lived mutant mice, including the Ames dwarf mice and calorically restricted mice, as well as fruit flies, and even show similarities to circulating metabolite differences observed in young human adults when compared to older humans. During evolution, some of these beneficial nutrient/stress response pathways may have been positively selected in the naked mole-rat. These observations suggest that interventions that modify the aging metabolomic profile to a more youthful one may enable people to lead healthier and longer lives.

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Surgical Management of Head and Neck Soft Tissue Sarcoma: 11-Year Experience at a Tertiary Care Centre in South India

Abstract

Head and neck soft tissue sarcoma (HNSTS) is a rare neoplasm accounting for 1% of all head and neck tumours. Because of rarity and varied biological behaviour among various subtypes, knowledge about these tumours is limited. This study aimed at analysing clinicopathological, recurrence and survival pattern of surgically treated HNSTS. Case records of 28 patients of HNSTS who underwent surgery at the Regional Cancer Centre (RCC), Trivandrum (India) between 2002 and 2012 were analysed retrospectively for demographic profile, clinical features, treatment given, recurrence pattern and outcome. The median age of patients was 37 years (range, 3–79) with male:female ratio of 3:2. Majority of patients presented with painless lump in the neck as the most common subsite affected followed by scalp and face. One patient had nodal disease, while none had distant metastasis at presentation. The most frequent histological subtypes were synovial sarcoma and fibrosarcoma followed by malignant fibrous histiocytoma, angiosarcoma and rhabdomyosarcoma. Majority (78.5%) of patients received adjuvant therapy in the form of radiation, chemotherapy or chemo-radiation. After mean follow-up of 49 months, four patients had died, and six developed local recurrence and four distant metastasis. The overall 5-year survival was 82.7% while 5-year disease-free survival was 55.3%. HNSTS is a rare entity that requires multimodality treatment to achieve optimum locoregional control and survival.

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Surgical Management of Head and Neck Soft Tissue Sarcoma: 11-Year Experience at a Tertiary Care Centre in South India

Abstract

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Genistein sensitizes glioblastoma cells to carbon ions via inhibiting DNA-PKcs phosphorylation and subsequently repressing NHEJ and delaying HR repair pathways

Previously, we found genistein could sensitize cancer cells to low linear energy transfer (LET) X-rays via inhibiting DNA-PKcs activities. Especially, high-LET heavy ion produces more DNA double strand breaks (DSBs) than low-LET radiation. Thus, the study was designed to investigate the detailed molecular mechanisms of genistein on sensitizing cancer cells to heavy ions.

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A Conversation about RAS Dimers

Data are persuasive that RAS proteins are dimeric in living cells, but monomeric in vitro. Pasi Jänne, Chiara Ambrogio, and Frank McCormick discuss the significance of understanding RAS dimers for finding treatments for RAS cancers.

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A Conversation about RAS Dimers

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Radiation-induced carotid artery lesions

Abstract

Purpose

To review the current aspects of knowledge related to the risk of cerebrovascular events in patients receiving head and neck radiotherapy.

Methods

A literature search was performed in PubMed. Papers meeting selection criteria were reviewed.

Results

We provide an update on the problem by identifying key studies that have contributed to our current understanding of the epidemiology, radiologic features, pathogenesis, and treatment of the disease. The incidence of carotid artery stenosis ranged from 18 to 38% in patients who underwent radiotherapy for head and neck cancer versus from 0 to 9.2% among the nonirradiated patients. Neck irradiation increases the intima-media thickness of the carotid artery wall. These changes are the earliest visible alteration in the carotid wall and are also detected with color Doppler ultrasonography. Endovascular treatment with a carotid angioplasty and stenting is the first-line treatment for most symptomatic patients.

Conclusions

Radiation-induced atherosclerosis is a different and accelerated form of atherosclerosis, which implies a more aggressive disease with a different biologic behavior. The disease is characterized by a high rate of carotid artery stenosis compared to those observed in nonirradiated control group patients. To prevent the risk of stroke, surveillance and imaging with ultrasonography should enable detection of severe stenosis. Endovascular treatment with a carotid angioplasty and stenting has been proposed as an attractive and minimally invasive alternative for some radiation-induced stenoses.

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NCI Expands Repository of Cancer Research Models: A Conversation with Drs. Doroshow and Evrard

NCI is expanding its Patient-Derived Models Repository (PDMR), which provides cancer research models made directly from human tumor tissue. In this Q&A, Drs. Yvonne Evrard and James Doroshow explain how the new models can help cancer researchers make more rapid progress.

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NCI Expands Repository of Cancer Research Models: A Conversation with Drs. Doroshow and Evrard

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Hypoxia-mediated miR-212-3p downregulation enhances progression of intrahepatic cholangiocarcinoma through upregulation of Rab1a.

Hypoxia-mediated miR-212-3p downregulation enhances progression of intrahepatic cholangiocarcinoma through upregulation of Rab1a.

Cancer Biol Ther. 2018 Apr 19;:1-28

Authors: Hou P, Kang Y, Luo J

Abstract
Rab1a, a member RAS oncogene family, has been reported playing important role in tumor proliferation and migration. However, the role of Rab1a in intrahepatic cholangiocarcinoma (ICC) is not clear. In this study, we found Rab1a was overexpressed in ICC tissues both in mRNA and protein level. Kaplan-meier analysis showed that high expression of Rab1a was associated with poor prognosis of ICC patients. Suppression of Rab1a led to lower proliferation rate and migration ability both in vitro and in vivo by inhibiting process of cell cycle and Epithelial-Mesenchymal Transition (EMT). Further study showed that Rab1a was targeting regulated by miR-212-3p.In addition, expression of Rab1a was increased while miR-212-3p was decreased under hypoxia condition. In conclusion, these findings extend our understanding of Rab1a in progression of ICC, and we found hypoxia/miR-212-3p/Rab1a pathway played important role for progression of ICC. This newly identified pathway should promote the development of novel therapeutic biomarker for ICC.

PMID: 29672195 [PubMed - as supplied by publisher]

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Hypoxia-mediated miR-212-3p downregulation enhances progression of intrahepatic cholangiocarcinoma through upregulation of Rab1a.

Hypoxia-mediated miR-212-3p downregulation enhances progression of intrahepatic cholangiocarcinoma through upregulation of Rab1a.

Cancer Biol Ther. 2018 Apr 19;:1-28

Authors: Hou P, Kang Y, Luo J

PMID: 29672195 [PubMed - as supplied by publisher]

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Hypoxia-mediated miR-212-3p downregulation enhances progression of intrahepatic cholangiocarcinoma through upregulation of Rab1a.

Hypoxia-mediated miR-212-3p downregulation enhances progression of intrahepatic cholangiocarcinoma through upregulation of Rab1a.

Cancer Biol Ther. 2018 Apr 19;:1-28

Authors: Hou P, Kang Y, Luo J

PMID: 29672195 [PubMed - as supplied by publisher]

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Long non-coding RNA (lncRNA) MAGI2-AS3 inhibits breast cancer cell growth by targeting the Fas/FasL signalling pathway

Abstract

Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts shown to play important roles in tumourigenesis and tumour progression. Our study aimed to examine expression of the lncRNA MAGI2-AS3 in breast cancer and to explore its function in cancer cell growth. First, MAGI2-AS3 expression levels in clinical samples and cell lines were determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The functional significance of MAGI2-AS3 in cancer cell proliferation and apoptosis was then examined in vitro. Our results showed MAGI2-AS3 to be down-regulated in breast cancer tissues compared to normal adjacent tissues. Moreover, MAGI2-AS3 markedly inhibited breast cancer cell growth and increased expression of Fas and Fas ligand (FasL). In conclusion, our data suggest that MAGI2-AS3 expression is decreased in breast cancer and that MAGI2-AS3 plays an important role as a tumour suppressor by targeting Fas and FasL signalling. These results provide new insight into novel clinical treatments for breast cancer.

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Angiolymphoid hyperplasia of external ear treated with intralesional radiofrequency ablation

A 21-year-old woman presented with multiple erythematous to skin-coloured dome-shaped firm papules and plaques over the right ear concha and external auditory canal for 1 year. It was associated with occasional itching and bleeding. Her main concern was cosmetic disfigurement. Biopsy showed presence of multiple proliferating blood vessels lined by plump epithelioid endothelial cells surrounded by dense infiltrate of lymphocytes, histiocytes and eosinophils. Other routine investigations were within normal limits. A diagnosis of angiolymphoid hyperplasia with eosinophilia was made. A single sitting of intralesional radiofrequency ablation (Vesalius, coagulation mode; fanning technique) using 18-G intravenous cannula was done. This led to almost complete resolution with no recurrence at 3 months follow-up. There was no evidence of scarring or depigmentation.

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Reversible metronidazole-induced neurotoxicity after 10 weeks of therapy

Metronidazole is a commonly used antimicrobial worldwide. The most common side effects that have been reported are nausea, vomiting and hypersensitivity reactions. However, neurotoxicity has been reported with the use of metronidazole but rather rare. The most common neurological manifestation is peripheral neuropathy involvement in the form of sensory loss. It is worth mentioning that central neurotoxicity is a rare side effect of metronidazole use but reversible. The manifestations vary from a headache, altered mental status to focal neurological deficits. The diagnosis is mainly by neuroimaging in the setting of acute neurological change in the patient status. Here, we report a case of metronidazole-induced neurotoxicity in a 38-year-old male patient who was admitted with a brain abscess and was started on metronidazole for more than 10 weeks.

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Trigeminal trophic syndrome following anterior inferior cerebellar artery infarction

Description

A 70-year-old woman with hypertension presented about 3 months ago with complaints of dysarthria, left lower motor neuron facial palsy with preserved Bell's phenomenon, sensory loss over the left side of her face (V1, V2, V3) along with the left half of the tongue, absent left corneal and conjunctival reflexes, and gait ataxia. MRI of the brain showed an acute left anterior inferior cerebellar artery infarction (figure 1). She was treated with antiplatelets, statins and antihypertensives.

Figure 1

MRI of the brain showing an acute infarct in the left anterior inferior cerebellar territory.

At present, she complained of 1-month history of multiple non-healing painless ulcers over the left side of her face below the nostril, and on the left side of the nose and forehead. Her left eye had undergone keratosis (figure 2). She had consulted local doctors, who prescribed her topical antibiotics...

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Long non-coding RNA (lncRNA) MAGI2-AS3 inhibits breast cancer cell growth by targeting the Fas/FasL signalling pathway

Abstract

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Hypercalcemia as a rare presentation of angioimmunoblastic T cell lymphoma: a case report

Angioimmunoblastic T cell lymphoma is a rare malignancy, accounting for only 2% of all non-Hodgkin lymphomas, first described in the 1970s and subsequently accepted as a distinct entity in the current World He...

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Hypoxia-mediated miR-212-3p downregulation enhances progression of intrahepatic cholangiocarcinoma through upregulation of Rab1a.

Hypoxia-mediated miR-212-3p downregulation enhances progression of intrahepatic cholangiocarcinoma through upregulation of Rab1a.

Cancer Biol Ther. 2018 Apr 19;:1-28

Authors: Hou P, Kang Y, Luo J

PMID: 29672195 [PubMed - as supplied by publisher]

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The perfect personalized cancer therapy: cancer vaccines against neoantigens

Optimization of training periods for the estimation model of three-dimensional target positions using an external respiratory surrogate

During therapeutic beam irradiation, an unvisualized three-dimensional (3D) target position should be estimated using an external surrogate with an estimation model. Training periods for the developed model wi...

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Prognostic factors of radiation dermatitis following passive-scattering proton therapy for breast cancer

To identify prognostic factors for grade 3 radiation dermatitis following passive-scattering proton therapy for breast cancer.

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Optimization of training periods for the estimation model of three-dimensional target positions using an external respiratory surrogate

Prognostic factors of radiation dermatitis following passive-scattering proton therapy for breast cancer

To identify prognostic factors for grade 3 radiation dermatitis following passive-scattering proton therapy for breast cancer.

https://ift.tt/2HgBqWd

Identification of subsets of actionable genetic alterations in KRAS-mutant lung cancers using association rule mining

Abstract

Background

Lung cancer is the leading cause of cancer-related death in both men and women. KRAS mutations occur in ~ 25% of patients with lung cancer, and the presence of these mutations is associated with a poor prognosis. Unfortunately, efforts to directly target KRAS or its associated downstream MAPK or PI3K/AKT/mTOR pathways have seen little or no benefits. Here, I hypothesize that KRAS-mutant tumors do not respond to KRAS pathway therapies due to the co-occurrence of other activated cell survival pathways and/or mechanisms.

Methods and results

To identify other potentially activated cell survival pathways in KRAS-mutant tumors, I performed association rule mining on somatic mutations in 725 metastatic lung cancer patient samples. I identified 67 additional genes that were mutated in at least 10% of the samples with KRAS mutations. This gene list was enriched with genes involved in the MAPK, AKT and STAT3 pathways, as well as in cell-cell adhesion, DNA repair, chromatin remodeling and the Wnt/β-catenin pathway. I also identified 160 overlapping subsets of three or more genes that code for oncogenic or tumor suppressive proteins that were mutated in at least 10% of the KRAS-mutant tumors.

Conclusions

I identified several genes that are co-mutated in primary KRAS-mutant lung cancer samples. I also identified subpopulations of KRAS-mutant lung cancers based on sets of genes that were co-mutated. Pre-clinical models that capture these subsets of KRAS-mutant tumors may enhance our understanding of lung cancer development and, in addition, facilitate the design of personalized treatment strategies for lung cancer patients carrying KRAS mutations.

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The perfect personalized cancer therapy: cancer vaccines against neoantigens

Abstract

In the advent of Immune Checkpoint inhibitors (ICI) and of CAR-T adoptive T-cells, the new frontier in Oncology is Cancer Immunotherapy because of its ability to provide long term clinical benefit in metastatic disease in several solid and liquid tumor types. It is now clear that ICI acts by unmasking preexisting immune responses as well as by inducing de novo responses against tumor neoantigens. Thanks to theprogress made in genomics technologies and the evolution of bioinformatics, neoantigens represent ideal targets, due to their specific expression in cancer tissue and the potential lack of side effects. In this review, we discuss the promise of preclinical and clinical results with mutation-derived neoantigen cancer vaccines (NCVs) along with the current limitations from bioinformatics prediction to manufacturing an effective new therapeutic approach.

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The perfect personalized cancer therapy: cancer vaccines against neoantigens

Abstract

https://ift.tt/2JZIckO

Stereotactic body radiation therapy as an effective and safe treatment for small hepatocellular carcinoma

Abstract

Background

To evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT) in patients with small hepatocellular carcinoma(sHCC) who were ineligible for surgery or ablation therapies.

Methods

From March 2011 to December 2012, 28 cases with sHCC which were ineligible or refused surgical resection, transplantation or local ablation were treated with CyberKnife SBRT. Median size of tumors was 2.1 cm (range:1.1–3.0 cm), a dose of 10-15Gy per faction was given over 3–6 consecutive days, resulting in a total dose of 35-60Gy.

Results

The median follow-up period was 36 months, with the response rate of complete response (CR) in 17 cases, partial response (PR) in 8 cases, stable disease (SD) in 2 cases and progressive disease (PD) in one case. Overall response rate was 89.28%. Overall survival rates in 1, 2 and 3 years were 92.86, 85.71 and 78.57%, respectively. Local control rates in 1, 2 and 3 years were 96.43, 92.86 and 89.28%, respectively. No grade ≥ 3 hepatic toxicity was observed.

Conclusion

CyberKnife treatment was a safe and effective option for sHCC, which had shown good local control, high overall survival rates and low toxicity. CyberKnife SBRT could be served as an alternative treatment for patients with sHCC which is unsuitable for surgical treatment or local ablation.

https://ift.tt/2HQodnO

Survival after recurrence in patients with gastric cancer who receive S-1 adjuvant chemotherapy: exploratory analysis of the ACTS-GC trial

Abstract

Background

Some patients develop recurrence after curative resection and adjuvant chemotherapy. S-1, an oral fluoropyrimidine, is one of the standard regimens in adjuvant chemotherapy, and is also used in first-line treatment for advanced/metastatic gastric cancer. It is controversial as to whether the same treatment strategy can be applied for patients who develop recurrence after adjuvant chemotherapy and those who did not receive adjuvant chemotherapy. To investigate this issue, we compared the outcomes of patients who developed recurrences after treatment with or without adjuvant chemotherapy using the results of the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC).

Methods

Patients who had confirmed recurrence in the ACTS-GC trial were analyzed. We defined 2 independent cohorts. Cohort 1 patients were divided by whether they received adjuvant chemotherapy (adjuvant S-1 group and surgery-only group). Cohort 2 patients were divided by whether they received a regimen including S-1 (IS) or not including S-1 (NIS) after recurrence.

Results

A total of 375 patients experienced recurrence (160 in the adjuvant S-1 group and 215 in the surgery-only group). In cohort 1, the median time from recurrence to death (TFRD) was 11.4 months (95% confidence interval [CI], 8.4–13.9) in the adjuvant S-1 group and 11.3 months (95% CI, 9.7–13.1) in the surgery-only group (hazard ratio [HR], 1.05; 95% CI, 0.84–1.31). In cohort 2, 292 patients received chemotherapy after recurrence and were divided into the IS (n = 189) or the NIS group (n = 103). The median TFRD was 13.9 months (95% CI, 12.7–15.6) in the IS group and 8.1 months (95% CI, 6.6–9.7) in the NIS group (HR, 0.59; 95% CI, 0.45–0.76), and there was no significant interaction between the adjuvant S-1 group and surgery-only group.

Conclusion

Adjuvant chemotherapy with S-1 prolonged overall survival without influencing the TFRD. The same treatment strategy may be applied for patients who develop recurrence after adjuvant chemotherapy and those who did not receive adjuvant chemotherapy.

Trial registration

NCT00152217. First Posted on September 9, 2005.

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Genetic variants in ATM , H2AFX and MRE11 genes and susceptibility to breast cancer in the polish population

Abstract

Background

DNA damage repair is a complex process, which can trigger the development of cancer if disturbed. In this study, we hypothesize a role of variants in the ATM, H2AFX and MRE11 genes in determining breast cancer (BC) susceptibility.

Methods

We examined the whole sequence of the ATM kinase domain and estimated the frequency of founder mutations in the ATM gene (c.5932G > T, c.6095G > A, and c.7630-2A > C) and single nucleotide polymorphisms (SNPs) in H2AFX (rs643788, rs8551, rs7759, and rs2509049) and MRE11 (rs1061956 and rs2155209) among 315 breast cancer patients and 515 controls. The analysis was performed using high-resolution melting for new variants and the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method for recurrent ATM mutations. H2AFX and MRE11 polymorphisms were analyzed using TaqMan assays. The cumulative genetic risk scores (CGRS) were calculated using unweighted and weighted approaches.

Results

We identified four mutations (c.6067G > A, c.8314G > A, c.8187A > T, and c.6095G > A) in the ATM gene in three BC cases and two control subjects. We observed a statistically significant association of H2AFX variants with BC. Risk alleles (the G of rs7759 and the T of rs8551 and rs2509049) were observed more frequently in BC cases compared to the control group, with P values, odds ratios (OR) and 95% confidence intervals (CIs) of 0.0018, 1.47 (1.19 to 1.82); 0.018, 1.33 (1.09 to 1.64); and 0.024, 1.3 (1.06 to 1.59), respectively. Haplotype-based tests identified a significant association of the H2AFX CACT haplotype with BC (P < 0.0001, OR = 27.29, 95% CI 3.56 to 209.5). The risk of BC increased with the growing number of risk alleles. The OR (95% CI) for carriers of ≥ four risk alleles was 1.71 (1.11 to 2.62) for the CGRS.

Conclusions

This study confirms that H2AFX variants are associated with an increased risk of BC. The above-reported sequence variants of MRE11 genes may not constitute a risk factor of breast cancer in the Polish population. The contribution of mutations detected in the ATM gene to the development of breast cancer needs further detailed study.

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Retrospective analysis of the impact of anthracycline dose reduction and chemotherapy delays on the outcomes of early breast cancer molecular subtypes

Abstract

Background

The objective of study was to determine the effect of anthracycline dose reduction and chemotherapy delays on 5-year overall survival in patients with stage I-III breast cancer, to establish the impact of molecular subtypes on the anthracycline modification effects and to analyze reasons for such chemotherapy scheme modifications.

Methods

Medical records of patients with stage I-III breast cancer were reviewed. Inclusion criteria involved stage I- III breast carcinoma; radical surgery performed and 4 courses of AC regimen (doxorubicin and cyclophosphamide), or at least 6 courses of FAC regimen (fluorouracil, doxorubicin and cyclophosphamide) completed; no neoadjuvant chemotherapy applied; no taxane group medications administered; medical records maintain comprehensive data on treatment and follow-up. 5- year overall survival were analyzed using Kaplan-Meier and Cox proportional hazards models.

Results

Significant 3.17 times higher death risk at 5 year period in patients who experienced anthracycline dose reduction compared with patients who did not experience any modifications was established (HR = 3.17, 95% CI 1.7–5.9, p < 0.001). Increased death risk in patients who experienced both chemotherapy dose reduction and treatment delays compared with patients who did not experience any modifications was also established (HR = 2.76, 95% CI 1.3–5.6, p < 0.05). 5- year overall survival was affected by anthracycline dose reduction by more than 15% in ER-HER2- group (80% v. 55.6%, p = 0.015), ER + HER2- group (90.7% v. 64.9%, p < 0.01) and ER+/-HER2+ group (100% v. 84.4%, p = 0.019). 5-year overall survival was affected by chemotherapy delays more than 2 cycles in ER-HER2- group (79.2% v. 51.4%, p = 0.002), ER + HER2- group (86.3% v. 58.8%, p = 0.014) and there was no difference in ER+/-HER2+ group. Main reasons for chemotherapy scheme modifications (in decreasing order) were the following: neutropenia, modifications with no objective medical reasons, thrombocytopenia, anaemia, fatigue, infection.

Conclusions

Anthracycline dose reduction in patients with stage I- III breast cancer were associated with higher mortality risk and significantly decreased 5- year absolute survival in all molecular subtypes. Chemotherapy delays alone were not associated with decreased survival only in HER2 positive subtype. The most common reason for dose reduction or chemotherapy delays was neutropenia.

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Evaluation of PET and laparoscopy in STagIng advanced gastric cancer: a multicenter prospective study (PLASTIC-study)

Abstract

Background

Initial staging of gastric cancer consists of computed tomography (CT) and gastroscopy. In locally advanced (cT3–4) gastric cancer, fluorodeoxyglucose positron emission tomography with CT (FDG-PET/CT or PET) and staging laparoscopy (SL) may have a role in staging, but evidence is scarce. The aim of this study is to evaluate the impact and cost-effectiveness of PET and SL in addition to initial staging in patients with locally advanced gastric cancer.

Methods

This prospective observational cohort study will include all patients with a surgically resectable, advanced gastric adenocarcinoma (cT3–4b, N0–3, M0), that are scheduled for treatment with curative intent after initial staging with gastroscopy and CT. The modalities to be investigated in this study is the addition of PET and SL. The primary outcome of this study is the proportion of patients in whom the PET or SL lead to a change in treatment strategy. Secondary outcome parameters are: diagnostic performance, morbidity and mortality, quality of life, and cost-effectiveness of these additional diagnostic modalities. The study recently started in August 2017 with a duration of 36 months. At least 239 patients need to be included in this study to demonstrate that the diagnostic modalities are break-even. Based on the annual number of gastrectomies in the participating centers, it is estimated that approximately 543 patients are included in this study.

Discussion

In this study, it is hypothesized that performing PET and SL for locally advanced gastric adenocarcinomas results in a change of treatment strategy in 27% of patients and an annual cost-reduction in the Netherlands of €916.438 in this patient group by reducing futile treatment. The results of this study may be applicable to all countries with comparable treatment algorithms and health care systems.

Trial registration

NCT03208621. This trial was registered prospectively on June 30, 2017.

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Radiosensitization of clioquinol and zinc in human cancer cell lines

Abstract

Background

We previously reported that clioquinol acts as a zinc ionophore and inhibits the NF-κB signalling pathway. Other research has demonstrated that zinc deficiency plays a vital role in the occurrence and development of some solid tumours, and intracellular zinc supplementation may reverse this process and enhance the tumour sensitivity to anticancer treatment. Thus, we investigated the radiosensitization effects of clioquinol combined with zinc on HeLa and MCF-7 cells in vitro.

Methods

The dose effect of growth inhibition of clioquinol combined with zinc on cell viability was determined by a cell counting kit 8 (CCK-8) assay. The radiosensitization effect of clioquinol combined with zinc and/or MG132 in HeLa and MCF-7 cells was detected by the clonogenic assay. The cell cycle distribution and apoptosis of clioquinol combined with zinc on HeLa cells were analyzed by flow cytometry. A luciferase reporter construct was used to study the effect of clioquinol combined with zinc on NF-κB activity in HeLa cells. DNA double-strand breaks were detected by immunofluorescence. The mRNA and protein levels of ATM were analyzed by quantitative real-time PCR and Western blotting, respectively.

Results

Our research showed that clioquinol combined with zinc markedly increased the radiosensitivity of HeLa and MCF-7 cells in low toxic concentrations and resulted in a post-irradiation decrease in G2 phase arrest and an increase in apoptosis. Clioquinol combined with zinc also inhibited NF-κB activation, decreased ATM expression and increased DNA double-strand breaks (DSBs) induced by ionizing radiation.

Conclusions

These findings indicated that clioquinol combined with zinc enhanced the radiosensitivity of HeLa and MCF-7 cells by the down-regulation of ATM through the NF-κB signalling pathway.

https://ift.tt/2F39RNS

Stereotactic body radiation therapy as an effective and safe treatment for small hepatocellular carcinoma

Abstract

Background

To evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT) in patients with small hepatocellular carcinoma(sHCC) who were ineligible for surgery or ablation therapies.

Methods

Results

Conclusion

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Survival after recurrence in patients with gastric cancer who receive S-1 adjuvant chemotherapy: exploratory analysis of the ACTS-GC trial

Abstract

Background

Methods

Results

Conclusion

Trial registration

NCT00152217. First Posted on September 9, 2005.

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Genetic variants in ATM , H2AFX and MRE11 genes and susceptibility to breast cancer in the polish population

Abstract

Background

Methods

Results

Conclusions

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Retrospective analysis of the impact of anthracycline dose reduction and chemotherapy delays on the outcomes of early breast cancer molecular subtypes

Abstract

Background

Methods

Results

Conclusions

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Evaluation of PET and laparoscopy in STagIng advanced gastric cancer: a multicenter prospective study (PLASTIC-study)

Abstract

Background

Methods

Discussion

Trial registration

NCT03208621. This trial was registered prospectively on June 30, 2017.

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Radiosensitization of clioquinol and zinc in human cancer cell lines

Abstract

Background

Methods

Results

Conclusions

These findings indicated that clioquinol combined with zinc enhanced the radiosensitivity of HeLa and MCF-7 cells by the down-regulation of ATM through the NF-κB signalling pathway.

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Long-term outcomes of surgery for choledochal cysts: a single-institution study focusing on follow-up and late complications

Abstract

Purpose

The late postoperative complications of choledochal cyst (CC) surgery are serious and include intrahepatic stones and biliary carcinoma; therefore, long-term follow-up is crucial.

Methods

The subjects of this retrospective study were patients who underwent surgery for CC at Kagoshima University Hospital between April, 1984 and December, 2016. We analyzed the operative results, early and late postoperative complications, and postoperative follow-up rate.

Results

The study population comprised 110 CC patients (male/female: 33/77) with a median age at surgery of 4 years, 3 months (range 12 days–17 years). The patients underwent hepaticoduodenostomy (n = 1; 0.9%) or hepaticojejunostomy (n = 109; 99.1%). Late complications included intrahepatic bile duct (IHBD) dilatation (n = 1; 0.9%), IHBD stones (n = 3; 2.7%), and adhesive ileus (n = 4; 3.6%). There was no incidence of biliary carcinoma in this series. The rates of follow-up at our institute within 10 years of surgery and more than 20 years after surgery were 69.2% (18 of 26) and 14.5% (8 of 55), respectively.

Conclusions

The follow-up rate after definitive surgery declined with time. Late complications were observed within 20 years, but biliary carcinoma was not observed. The follow-up rate should be increased to detect late complications. Moreover, patient education on long-term follow up is essential to prevent life-threatening events after definitive surgery for CC.

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Right and Transverse Colonic Multi-Visceral Resections for Locally Advanced Cancers—a Single-Center Experience

Abstract

Locally advanced colorectal tumors constitute to about 5–22% of all colorectal cancers at the time of presentation. Multi-visceral resection is usually required for such cases in order to achieve curative resection (R0). We aim to present our experience of right and transverse colonic en bloc resections and their outcomes. Retrospective review of a prospective database between February 2008 and December 2014. Case notes, operative findings, histopathology results, and follow-up records were analyzed. A total of 23 patients underwent en bloc multi-visceral resections for locally advanced right-sided or transverse colonic cancers. There were 11 males and 12 females. The mean age was 75 years. Fifteen patients were operated electively and eight were done as emergency. Median follow-up was 36 months. Eleven out of 23 (47%) had more than one organ resected. 78.3% had R0 resections, 17.4% were R1, and 4.3% were indeterminate. The average lymph node yield was 22 [range 5–45]. Senior trainees under supervision did 65% of procedures. Twelve-month disease-free survival was 90% and the 5-year survival was 65%. Right-sided and transverse colonic tumors have a propensity to become locally advanced making curative resections challenging. This is especially relevant when these patients present as an emergency or if the surgeon is less experienced and may opt for a palliative procedure, thus leading to suboptimal outcomes. Multi-visceral resections for locally advanced tumors can be feasible in the district general hospital setting with acceptable outcomes. Multi-disciplinary meeting (MDM) process, adequate training, and experience are vital.

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Long-term outcomes of surgery for choledochal cysts: a single-institution study focusing on follow-up and late complications

Abstract

Purpose

The late postoperative complications of choledochal cyst (CC) surgery are serious and include intrahepatic stones and biliary carcinoma; therefore, long-term follow-up is crucial.

Methods

Results

Conclusions

https://ift.tt/2vusP0x

Right and Transverse Colonic Multi-Visceral Resections for Locally Advanced Cancers—a Single-Center Experience

Abstract

https://ift.tt/2qO1uBJ

Reminders of cancer risk and pain catastrophizing: relationships with cancer worry and perceived risk in women with a first-degree relative with breast cancer

Abstract

First-degree relatives of women with breast cancer may experience increased worry or perceived risk when faced with reminders of their own cancer risk. Worry and risk reminders may include physical symptoms (e.g., persistent breast pain) and caregiving experiences. Women who engage in pain catastrophizing may be particularly likely to experience increased distress when risk reminders are present. We examined the degree to which persistent breast pain and experience as a cancer caregiver were related to cancer worry and perceived risk in first-degree relatives of women with breast cancer (N = 85) and how catastrophic thoughts about breast pain could impact these relationships. There was a significant interaction between persistent breast pain and pain catastrophizing in predicting cancer worry (p = .03); among women who engaged in pain catastrophizing, cancer worry remained high even in the absence of breast pain. Pain catastrophizing also moderated the relationships between caregiving involvement and cancer worry (p = .003) and perceived risk (p = .03). As the degree of caregiving responsibility increased, cancer worry and perceived risk increased for women who engaged in pain catastrophizing; levels of cancer worry and perceived risk remained low and stable for women who did not engage in pain catastrophizing regardless of caregiving experience. The results suggest that first-degree relatives of breast cancer survivors who engage in pain catastrophizing may experience greater cancer worry and perceived risk and may benefit from interventions aimed at reducing catastrophic thoughts about pain.

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Acquired long QT syndrome during conditioning for allogeneic stem cell transplantation—are we aware of this side effect?

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High proportion of TAFRO syndrome in Thai adult Castleman’s disease patients: a 10-year experience

Abstract

Castleman's disease (CD) is a rare lymphoproliferative disorder, and its prevalence in Thailand is not known. This 10-year period study investigated the prevalence of CD in Thailand, and the clinical characteristics and outcomes of Thai CD patients, with special focus on the existence and prevalence of TAFRO syndrome. TAFRO syndrome is defined as CD with thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly. Thirty-three CD patients diagnosed and treated at Siriraj Hospital during January 2007 to December 2016 were included. The prevalence of CD was 1.4 per 1,000,000 patients/10 years. Median age was 46 years, with slight female predominance. Six patients were assigned to the TAFRO group. A high proportion of TAFRO syndrome (18.2%) was found among Thai adult CD patients. In addition to routine TAFRO diagnostic criteria, significantly lower hemoglobin and albumin levels were observed in the TAFRO group than in the non-TAFRO group. Treatment outcomes of CD patients were complete remission (52%), stable disease (30%), and death (13%). Three-year overall survival in the non-TAFRO group and TAFRO group was 88 and 50%, respectively. While most CD patients had a good prognosis, severe cases with TAFRO syndrome had poor outcome.

https://ift.tt/2J9P7qk

Enlarged spleen is associated with low neutrophil and platelet engraftment rates and poor survival after allogeneic stem cell transplantation in patients with acute myeloid leukemia and myelodysplastic syndrome

Abstract

Primary graft failure can be a cause of early morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT), as it leads to a high risk of severe infections and bleeding. Splenomegaly is associated with primary graft failure in patients of myelofibrosis, but the association between splenomegaly and outcomes after HSCT in patients with myeloid malignancies has not been previously evaluated. The aim of this study was to investigate the effect of spleen volume on engraftment kinetics in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We enrolled 85 patients. The median spleen volume was 146 cm³ (quartile 88–201 cm³). The adjusted hazard ratios for neutrophil and platelet engraftments were 0.17 (0.07–0.40, p < 0.001) and 0.19 (0.05–0.69, p = 0.011), respectively, for the high-risk group, at a cutoff splenic volume of 320 cm³. Overall survival at 3 years after HSCT was significantly poor in the high-risk group with an adjusted hazard ratio of 13.8 (2.61–72.4, p = 0.002). Enlarged spleen was associated with low neutrophil and platelet engraftment rates and poor survival after allogeneic HSCT in patients of AML and MDS.

https://ift.tt/2K13a2A

Serum hepcidin levels, iron status, and HFE gene alterations during the first year of life in healthy Spanish infants

Abstract

The aims of this study were to describe hepcidin levels and to assess their associations with iron status and the main variants in the HFE gene in healthy and full-term newborns during the first year of life, as a longitudinal study conducted on 140 infants. Anthropometric and biochemical parameters, hepcidin, hemoglobin (Hb), serum ferritin (SF), transferrin saturation (TS), mean corpuscular volume (MCV), and C-reactive protein (CRP), were assessed in 6- and 12-month-olds. Infants were genotyped for the three main HFE variants: C282Y, H63D, and S65C. Hepcidin levels increased from 6 to 12 months of age (43.7 ± 1.5 to 52.0 ± 1.5 ng/mL; p < 0.001), showing higher levels in infants with better iron status compared to those with iron deficiency (ID) (44.8 ± 1.5 vs 37.9 ± 1.3 ng/mL, p < 0.018, and 54.3 ± 1.5 vs 44.0 ± 1.4 ng/mL, p < 0.038, in 6- and 12-month-olds, respectively). In multivariate linear regression models, iron status was found to be associated with hepcidin levels in infants with wild-type HFE gene (p = 0.046 and p = 0.048 in 6- and 12-month-olds, respectively). However, this association was not found in HFE-alteration-carrying infants. Hepcidin levels increased in healthy infants during the first year of life and were positively associated with iron levels only in infants with wild-type HFE gene, a situation that requires further investigation.

https://ift.tt/2HiKfP1

Philadelphia chromosome-negative acute promyelocytic leukemia manifesting after long-term imatinib treatment for chronic myeloid leukemia: a case report and literature review

https://ift.tt/2JZ7Ztg

Prognostic meaning of neutrophil to lymphocyte ratio (NLR) and lymphocyte to monocyte ration (LMR) in newly diagnosed Hodgkin lymphoma patients treated upfront with a PET-2 based strategy

Abstract

Recent reports identify NLR (the ratio between absolute neutrophils counts, ANC, and absolute lymphocyte count, ALC), as predictor of progression-free survival (PFS) and overall survival (OS) in cancer patients. We retrospectively tested NLR and LMR (the ratio between absolute lymphocyte and monocyte counts) in newly diagnosed Hodgkin lymphoma (HL) patients treated upfront with a PET-2 risk-adapted strategy. NLR and LMR were calculated using records obtained from the complete blood count (CBC) from 180 newly diagnosed HL patients. PFS was evaluated accordingly to Kaplan-Meier method. Higher NLR was associated to advanced stage, increased absolute counts of neutrophils and reduced count of lymphocytes, and markers of systemic inflammation. After a median follow-up of 68 months, PFS at 60 months was 86.6% versus 70.1%, respectively, in patients with NLR ≥ 6 or NLR < 6. Predictors of PFS at 60 months were PET-2 scan (p < 0.0001), NLR ≥ 6.0 (p = 0.02), LMR < 2 (p = 0.048), and ANC (p = 0.0059) in univariate analysis, but only PET-2 was an independent predictor of PFS in multivariate analysis. Advanced-stage patients (N = 119) were treated according to a PET-2 risk-adapted protocol, with an early switch to BEACOPP regimen in case of PET-2 positivity. Despite this strategy, patients with positive PET-2 still had an inferior outcome, with PFS at 60 months of 84.7% versus 40.1% (negative and positive PET-2 patients, respectively, p < 0.0001). Independent predictors of PFS by multivariate analysis were PET-2 status and to a lesser extend NLR in advanced stage, while LMR maintained its significance in early stage. By focusing on PET-2 negative patients, we found that patients with NLR ≥ 6.0 or LMR < 2 had an inferior outcome compared to patients with both ratios above the cutoff (78.7 versus 91.9 months, p = 0.01). We confirm NLR as predictor of PFS in HL patients independently from stage at diagnosis. Integration of PET-2 scan, NLR and LMR can result in a meaningful prognostic system that needs to be further validated in prospective series including patients treated upfront with PET-2 adapted-risk therapy.

https://ift.tt/2HhvYCr

Extramedullary involvement of the stomach presenting as multiple white elevations in the initial diagnosis of chronic myeloid leukemia treated with dasatinib

https://ift.tt/2K0n3Hi

Genome-wide genotype-based risk model for survival in core binding factor acute myeloid leukemia patients

Abstract

The present study attempted to build a single nucleotide polymorphism (SNP)-based risk model for predicting overall survival (OS) and event-free survival (EFS) in patients with core binding factor acute myeloid leukemia (CBF-AML). Adopting genome-wide SNP array using Affymetrix SNP array 6.0, we analyzed 868,157 SNPs with respect to OS and EFS in 104 patients with CBF-AML. Significant SNPs were identified from single SNP analysis. The risk model was constructed with incorporation of six SNPs and three clinical factors (age, c-kit exon 17 mutation, and LDH) for OS and six SNPs and three clinical factors (age, WBC, and LDH) for EFS. The model was further defined into low- and high-risk groups based on risk scores. The median age was 39 years, and the subgroup of t(8;21) and inv(16) or t(16;16) was assessed in 68 (65.4%) and 36 patients (34.6%). Finally, six SNPs per each OS (rs4353685, rs4908185, rs7709207, rs12034, rs1554844, and rs17241868) and EFS (rs13385610, rs11210617, rs11169282, rs7709207, rs4438401, and rs16894846) were incorporated into the risk model. OS was significantly different in favor of the low risk group (80.4 ± 8.4%) compared to the high-risk group (22.0 ± 7.3% at 3 years; p = 8.75 × 10^− 13; HR 8.67). For EFS, there was also a significant difference between the low- (75.0 ± 5.8%) versus high-risk group (17.1 ± 6.3% at 3 years; p = 5.95 × 10^− 13; HR 7.67). A genome-wide SNP-based risk model can stratify CBF-AML patients according to their OS and EFS in 104 patients.

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The potential role of clarithromycin addition to lenalidomide and dexamethasone therapy (BiRd) in multiple myeloma

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Adult T cell leukemia/lymphoma with different pathological features in each tumor site

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Allogeneic hematopoietic stem cell transplantation in Primary Cutaneous T Cell Lymphoma

Abstract

In our retrospective study, 16 patients affected by advanced cutaneous T cell lymphoma (CTCL) underwent allogeneic hematopoietic stem cell transplantation (HSCT). Two patients (12.5%) were in complete remission (CR), nine (56.3%) in partial remission (PR), and five (31.2%) with active disease. The patients were transplanted from an HLA-identical (n = 7) from a mismatched (n = 1) or haploidentical (n = 1) sibling, from matched unrelated donor (n = 5), or from a single cord blood unit (n = 2). Conditioning regimen was standard myeloablative in 6 patients and at reduced intensity in 10. Seven patients died from non relapse mortality (NRM) and four patients relapsed or progressed, three of them achieved a second CR after donor lymphocyte infusion (DLI) or chemotherapy plus DLI. To date, with a median follow-up of 76 months (range 6–130), nine patients are alive, eight in CR, and one with active disease. Overall survival (OS) and disease-free survival (DFS) at 1 and 10 years are 61% (95% CI 40–91%) and 54% (95% CI 33–86%), 40% (95% CI 22–74%), and 34% (95% CI 16–68%), respectively. The time from diagnosis to transplant seems to influence negatively both OS (log-rank p < 0.04) and DFS (log-rank p < 0.05). Our results confirm on a long follow-up that CTCL appears particularly susceptible to the graft versus lymphoma (GVL) effect, so that allogeneic HSCT represents a possibility of cure for advanced CTCL. The timing of HSCT in the clinical course of disease remains an open issue.

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