External Beam Radiation Therapy for Amyloidosis of the Urinary Bladder

Publication date: Available online 16 August 2017
Source:Practical Radiation Oncology
Author(s): Christopher T. Cooper, Bruce D. Greene, Jeffrey E. Fegan, Douglas Rovira, Morie A. Gertz, David M. Marcus




http://ift.tt/2uVUi6E

A multi-institutional phase II trial of prostate stereotactic body radiation therapy (SBRT) utilizing continuous real-time evaluation of prostate motion with patient reported quality of life

Publication date: Available online 16 August 2017
Source:Practical Radiation Oncology
Author(s): William C. Jackson, Robert T. Dess, Dale W. Litzenberg, Pin Li, Matthew Schipper, Seth A. Rosenthal, Garrick C. Chang, Eric M. Horwitz, Robert A. Price, Jeff M. Michalski, Hiram A. Gay, John T Wei, Mary Feng, Felix Y. Feng, Howard M. Sandler, Robert E. Wallace, Daniel E. Spratt, Daniel A. Hamstra
PurposeThe use of stereotactic body radiation therapy (SBRT) for prostate cancer has been reported predominantly from single institutional studies while concerns for broader adoption exist.Methods and MaterialsFrom 2011–2013, 66 men were accrued to a phase II trial at five centers. SBRT consisted of 5 fractions of 7.4 Gy to 37 Gy using conventional linear accelerators. Electromagnetic transponders were utilized for motion management. Health-related quality of life (HRQOL) was evaluated via the EPIC-26 questionnaire. Acute and late toxicities were collected by common terminology criteria for adverse events (CTCAE) version 4.0. Linear mixed modeling was performed to assess changes in HRQOL over time.ResultsMedian follow-up was 36 months. All men had low or intermediate-risk disease. There have been zero biochemical recurrences. No grade 3 urinary or bowel toxicity was reported. Twenty-three percent of patients had acute grade 2 urinary toxicity, with 9% late grade 2 urinary toxicity. Four and 5% experienced acute or late grade 2+ bowel toxicity, respectively. Urinary bother and bowel HRQOL transiently decreased during the first 6–12 months post-SBRT, and then returned to baseline. In men with good erectile function at baseline, sexual HRQOL declined during the first 6 months and stabilized thereafter. On linear mixed modeling the strongest predictor of sustained bowel and sexual HRQOL was baseline HRQOL.ConclusionsIn this multi-institutional phase II clinical trial utilizing continuous real-time evaluation of prostate motion, prostate SBRT has excellent intermediate-term tumor control with mild and expected treatment-related side effects.



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Measuring Safety Culture: Application of The Hospital Survey on Patient Safety Culture to Radiotherapy Departments Worldwide

Publication date: Available online 16 August 2017
Source:Practical Radiation Oncology
Author(s): Sarah Leonard, Anita O'Donovan
BackgroundMinimising errors and improving patient safety has gained prominence worldwide in high risk disciplines such as radiotherapy. Patient safety culture has been identified as an important factor in reducing the incidence of adverse events and improving patient safety in the healthcare setting.PurposeThe aim of distributing the Hospital Survey on Patient Safety Culture (HSPSC) to radiotherapy departments worldwide was to assess the current status of safety culture, identify areas for improvement and areas that excel, examine factors which influence safety culture and to raise staff awareness.Materials and MethodsThe safety culture in radiotherapy departments worldwide was evaluated by distributing the HSPSC. A total of 266 participants were recruited worldwide from radiotherapy departments and included radiation oncologists, radiation therapists, physicists and dosimetrists.ResultsThe positive percent scores for the 12 dimensions of the HSPSC varied from 50% to 79%. The highest composite score amongst the 12 dimensions was teamwork within units and the lowest composite score was handoffs and transitions.ConclusionThe results indicated that health care professionals in radiotherapy departments felt positively towards patient safety. The HSPSC was successfully applied to radiotherapy departments and provided a valuable insight into areas of potential improvement such as teamwork across units, staffing and handoffs and transitions. Managers and policy makers in radiotherapy may use this assessment tool for focused improvement efforts towards patient safety culture.



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Challenges in the anesthetic management of ambulatory patients in the MRI suites.

Purpose of review: MRI is becoming an indispensable diagnostic tool. The need for prolonged motion-free periods has substantially increased the need for deep sedation or anesthesia in a challenging environment. This review summarises recent literature with respect to pharmacological sedative strategies, nonpharmacological alternative approaches, airway management and safety issues in the ambulatory setting. Recent findings: Most literature researches the pediatric patient population. The American Society of Pediatrics published guidelines for monitoring and management of pediatric patients during sedation for diagnostic procedures. Dexmedetomidine is the most researched agent for sedation. It remains uncertain what the clinical implications are of the potential neurotoxicity of repeat sedation or anesthesia in young children. Airway strategies highlight the use of end-tidal carbon dioxide monitoring. Technical imaging advancement and nonpharmacological sedation alternatives allow for shorter procedures with a lower need for sedation. Summary: The anesthetic management of ambulatory patients in the MRI environment has its specific challenges and safety issues. However, the implementation of safety guidelines, new pharmacological and alternative nonpharmacological sedation strategies offer interesting perspectives to tackle these challenges. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Down-regulation of Aquaporin 5-mediated Epithelial-Mesenchymal Transition and Anti-metastatic Effect by Natural Product Cairicoside E in Colorectal Cancer

Abstract

Epithelial-mesenchymal transition (EMT) has emerged as an important determinant role in colorectal cancer (CRC) metastasis. It has been reported that aquaporin 5 (AQP5) is closely linked to CRC metastasis. However, the effect of AQP5 on the EMT process of CRC remains unknown. The current study showed that overexpression of AQP5 activated EMT in CRC cells. Cairicoside E (CE), a natural resin glycoside compound isolated from Ipomoea cairica, showed promising cytotoxic activity in our previous report. Further investigation found that CE inhibited the expression of AQP5 and the EMT process. Moreover, the inhibitory effect of CE on EMT was reversed by overexpression of AQP5. Importantly, CE also suppressed the EMT and p-Smad2/3 induced by TGF-β1. On the other hand, overexpression of AQP5 up-regulated the p-Smad2/3, which resulted in the activation of EMT. After silencing of AQP5, CE had no significant effect on EMT markers and p-Smad2/3 induced by TGF-β1, indicating that CE inhibited the EMT through down-regulation of AQP5 and suppression of p-Smad2/3. CE also inhibited the AQP5 expression in the lung metastatic nodules of HCT-116 cells in vivo. Our findings suggested that CE may serve as a promising drug for the treatment of CRC metastasis. This article is protected by copyright. All rights reserved

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A Novel Absorbable Radiopaque Hydrogel Spacer to Separate the Head of the Pancreas and Duodenum in Radiotherapy of Pancreatic Cancer

Publication date: Available online 14 August 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Avani D. Rao, Ziwei Feng, Eun Ji Shin, Jin He, Kevin M. Waters, Stephanie Coquia, Robert DeJong, Lauren M. Rosati, Lin Su, Dengwang Li, Juan Jackson, Stephen Clark, Jeffrey Schultz, Danielle Hutchings, Seong-Hun Kim, Ralph H. Hruban, John Wong, Amol Narang, Joseph M. Herman, Kai Ding
Purpose/Objectives: We assessed the feasibility and theoretical dosimetric advantages of an injectable hydrogel to increase space between the head of the pancreas (HOP) and duodenum in a human cadaveric model.Materials/MethodsUsing three human cadaveric specimens, an absorbable radiopaque hydrogel was injected between the HOP and duodenum via open laparotomy in one case and endoscopic-ultrasound (EUS) guidance in two cases. Cadavers were subsequently imaged using computed tomography and dissected for histologic confirmation of hydrogel placement. The duodenal dose reduction and planning target volume (PTV) coverage were characterized using pre- and post-spacer injection stereotactic body radiotherapy (SBRT) plans of the two cadavers with EUS, the delivery method which appears to be most clinically desirable. Modeling studies were performed using 60 SBRT plans consisting of 10 previously treated unresectable pancreatic cancer patients each with 6 different HOP-duodenum separation distances. Duodenal volume receiving 15 Gy (V15), 20 Gy (V20) and 33 Gy (V33) was assessed for each iteration.ResultsIn the three cadaveric studies, an average of 0.9 cm, 1.1 cm, and 0.9 cm HOP-duodenum separation was achieved, respectively. In the two EUS cases, V20 decreased from 3.86 cc→0.36 cc and 3.75 cc→1.08 cc (treatment constraint: <3 cc), and V15 decreased from 7.07 cc→2.02 cc and 9.12 cc→3.91 cc (treatment constraint: <9 cc), respectively. PTV coverage improved or was comparable between the pre- and post-injection studies. Modeling studies demonstrated that separation of 8 mm was sufficient to consistently reduce V15, V20 and V33 to acceptable clinical constraints.ConclusionsCurrently, dose-escalation is limited due to radiosensitive structures adjacent to the pancreas. We demonstrated the feasibility of hydrogel separation of the HOP and duodenum. Future studies will evaluate the safety and efficacy of this technique with the potential for more effective dose-escalation using SBRT or intensity-modulated radiotherapy to improve outcomes in unresectable pancreatic cancer patients.

Teaser

We demonstrated the feasibility of an endoscopic ultrasound-guided injectable hydrogel separation technique using a cadaveric model to increase the space between the head of the pancreas and duodenum. Using modeling studies, we identified the minimum distance of this separation for optimal sparing of the duodenum, setting the foundation for future clinical trials utilizing this technique to enable dose-escalation with either stereotactic or intensity-modulated radiotherapy for patients with unresectable pancreatic cancer.


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Zika-Virus-Encoded NS2A Disrupts Mammalian Cortical Neurogenesis by Degrading Adherens Junction Proteins

Publication date: Available online 17 August 2017
Source:Cell Stem Cell
Author(s): Ki-Jun Yoon, Guang Song, Xuyu Qian, Jianbo Pan, Dan Xu, Hee-Sool Rho, Nam-Shik Kim, Christa Habela, Lily Zheng, Fadi Jacob, Feiran Zhang, Emily M. Lee, Wei-Kai Huang, Francisca Rojas Ringeling, Caroline Vissers, Cui Li, Ling Yuan, Koeun Kang, Sunghan Kim, Junghoon Yeo, Yichen Cheng, Sheng Liu, Zhexing Wen, Cheng-Feng Qin, Qingfeng Wu, Kimberly M. Christian, Hengli Tang, Peng Jin, Zhiheng Xu, Jiang Qian, Heng Zhu, Hongjun Song, Guo-li Ming
Zika virus (ZIKV) directly infects neural progenitors and impairs their proliferation. How ZIKV interacts with the host molecular machinery to impact neurogenesis in vivo is not well understood. Here, by systematically introducing individual proteins encoded by ZIKV into the embryonic mouse cortex, we show that expression of ZIKV-NS2A, but not Dengue virus (DENV)-NS2A, leads to reduced proliferation and premature differentiation of radial glial cells and aberrant positioning of newborn neurons. Mechanistically, in vitro mapping of protein-interactomes and biochemical analysis suggest interactions between ZIKA-NS2A and multiple adherens junction complex (AJ) components. Functionally, ZIKV-NS2A, but not DENV-NS2A, destabilizes the AJ complex, resulting in impaired AJ formation and aberrant radial glial fiber scaffolding in the embryonic mouse cortex. Similarly, ZIKA-NS2A, but not DENV-NS2A, reduces radial glial cell proliferation and causes AJ deficits in human forebrain organoids. Together, our results reveal pathogenic mechanisms underlying ZIKV infection in the developing mammalian brain.

Graphical abstract

Teaser

Zika virus infects neural stem cells and causes microcephaly. In this study, Yoon et al. showed that NS2A protein encoded by Zika virus, but not by Dengue virus, impairs proliferation of radial glial cells in both embryonic mouse cortex and human forebrain organoids. Mechanistically, ZIKV-NS2A disrupts adherens junction formation.


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Hypoalbuminemia is a Predictive Factor for Fistula Formation in Recurrent Cervical Cancer.

Objective: Antivascular endothelial growth factor monoclonal antibodies inhibit tumor angiogenesis, consequently impeding the recruitment of new vasculature to existing and new tumor lesions. We sought to evaluate toxicities in women with recurrent cervical cancer after receiving bevacizumab combination chemotherapy. Methods: A review was conducted of women with recurrent and metastatic cervical cancer who were treated with salvage chemotherapy with or without bevacizumab between 2005 and 2015. Clinicopathologic data and reasons for treatment discontinuation were recorded. Patients that were excluded had other histology than squamous or adenocarcinoma, received 1 cycle of salvage chemotherapy, single agent bevacizumab, currently on treatment, or noncompliant. Statistical analysis was performed using the Fishers Exact Test, logistic regression, and Kaplan-Meier Survival Analysis. Results: A total of 74 patients were included in analysis. Twenty-six patients were treated with bevacizumab (BEV) and chemotherapy and 48 patients with chemotherapy alone (chemotherapy). The progression free survival was significant with median 12 months versus 7 months for the BEV cohort (P

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Successful treatment of metastatic alveolar rhabdomyosarcoma with MGMT gene promoter methylation by temozolomide-based combination chemotherapy

Abstract

A 3-year-old male presented with a large retroperitoneal mass and multiple metastases. Biopsy results suggested alveolar rhabdomyosarcoma bearing a methylated O6-methylguanine-DNA methyltransferase (MGMT) gene promoter. Serum microRNA-206 levels were elevated and remained high after three cycles of vincristine, dactinomycin, and cyclophosphamide (VAC). Replacement of vincristine, irinotecan, and temozolomide (VIT) for VAC induced a marked tumor reduction and normalization of the miR-206 levels. The patient completed 14 cycles of VIT with local radiotherapy and has been in remission for 31 months. Temozolomide could be effective for tumors with a methylated MGMT gene promoter. Individualized therapy is warranted for such patients.

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History of parvovirus B19 infection is associated with silent cerebral infarcts

Abstract

Background

The relationship between silent cerebral infarcts (SCIs) and history of parvovirus B19 (B19V) has not been systematically evaluated. As an ancillary study from the Silent Cerebral Infarct Trial (SIT) (NCT00072761), we tested the hypothesis that a history of B19V infection is associated with an increased prevalence of SCIs in children with sickle cell anemia.

Procedure

We used a retrospective cross-sectional cohort study design; each participant underwent a brain magnetic resonance imaging (MRI) scan and medical record review for prior B19V infection (n = 958).

Results

SCI was present in 30% (287 of 958) of participants and 17% (165 of 958) had a history of B19V infection. Based on prior evidence that low baseline hemoglobin (Hgb) levels are associated with increased odds of SCI, Hgb levels were divided into tertiles (<7.6 g/dl, ≥7.6–≤8.5 g/dl, ≥8.6 g/dl) and multivariable analysis was used to determine the relationship between the joint effect of prior B19V infection, Hgb levels, and SCI. Prior B19V infection and the lowest Hgb tertile were associated with increased risk of SCI (odds ratio [OR] 2.12; 95% CI, 1.17–3.84; P = 0.013); no prior B19V infection and the highest Hgb tertile were associated with a decreased risk (OR 0.56; 95% CI, 0.38–0.84; P = 0.004).

Conclusions

Efforts to decrease the incidence of B19V infection, such as the development of a B19V vaccine, may decrease SCI prevalence.

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Lack of mortality in 22 children with sickle cell anemia and severe malarial anemia

Abstract

Retrospective studies suggest that there is high mortality in children with sickle cell anemia (SCA) and severe malaria. We assessed mortality in Ugandan children with severe malarial anemia (SMA, n = 232) or cerebral malaria (CM, n = 267) by sickle cell hemoglobin genotype. Admission and 2-year follow-up mortality did not differ among children with SMA who had homozygous form of sickle cell hemoglobin (HbSS) versus normal form of adult hemoglobin (admission, 0/22, 0%, vs. 1/208, 0.5%; follow-up, 1/22, 4.5%; 7/207, 3.4%, respectively; all P > 0.6). The single child with CM and HbSS survived. The study findings highlight the need for large prospective studies of malaria-related mortality in children with SCA.

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Comment on: Acquired monosomy 7 myelodysplastic syndrome in a child with clinical features of dyskeratosis congenita and IMAGe association

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Lung Ultrasound in the Critically Ill: The BLUE Protocol.

No abstract available

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Boring Is Beautiful in Preoperative Assessment.

No abstract available

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Association of STOP-Bang Questionnaire as a Screening Tool for Sleep Apnea and Postoperative Complications: A Systematic Review and Bayesian Meta-analysis of Prospective and Retrospective Cohort Studies.

BACKGROUND: The risk of postoperative complications increases with undiagnosed obstructive sleep apnea (OSA). The high-risk OSA (HR-OSA) patients can be easily identified using the STOP-Bang screening tool. The aim of this systematic review and meta-analysis is to determine the association of postoperative complications in patients screened as HR-OSA versus low-risk OSA (LR-OSA). METHODS: The following data bases were searched from January 1, 2008, to October 31, 2016, to identify the eligible articles: Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Cochrane Databases of Systematic Reviews, Medline-in-Process & other nonindexed citations, Google Scholar, Embase, Web of Sciences and Scopus. The search included studies with adult surgical patients screened for OSA with STOP-Bang questionnaire that reported at least 1 cardiopulmonary or any other complication requiring intensive care unit admission as diagnosis of outcome. We used a Bayesian random-effects analysis to evaluate the existing evidence of STOP-Bang in relation to OSA and to assess the association of postoperative complications with the identified HR-OSA patients by study design and methodologies. RESULTS: This systematic review and meta-analysis was conducted using 10 cohort studies: 23,609 patients (HR-OSA, 7877; LR-OSA, 15,732). The pooled odds of perioperative complications were higher in the HR-OSA versus LR-OSA patients (odds ratio 3.93, 95% credible interval, 1.85-7.77, P= .003; 6.86% vs 4.62%). The length of hospital stay was longer in HR-OSA by 2 days when compared with LR-OSA (5.0 +/- 4.2 vs 3.4 +/- 2.8 days; mean difference 2.01; 95% credible interval, 0.77-3.24; P= .005). Meta-regression to adjust for baseline confounding factors and subgroup analysis did not materially change the results. CONCLUSIONS: This systematic review and meta-analysis suggests that HR-OSA is related with higher risk of postoperative adverse events and longer length of hospital stay when compared with LR-OSA patients. Our findings support the implementation of the STOP-Bang screening tool for perioperative risk stratification. (C) 2017 International Anesthesia Research Society

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Impact of Simulator-Based Training in Focused Transesophageal Echocardiography: A Randomized Controlled Trial.

BACKGROUND: The aim of the study was to determine if training in transesophageal echocardiography (TEE) using a TEE simulator improves the ability of novice operators to perform and interpret a focused critical care TEE. METHODS: In this prospective, randomized, controlled study with blinded outcome assessment, 44 intensive care unit trainees were randomly assigned to a control group receiving 4 hours of lecture-based training only, or an intervention group which was additionally trained for 4 hours using a TEE simulator. After the training intervention, each participant performed 2 TEEs in intensive care unit patients which were evaluated by blinded assessors. The imaging quality of TEEs was measured using a predefined examination quality score ranging from 0 to 100 points. The correct quantification of pathologies and the interpretation of the TEEs were evaluated by blinded assessors using focused and comprehensive expert TEEs as comparators. RESULTS: A total of 114 TEEs were assessed. The mean examination quality score was 55.9 (95% confidence interval [CI], 50.3-61.5) for TEEs of the control group, 75.6 (95% CI, 70.1-81.0) for TEEs of the intervention group, and 88.5 (95% CI, 79.3-97.7) for TEEs in the expert group. The multiple comparisons revealed significant differences between all groups (19.7 [95% CI, 12.8-26.6], P

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Hypothermia Risk With Intraoperative Continuous Renal Replacement Therapy.

No abstract available

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Surveying the Literature: Synopsis of Recent Key Publications.

No abstract available

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Novel Immunotherapies for Multiple Myeloma

Abstract

Purpose of Review

The treatment landscape of multiple myeloma is rapidly changing; however, despite improvement in patients' survival, it still remains a largely incurable disease. One hallmark of myeloma is substantial immune dysfunction leading to an increased infection rate and the inability of immune surveillance to detect neoplastic cells. Here, we critically analyze clinical approaches to harness the immune system to overcome this defect with a focus on antibody based and adoptive cellular therapies.

Recent Findings

Clinical trials exploring these immunotherapies to treat myeloma are now well underway and show promising results. In relapsed myeloma, monoclonal antibodies directed against plasma cell antigens and immune checkpoints have already shown substantial efficacy. In parallel, trials of adoptive cellular therapy have exciting promise in myeloma, having induced dramatic responses in a handful of early study participants.

Summary

Taken together, immunotherapeutic approaches hold enormous potential in the field of multiple myeloma and in the near future can be combined with or even replace the current standard of care.

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Erratum to: A novel tubulin polymerization inhibitor, MPT0B206, downregulates Bcr-Abl expression and induces apoptosis in imatinib-sensitive and imatinib-resistant CML cells

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CXCR4 blockade with AMD3100 enhances Taxol chemotherapy to limit ovarian cancer cell growth.

The standard of care for ovarian cancer includes initial treatment with chemotherapy. Despite initial efficacy, over 70% of patients develop recurrence; thus, there is a need to identify novel approaches that can improve therapeutic outcomes. We evaluated AMD3100 (Plerixafor), an FDA-approved CXCR4 inhibitor, as a potential adjunctive therapy for low-dose Taxol (Paclitaxel) by assessing the impact on in-vitro ovarian cancer cell proliferation. Proliferation was a measure for both human TOV-112D and murine ID8 ovarian cancer cells incubated with AMD3100 and Taxol, either individually or in combination. Impact of treatment was first determined for the simultaneous administration of AMD3100 and Taxol. We next assessed a sequential application of AMD3100 pretreatment, followed by AMD3100, Taxol, or a combination to test for sensitization to Taxol. In addition, we measured the impact of AMD3100 and Taxol, individually and in combination, on colony formation, an in-vitro model assay of tumor growth. Expression data, as measured by flow cytometry, show that both ID8 and TOV-112D cells are positive for CXCR4, CXCR7, and CXCL12. Combination treatment with AMD3100 (

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Loss of the tumor suppressor STAG2 promotes telomere recombination and extends the replicative lifespan of normal human cells

Sister chromatids are held together by cohesin, a tripartite ring with a peripheral SA1/2 subunit, where SA1 is required for telomere cohesion and SA2 for centromere cohesion. The STAG2 gene encoding SA2 is often inactivated in human cancer, but not in in a manner associated with aneuploidy. Thus, how these tumors maintain chromosomal cohesion and how STAG2 loss contributes to tumorigenesis remain open questions. Here we show that, despite a loss in centromere cohesion, sister chromatids in STAG2 mutant tumor cells maintain cohesion in mitosis at chromosome arms and telomeres. Telomere maintenance in STAG2 mutant tumor cells occurred by either telomere recombination or telomerase activation mechanisms. Notably, these cells were refractory to telomerase inhibitors, indicating recombination can provide an alternative means of telomere maintenance. STAG2 silencing in normal human cells which lack telomerase led to increased recombination at telomeres, delayed telomere shortening and postponed senescence onset. Insofar as telomere shortening and replicative senescence prevent genomic instability and cancer by limiting the number of cell divisions, our findings suggest that extending the lifespan of normal human cells due to inactivation of STAG2 could promote tumorigenesis by extending the period during which tumor-driving mutations occur.

http://ift.tt/2wkYaSi

PADI2-mediated citrullination promotes prostate cancer progression

Onset of castration-resistance prostate cancer (CRPC) after long-term androgen-deprivation therapy remains a major obstacle in the treatment of prostate cancer (PCa). The peptidylarginine deiminase PADI2 has been implicated in chronic inflammatory diseases and cancer. Here we show that PADI2 is an androgen-repressed gene and is upregulated in CRPC. PADI2 expression was required for survival and cell cycle progression of PCa cells, and PADI2 promoted proliferation of PCa cells under androgen-deprived or castration conditions in vitro and in vivo. Cytoplasmic PADI2 protected the androgen receptor (AR) against proteasome-mediated degradation and facilitated AR binding to its target genes after nuclear translocation and citrullination of histone H3 amino acid residue R26. By contrast, mutant PADI2 D180A failed to affect AR stability, nuclear translocation or transcriptional activity. PADI2 mediated AR control in a manner dependent on its enzymatic activity and nuclear localization, as correlated with increased histone H3 citrullination. Notably, co-administration of the PADI inhibitor Cl-amidine and the AR signaling inhibitor enzalutamide synergized in inhibiting CRPC cell proliferation in vitro and tumor growth in vivo. Overall, our results establish PADI2 as a key mediator for AR in PCa progression, especially CRPC, and they suggest PADI as novel therapeutic targets in this disease setting.

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Combination therapy with bispecific antibodies and PD-1 blockade enhances the antitumor potency of T cells

The DOCK-AND-LOCK (DNL®) method is a platform technology that combines recombinant engineering and site-specific conjugation to create multispecific, multivalent antibodies of defined composition with retained bioactivity. We have applied DNL® to generate a novel class of trivalent bispecific antibodies (bsAbs), each comprising an anti-CD3 scFv covalently conjugated to a stabilized dimer of different anti-tumor Fabs. Here we report the further characterization of two such constructs, (E1)-3s and (14)-3s, which activate T cells and target Trop-2- and CEACAM5-expressing cancer cells, respectively. (E1)-3s and (14)-3s, in the presence of human T cells, killed target cells grown as monolayers at subnanomolar concentrations, with a similar potency observed for drug-resistant cells. Antitumor efficacy was demonstrated for (E1)-3s co-administered with human peripheral blood mononuclear cells (PBMC) in NOD/SCID mice harboring xenografts of MDA-MB-231, a triple-negative breast cancer line constitutively expressing Trop-2 and PD-L1. Growth inhibition was observed following treatment with (E1)-3s or (14)-3s combined with human PBMC in 3D spheroids generated from target cell lines to mimic the in vivo behavior and microenvironment of these tumors. Moreover, addition of an antagonistic anti-PD-1 antibody increased cell death in 3D spheroids and extended survival of MDA-MB-231-bearing mice. These preclinical results emphasize the potential of combining T cell-redirecting bsAbs with antagonists or agonists that mitigate T cell inhibition within the tumor microenvironment to improve immunotherapy of solid cancers in patients. They also support the use of 3D spheroids as a predictive alternative to in vivo models for evaluating T cell functions.

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Therapeutic targeting of the CBP/p300 bromodomain blocks the growth of castration-resistant prostate cancer

Resistance invariably develops to anti-androgen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here we report that the transcriptional co-activator CBP/p300 is required to maintain the growth of castration-resistant prostate cancer. To exploit this vulnerability, we developed a novel small-molecule inhibitor of the CBP/p300 bromodomain that blocks prostate cancer growth in vitro and in vivo. Molecular dissection of the consequences of drug treatment revealed a critical role for CBP/p300 in histone acetylation required for the transcriptional activity of the androgen receptor and its target gene expression. Our findings offer a preclinical proof of concept for small molecule therapies to target the CBP/p300 bromodomain as a strategy to treat castration-resistant prostate cancer.

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Trastuzumab Increases HER2 Uptake and Cross-Presentation by Dendritic Cells

Early phase clinical trials evaluating CD8+ T cell-eliciting, HER2-derived peptide vaccines administered to HER2-positive breast cancer patients in the adjuvant setting suggest synergy between the vaccines and trastuzumab, the monoclonal antibody targeting the HER2 protein. Among 60 patients enrolled on clinical trials evaluating the E75+GM-CSF and GP2+GM-CSF vaccines, there have been no recurrences in patients vaccinated after receiving trastuzumab as part of standard therapy in the per treatment analyses conducted after a median follow-up of greater than 34 months. Here we describe a mechanism by which this synergy may occur. Flow cytometry showed that trastuzumab facilitated uptake of HER2 by dendritic cells (DC), which was mediated by the Fc receptor and was specific to trastuzumab. In vitro, increased HER2 uptake by DC increased cross-presentation of E75, the immunodominant epitope derived from the HER2 protein; an observation confirmed in two in vivo mouse models. This increased E75 cross-presentation, mediated by trastuzumab treatment, enabled more efficient expansion of E75-specific cytotoxic T cells (E75-CTL). These results demonstrate a mechanism by which trastuzumab links innate and adaptive immunity by facilitating activation of antigen-specific T cells. Based on these data, we conclude that HER2-positive breast cancer patients that have been treated with trastuzumab may experience a more robust antitumor immune response by restimulation of T cells with the E75 peptide vaccine, thereby accounting for the improved disease-free survival observed with combination therapy.

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MRE11 promotes tumorigenesis by facilitating resistance to oncogene-induced replication stress

Hypomorphic mutations in the genes encoding the MRE11/RAD50/NBS1 (MRN) DNA repair complex lead to cancer-prone syndromes. MRN binds DNA double strand breaks where it functions in repair and triggers cell cycle checkpoints via activation of the ataxia-telangiectasia mutated (ATM) kinase. To gain understanding of MRN in cancer, we engineered mice with B lymphocytes lacking MRN, or harboring MRN in which MRE11 lacks nuclease activities. Both forms of MRN deficiency led to hallmarks of cancer, including oncogenic translocations involving c-Myc and the immunoglobulin locus. These pre-neoplastic B lymphocytes did not progress to detectable B lineage lymphoma, even in the absence of p53. Moreover, Mre11 deficiencies prevented tumorigenesis in a mouse model strongly predisposed to spontaneous B cell lymphomas. Our findings indicate that MRN cannot be considered a standard tumor suppressor and instead imply that nuclease activities of MRE11 are required for oncogenesis. Inhibition of MRE11 nuclease activity increased DNA damage and selectively induced apoptosis in cells overexpressing oncogenes, suggesting MRE11 serves an important role in countering oncogene-induced replication stress. Thus, MRE11 may offer a target for cancer therapeutic development. More broadly, our work supports the idea that subtle enhancements of endogenous genome instability can exceed the tolerance of cancer cells and be exploited for therapeutic ends.

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Therapeutic effects of XPO1 inhibition in thymic epithelial tumors

Exportin 1 (XPO1) mediates nuclear export of many cellular factors known to play critical roles in malignant processes, and selinexor (KPT-330) is the first XPO1-selective inhibitor of nuclear export (SINE) compound in advanced clinical development phase for cancer treatment. We demonstrated here that inhibition of XPO1 drives nuclear accumulation of important cargo tumor suppressor proteins (TSP) including transcription factor FOXO3a and p53 in thymic epithelial tumor (TET) cells and induces p53-dependent and -independent antitumor activity in vitro. Selinexor suppressed the growth of TET xenograft tumors in athymic nude mice via inhibition of cell proliferation and induction of apoptosis. Loss of p53 activity or amplification of XPO1 may contribute to resistance to XPO1 inhibitor in TET. Using mass spectrometry-based proteomics analysis, we identified a number of proteins whose abundances in the nucleus and cytoplasm shifted significantly following selinexor treatment in the TET cells. Furthermore, we found that XPO1 was highly expressed in aggressive histotypes and advanced stages of human TET, and high XPO1 expression was associated with poorer patient survival. These results underscore an important role of XPO1 in the pathogenesis of TET and support clinical development of XPO1 inhibitor for the treatment of patients with this type of tumors.

http://ift.tt/2uVxhAO

{beta}-adrenergic signaling in mice housed at standard temperatures suppresses an effector phenotype in CD8+ T cells and undermines checkpoint inhibitor therapy

The immune context of tumors has significant prognostic value and is predictive of responsiveness to several forms of therapy, including immunotherapy. We report here that CD8+ T cell frequency and functional orientation within the tumor microenvironment is regulated by β2-adrenergic receptor (β-AR) signaling in host immune cells. We used three strategies - physiologic (manipulation of ambient thermal environment), pharmacologic (β-blockers), and genetic (β2-adrenergic receptor knockout mice) to reduce adrenergic stress signaling in two widely studied preclinical mouse tumor models. Reducing β-AR signaling facilitated conversion of tumors to an immunologically active tumor microenvironment with increased intra-tumoral frequency of CD8+ T cells with an effector phenotype and decreased expression of PD-1, in addition to an elevated effector CD8+ T cell to CD4+ regulatory T cell ratio (IFN-γ+CD8+:Treg). Moreover, this conversion significantly increased the efficacy of anti-PD-1 checkpoint blockade. These data highlight the potential of adrenergic stress and norepinephrine-driven β-adrenergic receptor signaling to regulate the immune status of the tumor microenvironment and supports the strategic use of clinically available β-blockers in patients to improve responses to immunotherapy.

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Phenotypic Heterogeneity of Circulating Tumor Cells Informs Clinical Decisions between AR Signaling Inhibitors and Taxanes in Metastatic Prostate Cancer

The heterogeneity of an individual patient's tumor has been linked to treatment resistance, but quantitative biomarkers to rapidly and reproducibly evaluate heterogeneity in a clinical setting are currently lacking. Using established tools available in a CAP-accredited and CLIA-certified clinical laboratory, we quantified digital pathology features on 9,225 individual circulating tumor cells (CTCs) from 179 unique metastatic castration-resistant prostate cancer (mCRPC) patients to define phenotypically distinct cell types. Heterogeneity was quantified based on the diversity of cell types in individual patient samples using the Shannon index and associated with overall survival (OS) in the 145 specimens collected prior to initiation of second or later lines of therapy. Low CTC phenotypic heterogeneity was associated with better OS in patients treated with androgen receptor signaling inhibitors (ARSI), whereas high heterogeneity was associated with better OS in patients treated with taxane chemotherapy. Overall, the results show that quantifying CTC phenotypic heterogeneity can help inform the choice between ARSI and taxanes in mCRPC patients.

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Effect of alisertib, an investigational aurora a kinase inhibitor on the QTc interval in patients with advanced malignancies

Summary

Aims A primary objective of this study was to investigate the effect of single and multiple doses of alisertib, an investigational Aurora A kinase inhibitor, on the QTc interval in patients with advanced malignancies. The dose regimen used was the maximum tolerated dose which was also the recommended phase 3 dose (50 mg twice daily [BID] for 7 days in 21-day cycles). Methods Patients received a single dose of alisertib (50 mg) on Day 1, and multiple doses of alisertib (50 mg BID) on Days 4 through to the morning of Day 10 of the first cycle of treatment. Triplicate ECGs were collected at intervals over 10 to 24 h via Holter recorders on Days −1 (baseline), 1 and 10. Changes from time-matched baseline values were calculated for various ECG parameters including QTc, heart rate, PR and QRS intervals. Alisertib pharmacokinetics were also assessed during the study, and an exposure-QTc analysis was conducted. Results Fifty patients were included in the QTc analysis. The upper bounds of the 95% confidence intervals for changes from time-matched baseline QTcF and QTcI values were <5 ms across all study days, time points and correction methods. Alisertib did not produce clinically relevant effects on heart rate, PR or QRS intervals. There was no evidence of a concentration-QTc effect relationship. Conclusions Alisertib does not cause QTc prolongation and can be concluded to not have any clinically relevant effects on cardiac repolarization or ECG parameters at the single agent maximum tolerated dose of 50 mg BID.

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Signaling Pathways as Potential Therapeutic Targets in Hepatocarcinogenesis

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Bevacizumab as an effective treatment for radiation necrosis after radiotherapy for melanoma brain metastases.

Radiation necrosis (RN) is a potential late complication of radiotherapy for intracranial malignancy, which is often associated with significant neurological morbidity. Prolonged treatment with high-dose corticosteroids or surgical resection has been the standard care for RN, but protracted steroid use can lead to significant side effects and surgical resection is not always feasible. The antivascular endothelial growth factor monoclonal antibody bevacizumab induces clinical and radiographic improvements in RN, with overall good tolerance. However, evidence supporting its use for RN in melanoma brain metastases is minimal, likely secondary to concern for intracranial bleeding. Immunotherapy is now one of the most commonly used and effective therapies for metastatic melanoma. A higher risk of RN has been reported with immunotherapy, making alternative treatment for RN in this population a priority, especially as prolonged use of steroids may counteract the treatment efficacy of immunotherapy. We report on seven melanoma patients who developed RN after stereotactic radiosurgery with or without whole-brain radiation therapy who were treated with 2-6 doses of bevacizumab. All patients experienced improvements in symptoms and quality of life, with a concurrent improvement in imaging in six patients. Furthermore, bevacizumab was well tolerated and none of the seven patients experienced intracranial or extracranial bleeding. Our series suggests that in selected melanoma brain metastases patients, bevacizumab may be a safe and effective treatment for RN, especially for those who are undergoing immunotherapy, and should be further evaluated in a prospective setting. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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The safety of pembrolizumab in metastatic melanoma and rheumatoid arthritis.

Immunotherapy has been in use for the treatment of melanoma since a very long time, but only recently have the cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody ipilimumab and programmed cell death-1 inhibitors such as nivolimumab and pembrolizumab been shown to induce marked improvements in survival in patients with metastatic melanoma. An important concern arises in terms of the safety of the use of these agents in patients with autoimmune diseases, solid organ transplant recipients on immunosuppression, patients with a history of previous hepatitis B or C, and patients with HIV infections as these patients were excluded from pivotal immunotherapy studies. Here, we report on the safety and efficacy of pembrolizumab in a melanoma patient with multiple medical problems including poorly controlled rheumatoid arthritis and we review the available literature on the use of immunotherapy and autoimmune diseases. The weight of evidence suggests that these patients should be offered the opportunity to benefit from immune check point inhibitors, with drugs targeting programmed cell death-1 being preferred. More research is required to study the long-term effects of immunotherapy on patients with autoimmune diseases. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Radiotoxicity in robotic radiosurgery: proposing a new quality index for optimizing the treatment planning of brain metastases

As irradiated brain volume at 12 Gy (V12) is a predictor for radionecrosis, the purpose of the study was to develop a model for Cyberknife (CK) plans that is able to predict the lowest achievable V12 at a give...

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Patient safety is improved with an incident learning system—Clinical evidence in brachytherapy

Health leaders have advocated for incident learning systems (ILSs) to prevent errors, but there is limited evidence demonstrating that ILSs improve cancer patient safety. Herein, we report a long-term retrospective review of ILS reports for the brachytherapy practice at a large academic institution.

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A comparative study for the analgesic efficacy and safety profile of fentanyl versus clonidine as an adjuvant to epidural ropivacaine 0.75% in lower abdominal surgeries

Shuchi Nigam, Shivani Rastogi, Amit Tyagi, Rajlakshmi Bhandari

Anesthesia: Essays and Researches 2017 11(3):692-696

Context: Different adjuvants are coadministered with local anesthetics to improve the speed of onset and duration of analgesia, and to reduce the dose, the selection of which is often left to the choice of an anesthesiologist. Aim: The aim of this study was to compare the analgesic efficacy and safety profile of fentanyl and clonidine as an adjuvant to epidural ropivacaine anesthesia. Setting and Design: With institutional ethical committee clearance, a prospective, randomized, placebo-controlled double-blind clinical study was conducted at Vivekananda Polyclinic and Institute of Medical Sciences, Lucknow. Material and Methods: Two groups with thirty patients each were randomly allocated to receive 15–20 ml of 0.75% ropivacaine with 75 μg clonidine or 15–20 ml of 0.75% ropivacaine with 75 μg fentanyl, respectively. Block characteristics such as onset of analgesia, maximum level of sensory blockade, complete motor blockade, hemodynamic, time to two-segment regressions, time for rescue analgesia, time to complete motor recovery, and side effects were analyzed. Results: Results showed that the onset of blockade is faster when fentanyl is used as additives. Time for two-segment regression was earlier in fentanyl group but time for rescue analgesia was longer in clonidine group. Statistical Analysis: Two groups were compared by Student's t-test and Chi-square test; ANOVA and significance of mean difference bet were done by Newman–Keuls test. Conclusion: Addition of clonidine to epidural ropivacaine provides superior analgesia than the addition of fentanyl to epidural ropivacaine without much difference in side effect profile.

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Laparoscopic cholecystectomy under segmental thoracic spinal anesthesia: A feasible economical alternative

Aditya Kumar Kejriwal, Shaheen Begum, Gopal Krishan, Richa Agrawal

Anesthesia: Essays and Researches 2017 11(3):781-783

Laparoscopic surgery is normally performed under general anesthesia, but regional techniques like thoracic epidural and lumbar spinal have been emerging and found beneficial.We performed a clinical case study of segmental thoracic spinal anaesthesia in a healthy patient.We selected an ASA grade I patient undergoing elective laparoscopic cholecystectomy and gave spinal anesthetic in T10-11 interspace using 1 ml of bupivacaine 5 mg ml−1 mixed with 0.5 ml of fentanyl 50 μg ml−1. Other drugs were only given (systemically) to manage patient anxiety, pain, nausea, hypotension,or pruritus during or after surgery. The patient was reviewed 2 days postoperatively in ward.The thoracic spinal anesthetia was performed easily in the patient.Some discomfort which was readily treated with 1mg midazolam and 20 mg ketamine intravenously.There was no neurological deficit and hemodynamic parameters were in normal range intra and post-operatively and recovery was uneventful. We used a narrow gauze (26G) spinal needle which minimized the trauma to the patient and the chances of PDPH, which was more if 16 or 18G epidural needle had been used and could have increased further if there have been accidental dura puncture. Also using spinal anesthesia was economical although it should be done cautiously as we are giving spinal anesthesia above the level of termination of spinal cord.

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Role of anesthesiologist in the management of a child with cerebral palsy

Safiya Imtiaz Shaikh, Ganapati Hegade

Anesthesia: Essays and Researches 2017 11(3):544-549

Cerebral palsy (CP) refers to a spectrum of nonprogressive neurological disorders with disturbances in posture and movement, resulting from perinatal intrauterine insult to developing infant brain. Many conditions associated with CP require surgery. Such cases pose important gastrointestinal, respiratory, and other perioperative considerations. Anesthetic management in these cases is delicate. Intraoperative complications including hypovolemia, hypothermia, muscle spasms, seizures, and delayed recovery might complicate the anesthetic management. A thorough preanesthetic evaluation allows for a better intra- and post-operative care. Postoperative analgesia is important, particularly in orthopedic surgeries one for pain relief. This review highlights the clinical manifestations in CP and anesthetic considerations in such child presenting for various surgeries.

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A comparative study of intravenous esmolol, labetalol and lignocaine in low doses for attenuation of sympathomimetic responses to laryngoscopy and endotracheal intubation

Ekta Ratnani, Om Prakash Sanjeev, Abhishek Singh, Manoj Tripathi, Hemant Kumar Chourasia

Anesthesia: Essays and Researches 2017 11(3):745-750

Background: Direct layngoscopy and endotracheal intubation is a noxious stimuli and induces sympathomimetic responses. Although well tolerated in healthy subjects, it may impose life threatening arrhythmias, left ventricular failure or rupture of cerebral aneurysm in susceptible patients. Esmolol, Labetalol and Lignocaine attenuate these responses but are associated with side effects of bradycardia, hypotension etc. In lower doses, chances of these side effects are comparatively low. So we designed this prospective clinical trial to assess the efficacy of intravenous esmolol, labetalol and lignocaine in low doses for attenuation of sympathomimetic responses to endotracheal intubation. Materials and Methods: Seventy-five consenting patients of ASA physical status I or II of age range 20 to 60 years, scheduled for different general surgical procedures were randomly assigned to one of the three groups; group ES, group LB and group LG. Participants of group ES, group LB and group LG was given esmolol HCL 0.5 mg/Kg, labetalol HCL 0.25 mg/kg and lignocaine HCL 1 mg/Kg body weight respectively. Outcome variables were HR, SBP, DBP, MAP and RPP. These variables were recorded just after intubation and thereafter at 1,3,5, 7 and 10 minutes of intubation. Results: There was no statistically significant difference regarding the demographic characteristics of the groups. Heart rate and systolic blood pressure was lower throughout the study period in labetalol group. But the values of study parameters were always higher than the baseline in esmolol and lignocaine group. Values of mean arterial pressure was slightly higher in labetalol group but it was much higher in two other groups throughout the study period. Diastolic blood pressure was higher in all the groups. Values of rate pressure product was higher during intubation and at 1minute after intubation in labetalol group but thereafter it was always lower than baseline values. Conclusion: Labetalol 0.25 mg Kg-1 is an effective and safe drug to be used for attenuation of sympathomimetic responses to endotracheal intubation. Esmolol 0.5 mg Kg-1 and lignocaine 1 mg Kg-1 are also effective to some extent and are safe.

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Nasogastric tube insertion in anesthetized intubated patients undergoing laparoscopic hysterectomies: A comparative study of three techniques

B S. Vijay Siddhartha, N G. Anish Sharma, Shashank Kamble, P Shankaranarayana

Anesthesia: Essays and Researches 2017 11(3):550-553

Background: Insertion of a nasogastric tube (NGT) in an anesthetized, comatose intubated patient is not always as easy as in a conscious, cooperative patient. Various techniques have been tried with varying success. The aim of this randomized study was to compare and evaluate the two techniques of NGT insertion with the conventional technique of insertion with respect to success rate, time taken for insertion and adverse effects. Materials and Methods: Patients admitted for laparoscopic hysterectomy were chosen and then were divided into three equal groups of forty each, by randomized technique. Group C included patients in whom conventional method was used to insert NGT. Group R where reverse Sellick's technique was used. Group F where neck flexion with lateral pressure was used. Results: Both the techniques were better than the conventional method. Among both the techniques, reverse Sellick's technique was the best method but not without adverse effects. The required insertion time was very less and success in the first attempt was more in the group where reverse Sellick's was used. Conclusion: Modified techniques of NGT insertion were better than the conventional method. Further studies after eliminating major limitations are required to really find a superior technique.

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Hyperparathyroid crisis: It's not all about calcium!

Abinash Patro, Rameez Riaz, Vansh Priya, Aruna Bharti

Anesthesia: Essays and Researches 2017 11(3):804-806



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Influence of addition of dexmedetomidine or fentanyl to bupivacaine lumber spinal subarachnoid anesthesia for inguinal hernioplasty

Ayman Eskander T Saadalla, Osama Yehia A Khalifa

Anesthesia: Essays and Researches 2017 11(3):554-557

Background: No drug, used as adjuvant to spinal bupivacaine, has yet been identified that specifically inhibits nociception without its associated side effects. Aim of the Work: The purpose of this study is to compare the efficacy of dexmedetomidine and fentanyl with spinal bupivacaine in inguinal hernioplasty. Patients and Methods: Sixty patients of inguinal hernioplasty were randomly allocated to one of three groups, Group C (n = 20) – the patients received 15 mg hyperbaric bupivacaine + 0.5 ml saline. Group D – (n = 20) the patients received 15 mg hyperbaric bupivacaine + 10 μg dexmedetomidine diluted with 0.5 ml saline. Group F (n = 20) – the patients received 15 mg hyperbaric bupivacaine + 25 μg fentanyl (0.5 ml). Onset, duration of anesthesia, degree of sedation, and side effects were recorded. Results: The onset of anesthesia was shorter in Groups D and F as compared with the control Group C, but it was shorter in Group D than in Group F. The duration of sensory and motor block was prolonged in Group D and F as compared with the control Group C, but it was longer in Group D than in Group F. The postoperative analgesic consumption in the first 24 h was lower in Groups D and F than in Group C, and it was lower in Group D than in Group F. Conclusion: Onset of anesthesia is more rapid and duration is longer with less need for postoperative analgesia in patients undergoing inguinal hernioplasty under spinal anesthesia with dexmedetomidine and fentanyl than those with spinal alone with tendency of dexmedetomidine to produce faster onset, longer duration, and less analgesic need than fentanyl with similar safety profile.

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A prospective, observational study to evaluate the role of gabapentin as preventive analgesic in thyroidectomy under general anesthesia

Vadakkoot Raghavan Hema, Konnanath Thekkethil Ramadas, Kannammadathy Poulose Biji, Suseela Indu, Aravind Arun

Anesthesia: Essays and Researches 2017 11(3):718-723

Background: Effective management of postoperative pain is a part of well-organized perioperative care, which helps in reduced morbidity and improved patient satisfaction. Preventive analgesia can reduce acute and chronic pain by blocking the noxious inputs to pain pathways, preventing sensitization. Studies have reported efficacy of gabapentin as a preventive analgesic in perioperative pain. In this study, we aimed to determine whether preoperative gabapentin reduced postoperative pain and tramadol consumption after thyroidectomy under general anesthesia. Materials and Methods: Sixty patients scheduled for thyroidectomy were allocated to two groups of thirty each for this prospective, observational study. Patients in Group A and Group B received oral gabapentin 600 mg (6 × 10−4 kg) and diazepam 10 mg (1 × 10−5 kg), respectively, 2 h prior to surgery. Tramadol was given as rescue analgesic for postoperative pain with a verbal rating score of two. The analgesic efficacy of preoperative gabapentin was assessed in terms of postoperative pain scores at rest or swallowing, time to first rescue analgesic, and total tramadol consumption for 24 h. Ramsay sedation score and side effects of drug were also looked into. Results: Postoperative pain scores and total tramadol consumption were significantly lower in Group A during 24 h (P = 0.00). Time to first rescue analgesic was significantly prolonged in Group A (P = 0.001). Side effects were comparable. Conclusion: Oral gabapentin is effective as a preventive analgesic in reducing postoperative pain and tramadol consumption after thyroidectomy under general anesthesia.

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Comparative study of oral gabapentin, pregabalin, and clonidine as premedication for anxiolysis, sedation, and attenuation of pressor response to endotracheal intubation

Chandrakant Waikar, Jaideep Singh, Deepesh Gupta, Aditya Agrawal

Anesthesia: Essays and Researches 2017 11(3):558-560

Introduction: The aim of the present study was to evaluate and compare the effect of clonidine 200 μg and gabapentin 900 mg and pregabalin 150 mg in attenuation of the hemodynamic response to laryngoscopy and intubation in normotensive patients undergoing elective surgery. Methods: Ninety adult patients between 18 and 60 years are enrolled in the study. Patients with American Society of Anesthesiologists Grade-I and Grade-II are included which are posted for elective surgery under general anesthesia. Patients were divided into three groups: A, B, and C and received oral drugs 90 min before induction of general anesthesia, pregabalin 150, gabapentin 900mg, and clonidine 200 μg, respectively. Hemodynamic parameters such as heart rate and blood pressure were noted just before the (basal) administration of the drug, and in operation room, readings were recorded before intubation (T0) and after intubation at 1, 3, 5, and 10 min. Sedation and anxiety score were noted after 1 h of oral administration of the drug. Results: Mean arterial pressure was well attenuated by pregabalin than others, and mean heart rate following laryngoscopy and intubation was attenuated by clonidine group significantly. Conclusion: We conclude that oral pregabalin and gabapentin attenuate blood pressure response fairly well and heart rate significantly attenuated by clonidine. All three drugs are very effective for relieving anxiety and improving sedation.

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Postoperative analgesic efficacy of bilateral transversus abdominis plane block in patients undergoing midline colorectal surgeries using ropivacaine: A randomized, double-blind, placebo-controlled trial

Nahida Qazi, Wasim Mohammad Bhat, Malik Zaffar Iqbal, Anisur Rehman Wani, Showkat A Gurcoo, Sahir Rasool

Anesthesia: Essays and Researches 2017 11(3):767-772

Background: Ultrasound-guided transversus abdominis plane (TAP) block is done as a part of multimodal analgesia for pain relief after abdominal surgeries. This prospective randomized, double-blind, placebo-controlled trial was conducted to evaluate the postoperative analgesic efficacy of bilateral TAP block in patients undergoing midline colorectal surgeries using ropivacaine. Materials and Methods: Eighty patients scheduled for elective colorectal surgeries involving midline abdominal wall incision under general anesthesia were enrolled in this prospective randomized controlled trial. Group A received TAP block with 20 ml of 0.2% ropivacaine on either side of the abdominal wall, and Group B received 20 ml of normal saline. The time to request for rescue analgesia, total analgesic consumption in 24 h, and satisfaction with the anesthetic technique were assessed. Results: The mean visual analog scale scores at rest and on coughing were higher in control group (P > 0.05). Time (min) to request for the first rescue analgesia was prolonged in study group compared to control group (P < 0.001). The total tramadol consumption in 24 h postoperatively was significantly high in control group (P < 0.001). Nausea/vomiting was more common in control group (P > 0.05). The level of satisfaction concerning postoperative pain control/anesthetic technique was higher in study group (P < 0.001). Conclusion: TAP block produces effective and prolonged postoperative analgesia in patients undergoing midline colorectal surgery. It is a technically simple block to perform with a high margin of safety. It produces a considerable reduction in mean intravenous postoperative tramadol requirements, reduction in postoperative pain scores, and increased time to first request for further analgesia, both at rest and on movement.

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A prospective comparative observational study of clinical efficacy of isobaric ropivacaine 0.75% with of isobaric bupivacaine 0.5% intrathecally in elective inguinal hernia repair surgeries

Shivam Bipin Parekh, Suchita Shailesh Parikh, Harsha Patel, Malini Mehta

Anesthesia: Essays and Researches 2017 11(3):561-566

Aims: To evaluate the efficacy of intrathecal isobaric Ropivacaine and its comparison with intrathecal isobaric Bupivacaine in elective inguinal hernia repair surgeries. Settings and Design: A prospective, randomized study was conducted in a tertiary care hospital with 80 patients of ASA grade I-III undergoing elective inguinal hernia repair surgery under spinal anaesthesia .Ethical committee clearance and written consent taken. The patients were randomly divided into two equal groups to the Ropivicaine group (Group R) and to theBupivicaine group (Group B). Parameters observed were onset and duration of sensory and motor block, maximum sensory level achieved degree of motor blockade, two segment regression, and haemodynamic changes. Results: The development of sensory block was faster with Isobaric Ropivicaine (12.1 ± 4.9 minutes) as than isobaric Bupivicaine (13.94 ± 4.52 minutes) but the difference was not statistically significant. Onset of Grade III Motor block was longer with Isobaric Ropivicaine (8.51 ± 3.39 minutes) as compared to isobaric Bupivicaine ( 8.51 ± 3.39 minutes), but the difference was not statistically significant. Time of Complete Sensory Regression was significantly shorter with Isobaric Ropivicaine (212.69 ± 27.31 minutes) with statistical significance. Time to complete motor recovery was significantly shorter in Ropivacaine group (253.38 ± 27.13 minutes)as compared to Bupivacaine group (258.55 ± 35.81min), with statistical significance.Time to achieve discharge criteria was relatively shorter with Isobaric Ropivicaine. Haemodynamic Parameters did not differ significantly in both the groups during the entire study period. Conclusion: Intrathecal administration of isobaric Ropivacaine (0.75%) 15 mg provides similar quality of spinal anaesthesia but of significantly shorter duration, maintaining similar hemodynamic stability and discharge criteria without significant adverse effects when compared to isobaric Bupivicaine (0.5%) 10 mg.

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A complication after percutaneous nephrolithotomy: Anesthesia mumps

Ezgi Erkiliç, Elvin Kesimci, Aysun Yüngül, Ferit Alaybeyoğlu, Mustafa Aksoy

Anesthesia: Essays and Researches 2017 11(3):794-796

Some surgical procedures performed under moderate and sometimes extreme positions expose patients to nonphysiological changes. Especially, the manipulations of a patient in prone and lateral decubitus position might increase complications. Anesthesia mumps has been reported as one of these complications. It has been found to be rare but known entity associated with patients of all age groups and all surgical positions. We herein describe an early noticed acute case of unilateral anesthesia mumps that developed after endotracheal intubation in prone position in a 54-year-old female. Anesthesia mumps may occur in the immediate postoperative period with no suspicious predisposing factor. The reports of such cases would increase the awareness among anesthesiologists and postoperative caregivers regarding this benign complication.

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Efficacy of tramadol or dexamethasone as an adjuvant to levobupivacaine in ultrasound-guided supraclavicular plexus block for upper limb surgery: A randomized double-blinded controlled study

S Aravind Raj, Dewan Roshan Singh, S Antony John Charles, N Krishnaveni

Anesthesia: Essays and Researches 2017 11(3):567-571

Aims and Objectives: To evaluate the efficacy of tramadol or dexamethasone as an adjuvant to levobupivacaine in ultrasound-guided supraclavicular brachial plexus block in terms of onset time of complete sensory and motor blockade, duration of motor blockade, duration of analgesia, and any complication. Settings and Design: This was a randomized controlled trial conducted in the Department of Anesthesiology, a tertiary care hospital. Materials and Methods: Sixty consecutive patients of the American Society of Anesthesiologists physical status Class I and II who were posted for upper limb surgeries were recruited. Patients were divided into two groups of thirty patients each. Group T (tramadol) received 20 ml of 0.5% levobupivacaine with 100 mg tramadol, and Group D (dexamethasone) received 20 ml of 0.5% levobupivacaine with 8 mg dexamethasone under ultrasound guidance. Sensory and motor block assessment was done every 2 min until the development of complete sensory and motor block till 45 min. Verbal numerical rating scale score was assessed in postoperative ward at regular intervals. Patients were followed up to check for any residual neurological deficits. Results: There was no statistical difference in demographic data between the two groups. The onset time of sensory and motor blockade shows no significant difference between groups. The mean time duration of motor blockade in Group T was 764.63 min and for Group D was 1150.27 min which was statistically significant (P < 0.05). The duration of analgesia in Group D was 1300.83 min and in Group T was 820.47 min which was statistically significant (P < 0.05). Side effects such as nausea, vomiting, pruritis, hypoxemia, and long-term neurological deficits were not reported in any of the patients in either group. Conclusion: Dexamethasone 8 mg as an adjuvant to 0.5% levobupivacaine for supraclavicular brachial plexus block using ultrasound guidance increases the duration of analgesia in comparison to 100 mg tramadol and provides excellent postoperative pain-free period without any neurological deficits.

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Glucose for children during surgery: Pros, cons, and protocols: A postgraduate educational review

Priyankar Kumar Datta, Ajisha Aravindan

Anesthesia: Essays and Researches 2017 11(3):539-543

The question of whether glucose supplementation is required in children during surgery is still under debate. The impact of perioperative glucose supplementation, or its restriction, on their metabolism remains unclear. We discuss the findings of various studies that have addressed this question and the rationale for current recommendations.

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Evaluating the efficacy of tramadol as an adjuvant to intrathecal isobaric levobupivacaine for elective infraumbilical surgeries

Dewan Roshan Singh, Hajer Mohamed, N Krishnaveni, Kusha Nag

Anesthesia: Essays and Researches 2017 11(3):572-577

Background: Long-acting local anesthetics are used in subarachnoid block to increase the duration of anesthesia. Adjuvants are added to improve the duration of analgesia. Settings: Randomized controlled trial was conducted in the Department of Anesthesiology in a tertiary care hospital.Aims and Objectives: The objective of this study was to evaluate the efficacy of low-dose tramadol as an intrathecal adjuvant to levobupivacaine in terms of duration of analgesia, onset of sensory blockade, onset of motor blockade, and duration of motor blockade. Methodology: After obtaining the Institutional Ethics Committee approval and informed consent, sixty patients posted for infraumbilical surgeries were recruited. Randomization was done using a sealed envelope technique. Patients were divided into two groups: LT received 3 ml of 0.5% isobaric levobupivacaine with tramadol 10 mg (0.2 ml) and LS received 3 ml of 0.5% isobaric levobupivacaine with 0.2 ml of normal saline. Duration of analgesia, onset of sensory blockade, and onset and duration of motor blockade were recorded. Results: There was no statistical difference in demographic data between the two groups. The mean onset time of sensory blockade in Group LS was 12.7 ± 9.81 min and for Group LT was 12.9 ± 0.81 min, which was not statistically significant between two groups (P = 0.93). The mean onset time of motor blockade in Group LS was 13.4 ± 10 min and for Group LT was 14.4 ± 10 min, which was no statistically significant between the two groups (P = 0.71). The mean time duration of analgesia in Group LS was 170.3 ± 59 min and for LT was 198.9 ± 57.33 min. There was mild prolongation of analgesia in Group LT, but it was not statistically significant (P = 0.0615). The mean duration of motor blockade in Group LS was 170.23 ± 58 min and Group LT was 190.76 ± 4 min, which was not statistically significant between the two groups (P = 0.14). Conclusion: Low-dose tramadol as an adjuvant to isobaric intrathecal levobupivacaine does not prolong analgesia significantly.

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Referrral systems development and survey of perioperative and critical care referral to anesthetists

PL Narendra, Harihar V Hegde, Maroof Ahmad Khan, Dayanand G Talikoti, Samson Nallamilli

Anesthesia: Essays and Researches 2017 11(3):702-712

Introduction: Anesthetists come in contact with more than two-third of hospital patients. Timely referral to anesthetists is vital in perioperative and remote site settings. Delayed referrals, improper referrals, and referrals at inappropriate levels can result in inadequate preparation, perioperative complications, and poor outcome. Methods: The self administered paper survey to delegates attending anesthesia conferences. Questions were asked on how high-risk, emergency surgical cases remote site and critical care patients were referred to anesthetists and presence of rapid response teams. Results: The response rate was 43.8%. Sixty percent (55.3–64.8, P - 0.001) reported high-risk elective cases were referred after admission. Sixty-eight percent (63.42–72.45, P - 0.001) opined preoperative resting echocardiographs were useful. Six percent (4.16–8.98, P - 0.001) reported emergency room referral before arrival of the patient. Twenty-five percent (20.92–29.42, P - 0.001) indicated high-risk obstetric cases were referred immediately after admission. Consultants practiced preoperative stabilization more commonly than residents (32% vs. 22%) (P - 0.004). For emergency surgery, resident referrals occurred after surgery time was fixed (40% vs. 28%) (P - 0.012). Residents dealt with more cases without full investigations in obstetrics (28% vs. 15) (P = 0.002). Remote site patients were commonly referred to residents after sedation attempts (32% vs. 20%) (P = 0.036). Only 34.8 said hosptals where tbey practiced had dedicated cardiac arrest team in place. Conclusions: Anesthetic departments must periodically assess whether subgroups of patients are being referred in line with current guidelines. Cancellations, critical incidents and complications arising out of referral delays, and improper referrals must be recorded as referral incidents and a separate referral incident registry must be maintained in each department. Regular referral audits must be encouraged.

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A survey of current practice of supraglottic airway devices in pediatric anesthesia from India

Suvarna Kaniyil, PB Smithamol, Elizabeth Joseph, A Krishnadas, KT Ramadas

Anesthesia: Essays and Researches 2017 11(3):578-582

Background and Objectives: Supraglottic airway devices (SADs) have revolutionized the pediatric anesthetic practice and got a key role in difficult airway (DA) management. Several modifications of SADs design had come up to improve their safety. Aim: The aim of this survey was to determine the current usage of SADs in pediatric anesthetic practice, their availability, and to know any difficulties noted in practice. Methods: It was a questionnaire survey among the anesthesiologists who attended the National Pediatric Anesthesia Conference-2016. The questionnaire assessed the current practice preferences of SADs in routine pediatric cases and DA management, availability of various devices, and any difficulties noted in their usage. Results: First-generation SADs were widely available (97%), and 64% of respondents preferred to use it for pediatric short cases. 64% felt the use of SADs free their hands from holding the facemask and 58% found better airway maintenance with it. Intraoperative displacement (55%) was the common problem reported and only 11% felt aspiration as a problem. Most of the respondents (73%) accepted its use as rescue device in airway emergency, and 84% felt the need of further randomized controlled studies on safety of SADs in children. The majority were not confident to use SADs in neonates. Interpretation and Conclusions: The key role of SADs in DA management was well accepted, and aspiration was not a major problem with the use of SADs. Although many newer versions of SADs are available, classic laryngeal mask remains the preferred SAD for the current practitioner. Further, RCTs to ensure the safety of SADs in children are warranted.

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To evaluate the efficacy of fentanyl and dexmedetomidine as adjuvant to ropivacaine in brachial plexus block: A double-blind, prospective, randomized study

Nyla Farooq, Raj Bahadur Singh, Arindam Sarkar, Mohd Asim Rasheed, Sanjay Choubey

Anesthesia: Essays and Researches 2017 11(3):730-739

Context: Anesthesia and analgesia for surgeries to the upper extremity are commonly provided using brachial plexus anesthesia. There are limited or almost no studies comparing the use of ropivacaine with fentanyl to ropivacaine with dexmedetomidine. Aims: To compare the efficacy of fentanyl and dexmedetomidine as adjuvants to ropivacaine for brachial plexus block among patients undergoing upper limb orthopedic surgeries. Settings and Design: This was a prospective, randomized, double-blinded study. Subjects and Methods: The patients were randomly divided into three groups of 35 each using computerized randomization table. Group I patients received 3 mg/kg of 0.75% ropivacaine with 1 μg/kg of fentanyl diluted with normal saline (NS) to make a total volume of 35 ml. Group II patients received 3 mg/kg of 0.75% ropivacaine with 1 μg/kg of dexmedetomidine diluted with NS to make a total volume of 35 ml. Group III patients received 3 mg/kg of 0.75% ropivacaine with NS making a total volume of 35 ml. Statistical Analysis Used: Statistical analysis was performed using Statistical Package for Social Sciences, version 15.0. Analysis of variance followed by independent samples t-test was performed for parametric data, and Kruskal–Wallis test followed by Mann–Whitney U-test was performed for nonparametric data. Results: Mean motor and sensory block onset time was minimum in Group I and maximum in Group III while mean duration of sensory and motor block was maximum in Group I and minimum in Group III. Time taken for first rescue analgesic dose was also maximum in Group I and minimum in Group III. Conclusions: It can be concluded that 3 mg/kg of 0.75% ropivacaine along with 1 μg/kg of fentanyl diluted with NS to make a total volume of 35 ml was the most efficacious regimen for brachial plexus block among patients undergoing upper limb orthopedic surgeries.

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Comparative efficacy of minimal concentration of racemic bupivacaine (0.0625%) with fentanyl and ropivacaine (0.1%) with fentanyl for epidural labor analgesia

TN Chethanananda, MR Shashank, N Madhu, J Achyutha, Karna Venkata Siva Kumar

Anesthesia: Essays and Researches 2017 11(3):583-588

Background and Aims: This study aims to compare the minimum effective concentration of local anesthetic (LA) bupivacaine and ropivacaine with highly lipid soluble opioids fentanyl for providing optimal labor epidural analgesia. Settings and Design: The objective of this study was to evaluate the efficacy of racemic bupivacaine 0.0625% and 0.1% of ropivacaine both mixed with 2 μg/ml of fentanyl for epidural labor analgesia in parturients with spontaneous labor and normal fetal heart rate tracing. Methodology: Sixty parturients requesting for labor analgesia were divided into two groups. Group B (n = 30) received racemic bupivacaine (0.0625%) and fentanyl 2 μg/ml of 10 ml and Group R (n = 30) received ropivacaine (0.1%) and fentanyl 2 μg/ml. In both groups, the drug was given in 5 ml fractionated doses at 5 min interval. Parturients not experiencing analgesia within 15 min of initial bolus were supplemented with additional 5 ml of the same concentration of the solution. Epidural analgesia was maintained by timed top ups at the end of 90 min with the dosage equal to the initial dose of the drug. Duration of labor analgesia, motor block, visual analog scale, maternal hemodynamic parameters, mode of delivery, and maternal satisfaction was assessed. Statistical Analysis: Data were analyzed with odds variance, unpaired t-test, and Chi-square tests. P < 0.05 was considered statistically significant. Results: In our study, results indicate that both drugs were equally effective clinically. Maternal demographic characteristics were comparable. There were no statistically significant differences in visual analog pain score, highest sensory block, maternal satisfaction, mode of delivery, total dose of LAs during labor and motor block at delivery between the groups. Conclusions: In our study, both the drugs produced equivalent analgesia for labor at low concentration when used with highly lipid soluble opioid such as fentanyl.

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Single minute of positive end-expiratory pressure at the time of induction: Effect on arterial blood gases and hemodynamics in morbidly obese patients undergoing laparoscopic bariatric surgery

Dipti Saxena, Priyank Singh, Atul Dixit, Bipin Arya, Mohit Bhandari, Sadhana Sanwatsarkar

Anesthesia: Essays and Researches 2017 11(3):758-761

Background: The effect of positive end-expiratory pressure (PEEP) has been studied in detail after induction of general anesthesia especially in obese individuals. However, sparse information can be gathered from the literature regarding its effect when applied at the time of induction and the time of onset of its effect. Thus, this study was planned to assess the effect of PEEP when applied for a single minute in morbidly obese patients. Materials and Methods: This was a randomized prospective study comprising seven morbidly obese patients (body mass index ≥40 kg/m2). Control group included 30 patients who received no PEEP at the time of induction. The study group consisted of thirty patients who were given a PEEP of 10 cmH2O. Serial arterial blood gas samples were taken preoperatively, at the time of intubation, 5 min after intubation and 10 min after intubation. Results: PaO2was significantly higher in test group (242.0 ± 116.0 mmHg) than in control group (183.0 ± 107.0 mmHg) just after intubation. PaCO2was comparable in control group (43.73 ± 6.32 mmHg) and test group (44.52 ± 6.33 mmHg) just after intubation but was significantly less in test group than in control group at 5 and 10 min thereafter. Hemodynamic parameters were comparable in both groups at all time intervals. Conclusion: Application of even a single minute of PEEP at the time of induction improves oxygenation without any adverse effects on hemodynamics, in morbidly obese patients undergoing laparoscopic Bariatric surgery.

http://ift.tt/2weJAMI

Immunohistochemical prognostic markers of esophageal squamous cell carcinoma: a systematic review

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy, with a high incidence and poor prognosis. In the past several decades, hundreds of proteins have been reported to be associated with the p...

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Estimates of cancer incidence and mortality in China, 2013

Population-based cancer registration data are collected by the National Central Cancer Registry in China every year. Cancer incident cases and cancer deaths in 2013 were analyzed.

http://ift.tt/2iaD8QR

Ras–dependent Paracrine Cascades

Most pancreatic cancers are driven by mutant K-Ras genes, and comprise a minority of cancer cells in a densely fibrotic and highly secretory tumor microenvironment. Interrupting the paracrine cascades in pancreatic cancers may improve treatment.

http://ift.tt/2wecooF

FDA Approves Nivolumab for Some Metastatic Colorectal Cancers

FDA has granted accelerated approval to the immunotherapy drug nivolumab (Opdivo®) for patients with metastatic colorectal cancer whose tumors have alterations that affect DNA repair.

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Management of contralateral breast following mastectomy and breast reconstruction using a mirror adjustment with crescent mastopexy technique

Abstract

Introduction

Heterologous breast reconstruction after mastectomy sometimes requires the management of the contralateral breast to achieve symmetric long lasting aesthetic results. Some techniques could be used for the symmetrization of contralateral breast with or without implants as breast augmentation, reduction mammoplasty, mastopexy, with T inverted, J, vertical, periareolar, semi-circular, or axillary scars. The aim of this study is to present the use of crescent mastopexy technique with implants in contralateral adjustment following monolateral breast reconstruction compared with a control group in which patients underwent other contralateral procedures. We used BREAST-Q to evaluate breast perception and patient's satisfaction and surgeon-rated aesthetic outcomes were measured using the Kroll evaluation (a global and itemized aesthetic tool).

Materials and methods

A retrospective study was designed. We enrolled in the study 55 patients who had undergone breast reconstruction with implants and contralateral breast symmetrization procedure at our hospital between 2010 and 2016, and they answered to BREAST-Q postoperative module after almost 1 year from breast reconstruction. The study population consisted of 2 groups of women: patient underwent contralateral adjustment with crescent mastopexy and augmentation and patients underwent other contralateral procedures. Statistical analysis was performed using descriptive and summary statistics to identify a central tendency between the two groups, we applied Fisher's exact test to the results to obtain answers 1 year after the last procedure for the two groups.

Results

This cross-sectional study compared two cohorts in which 55 women underwent monolateral mastectomy and breast reconstruction with contralateral adjustment, 15 of these underwent contralateral crescent mastopexy with augmentation, and 40 (control group) underwent contralateral breast adjustment with other mastopexy and augmentation technique (27 patients underwent T inverted mastopexy, 2 J mastopexy, 6 vertical scar mastopexy, 5 periareolar mastopexy). Nineteen patients suffered of co-morbidities (smoking, autoimmune disease, cardiological, neurological, and dismetabolic). All patients answered the postoperative BREAST-Q reconstruction module almost 1 year from last surgical procedure.

Conclusions

In patients with a pseudoptosis or mild ptosis of the contralateral breast, crescent mastopexy could be a valid procedure with minimal scars, better symmetry, and global cosmetic results than other procedures. This is the first study which compares crescent mastopexy with augmentation with other mastopexy procedures. Level III: evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group.

Level (III)

Evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group.

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Clinical features and long-term outcomes of primary spinal malignant melanoma: a single center experience

Abstract

Primary malignant melanomas are very rare tumors in the spinal canal. In this study, the authors review their experience in a series of seven patients with histologically proven primary spinal malignant melanoma (PSMM) and discuss the clinical features, treatment strategy, and long-term outcomes. Clinical data of seven patients with PSMM treated at a single institution were retrospectively analyzed. There were three male and four female patients, with a mean age of 44 years. The mean duration of illness was 5.4 months. The tumors showed hyperintensity in six cases on T1-weighted image (WI) and isointensity or hypointensity in five cases on T2WI. Gross total resection (GTR) of the tumor was achieved in two cases, and subtotal resection (STR) was achieved in five cases. Four STR patients underwent postoperative local radiation therapy. Postoperative MRI results showed no tumor recurrence in all four female patients after an average follow-up period of 64.5 months. Three male patients had tumor recurrence and dissemination after postoperative 14.7 months (8–24 months), and all died 16.3 months (10–25 months) after initial diagnosis. PSMM should be considered in the differential diagnosis of a middle-aged patient with spinal lesion if the tumor shows hyperintensity on T1WI and hypointensity or isointensity on T2WI on MRI. STR followed by radiotherapy is not excessively associated with deterioration of the final outcome compared to GTR. Our study suggests that PSMM might have female predominance in favorable outcome. Surgical resection followed by adjuvant radiotherapy and regular follow-up are recommended.

http://ift.tt/2wdRZjL

Upregulation of vascular endothelial growth factor (VEGF), its role in progression and prognosis of non-small cell lung carcinoma

Publication date: October 2017
Source:Cancer Genetics, Volumes 216–217
Author(s): Niyaz A. Naikoo, Roohi Rasool, Sonaullah Shah, A.G. Ahangar, Mushtaq A. Siddiqi, Zafar A. Shah
Elevated VEGF mRNA (−ΔCT) was significantly associated with adenocarcinoma histology (vs squamous) and advanced NSCLC clinical stages in a univariable analysis; however, this association did not remain significant in the multivariable analysis. Of interest, a Kaplan–Meier analysis showed that NSCLC patients with higher VEGF mRNA (−ΔCT ≥10) had a significantly poorer overall survival and shorter postoperative relapse time in adenocarcinoma and in stage III/IV than those with VEGF mRNA of −ΔCT <10 (P < 0.001). The multivariable analysis confirmed that patients with higher VEGF mRNA levels, as well as with adenocarcinoma and advanced stages, were independent predictors of a poorer survival. However, only the histology of adenocarcinoma remained a significant prognostic factor of a shorter postoperative relapse in the multivariable model. Quantity of VEGF mRNA can be used as a prognosis factor to predict shorter overall survival in patients with NSCLC.



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Acute myeloid leukemia with t(14;21) involving RUNX1 and SYNE2: A novel favorable-risk translocation?

Publication date: October 2017
Source:Cancer Genetics, Volumes 216–217
Author(s): Nicole Foley, Jessica Van Ziffle, Jingwei Yu, Zhongxia Qi, James P. Grenert, Iwei Yeh, Boris Bastian, Scott Kogan, Gabriel N. Mannis
In acute myeloid leukemia (AML), a translocation between chromosomes 8q22 and 21q22 leads to the RUNX1-RUNXT1 fusion gene which, in the absence of a concomitant KIT mutation, generally portends a more favorable prognosis. Translocations at 21q22, other than those involving 8q22, are uncommon, and the specific prognostic and therapeutic implications are accordingly limited by the small number of reported cases. In this report, we describe the case of a 67-year-old gentleman who presented with AML harboring t(14;21)(q23;q22). Subsequent molecular analysis revealed mutations in RUNX1, ASXL1, and SF3B1, with translocation breakpoints identified within SYNE2 on chromosome 14 and RUNX1 on chromosome 21. The functional consequence of the DNA fusion between SYNE2 and RUNX1 is unclear. Nonetheless, despite several adverse risk factors associated with this patient's AML, he achieved a long-lasting remission with standard chemotherapy alone, potentially suggestive of a novel favorable-risk translocation in AML involving 21q22.



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Genetic gastric cancer susceptibility in the international clinical cancer genomics cancer research network

Publication date: Available online 17 August 2017
Source:Cancer Genetics
Author(s): Thomas Slavin, Susan L. Neuhausen, Christina Rybak, Ilana Solomon, Bita Nehoray, Kathleen Blazer, Mariana Niell-Swiller, Aaron W. Adamson, Yate-Ching Yuan, Kai Yang, Sharon Sand, Danielle Castillo, Josef Herzog, Xiwei Wu, Shu Tao, Tanya Chavez, Yanghee Woo, Joseph Chao, Pamela Mora, Darling Horcasitas, Jeffrey Weitzel
Few susceptibility genes for gastric cancer have been identified. We sought to identify germline susceptibility genes from participants with gastric cancer from an international hereditary cancer research network. Adults with gastric cancer of any histology, and with a germline DNA sample (n= 51), were retrospectively selected. For those without previously identified germline mutations (n= 43), sequencing was performed for 706 candidate genes. Twenty pathogenic or likely pathogenic variants were identified among 18 participants. Eight of the 18 participants had previous positive clinical testing, including six with CDH1 pathogenic or likely pathogenic variants, and two with pathogenic MSH2 and TP53 variants. Of the remaining 10, six were in BRCA1 DNA damage response pathway genes (ATM, ATR, BRCA2, BRIP1, FANCC, TP53), other variants were identified in CTNNA1, FLCN, SBDS, and GNAS. Participants identified with pathogenic or likely pathogenic variants were younger at gastric cancer diagnosis than those without, 39.1 versus 48.0 years, and over 50% had a close family member with gastric cancer (p-values <0.0001). In conclusion, many participants were identified with mutations in clinically-actionable genes. Age of onset and family history of gastric cancer were mutation status predictors. Our findings support multigene panels in identifying gastric cancer predisposition.



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Prognostic classification of MDS is improved by the inclusion of FISH panel testing with conventional cytogenetics.

Publication date: Available online 16 August 2017
Source:Cancer Genetics
Author(s): Prajakta Kokate, Rupa Dalvi, Neeraja Koppaka, Swarna Mandava
Cytogenetics is a critical independent prognostic factor in myelodysplastic syndromes (MDS). Conventional cytogenetics (CC) and Fluorescence in situ hybridization (FISH) Panel Testing are extensively used for the prognostic stratification of MDS, although the FISH test is not yet a bona fide component of the International Prognostic Scoring System (IPSS). The present study compares the utility of CC and FISH to detect chromosomal anomalies and in prognostic categorization. GTG-Banding and FISH Panel Testing specifically for -5/-5q, -7/-7q, +8 and -20q was performed on whole blood or bone marrow samples from 136 patients with MDS. Chromosomal anomalies were found in 40 cases by CC, including three novel translocations. FISH identified at least one anomaly in 54/136 (39.7%) cases. More than one anomaly was found in 18/54 (33.3%) cases, therefore, overall FISH identified 75 anomalies of which 32 (42.6%) were undetected by CC. FISH provided additional information in cases with CC failure and in cases with a normal karyotype. Further, in ten cases with an abnormal karyotype, FISH could identify additional anomalies, increasing the number of abnormalities per patient. Although CC is the gold standard in the cytogenetic profiling of MDS, FISH has proven to be an asset in identifying additional abnormalities. The number of anomalies per patient can predict the prognosis in MDS and hence, FISH contributed towards prognostic re-categorization. The FISH Panel testing should be used as an adjunct to CC, irrespective of the adequacy of the number of metaphases in CC, as it improves the prognostic classification of MDS.



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Addition of chromosomal microarray and next generation sequencing to FISH and classical cytogenetics enhances genomic profiling of myeloid malignancies

Publication date: Available online 14 August 2017
Source:Cancer Genetics
Author(s): S Mukherjee, M Sathanoori, Z Ma, M Andreatta, PA Lennon, SR Wheeler, JL Prescott, C Coldren, T Casey, H Rietz, K Fasig, R Woodford, T Hartley, D Spence, W Donnelan, J Berdeja, I Flinn, N Kozyr, M Bouzyk, M Correll, H Ho, V Kravtsov, D Tunnel, P Chandra
Comprehensive genetic profiling is increasingly important for the clinical workup of hematologic tumors, as specific alterations are now linked to diagnostic characterization, prognostic stratification and therapy selection. To maximally characterize relevant genetic and genomic alterations in myeloid malignancies, we utilized a comprehensive strategy spanning fluorescence in situ hybridization (FISH), classical karyotyping, Chromosomal Microarray (CMA) for detection of copy number variants (CNVs) and Next generation Sequencing (NGS) analysis. In our cohort of 569 patients spanning the myeloid spectrum, NGS and CMA testing frequently identified mutations and copy number changes in the majority of genes with important clinical associations, such as TP53, TET2, RUNX1, SRSF2, APC and ATM. Most importantly, NGS and CMA uncovered medically actionable aberrations in 75.6% of cases normal by FISH/cytogenetics testing. NGS identified mutations in 65.5% of samples normal by CMA, cytogenetics and FISH, whereas CNVs were detected in 10.1% cases that were normal by all other methodologies. Finally, FISH or cytogenetics, or both, were abnormal in 14.1% of cases where NGS or CMA failed to detect any changes. Multiple mutations and CNVs were found to coexist, with potential implications for patient stratification. Thus, high throughput genomic tumor profiling through targeted DNA sequencing and CNV analysis complements conventional methods and leads to more frequent detection of actionable alterations.



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New Views into the Genetic Landscape of Metastatic Breast Cancer

Publication date: 14 August 2017
Source:Cancer Cell, Volume 32, Issue 2
Author(s): Xiaoyu Zhao, Scott Powers
Whether metastasis-specific genetic alterations exist remains controversial. The study by Yates et al. in this issue of Cancer Cell provides evidence that metastases emerge late during primary breast cancer progression and that additional driver mutations are often acquired, posing both challenges and opportunities for precision treatment of metastatic breast cancer.

Teaser

Whether metastasis-specific genetic alterations exist remains controversial. The study by Yates et al. in this issue of Cancer Cell provides evidence that metastases emerge late during primary breast cancer progression and that additional driver mutations are often acquired, posing both challenges and opportunities for precision treatment of metastatic breast cancer.


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A Viro-Immunotherapy Triple Play for the Treatment of Glioblastoma

Publication date: 14 August 2017
Source:Cancer Cell, Volume 32, Issue 2
Author(s): John C. Bell, Carolina S. Ilkow
In this issue of Cancer Cell, Saha et al. systematically test and optimize combination therapy strategies in a challenging model of glioblastoma. Durable complete responses were seen only when an oncolytic virus expressing IL12 was coupled with anti-CTLA-4 and anti-PD-1 therapeutics.

Teaser

In this issue of Cancer Cell, Saha et al. systematically test and optimize combination therapy strategies in a challenging model of glioblastoma. Durable complete responses were seen only when an oncolytic virus expressing IL12 was coupled with anti-CTLA-4 and anti-PD-1 therapeutics.


http://ift.tt/2wjSiZA

Control of Metastasis by NK Cells

Publication date: 14 August 2017
Source:Cancer Cell, Volume 32, Issue 2
Author(s): Alejandro López-Soto, Segundo Gonzalez, Mark J. Smyth, Lorenzo Galluzzi
The metastatic spread of malignant cells to distant anatomical locations is a prominent cause of cancer-related death. Metastasis is governed by cancer-cell-intrinsic mechanisms that enable neoplastic cells to invade the local microenvironment, reach the circulation, and colonize distant sites, including the so-called epithelial-to-mesenchymal transition. Moreover, metastasis is regulated by microenvironmental and systemic processes, such as immunosurveillance. Here, we outline the cancer-cell-intrinsic and -extrinsic factors that regulate metastasis, discuss the key role of natural killer (NK) cells in the control of metastatic dissemination, and present potential therapeutic approaches to prevent or target metastatic disease by harnessing NK cells.

Teaser

The metastatic spread of malignant cells to distant anatomical locations is a prominent cause of cancer-related death. Metastasis is governed by cancer-cell-intrinsic mechanisms that enable neoplastic cells to invade the local microenvironment, reach the circulation, and colonize distant sites, including the so-called epithelial-to-mesenchymal transition. Moreover, metastasis is regulated by microenvironmental and systemic processes, such as immunosurveillance. Here, we outline the cancer-cell-intrinsic and -extrinsic factors that regulate metastasis, discuss the key role of natural killer (NK) cells in the control of metastatic dissemination, and present potential therapeutic approaches to prevent or target metastatic disease by harnessing NK cells.


http://ift.tt/2uTVmYR

Genomic Evolution of Breast Cancer Metastasis and Relapse

Publication date: 14 August 2017
Source:Cancer Cell, Volume 32, Issue 2
Author(s): Lucy R. Yates, Stian Knappskog, David Wedge, James H.R. Farmery, Santiago Gonzalez, Inigo Martincorena, Ludmil B. Alexandrov, Peter Van Loo, Hans Kristian Haugland, Peer Kaare Lilleng, Gunes Gundem, Moritz Gerstung, Elli Pappaemmanuil, Patrycja Gazinska, Shriram G. Bhosle, David Jones, Keiran Raine, Laura Mudie, Calli Latimer, Elinor Sawyer, Christine Desmedt, Christos Sotiriou, Michael R. Stratton, Anieta M. Sieuwerts, Andy G. Lynch, John W. Martens, Andrea L. Richardson, Andrew Tutt, Per Eystein Lønning, Peter J. Campbell
Patterns of genomic evolution between primary and metastatic breast cancer have not been studied in large numbers, despite patients with metastatic breast cancer having dismal survival. We sequenced whole genomes or a panel of 365 genes on 299 samples from 170 patients with locally relapsed or metastatic breast cancer. Several lines of analysis indicate that clones seeding metastasis or relapse disseminate late from primary tumors, but continue to acquire mutations, mostly accessing the same mutational processes active in the primary tumor. Most distant metastases acquired driver mutations not seen in the primary tumor, drawing from a wider repertoire of cancer genes than early drivers. These include a number of clinically actionable alterations and mutations inactivating SWI-SNF and JAK2-STAT3 pathways.

Graphical abstract

Teaser

By sequencing primary, locally relapsed, and metastatic breast cancers, Yates et al. show that clones seeding metastasis or relapse disseminate late from primary tumors but continue to acquire mutations, including clinically actionable alterations and mutations inactivating the SWI/SNF and JAK2-STAT3 pathways.


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Cliques and Schisms of Cancer Genes

Publication date: 14 August 2017
Source:Cancer Cell, Volume 32, Issue 2
Author(s): Peter J. Campbell
With a few exceptions, cancers typically carry more than one driver mutation, sometimes five, ten, or more, and these driver mutations do not necessarily assort randomly. In this issue of Cancer Cell, Mina et al. systematically characterize patterns of co-mutation and mutual exclusivity in 6,456 cancers across 23 tumor types.

Teaser

With a few exceptions, cancers typically carry more than one driver mutation, sometimes five, ten, or more, and these driver mutations do not necessarily assort randomly. In this issue of Cancer Cell, Mina et al. systematically characterize patterns of co-mutation and mutual exclusivity in 6,456 cancers across 23 tumor types.


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Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma

Publication date: 14 August 2017
Source:Cancer Cell, Volume 32, Issue 2
Author(s): The Cancer Genome Atlas Research NetworkBenjamin J.RaphaelRalph H.HrubanAndrew J.AguirreRichard A.MoffittJen JenYehChipStewartA. GordonRobertsonAndrew D.CherniackManaswiGuptaGadGetzStacey B.GabrielMatthewMeyersonCarrieCibulskisSuzanne S.FeiToshinoriHinoueHuiShenPeter W.LairdShiyunLingYilingLuGordon B.MillsRehanAkbaniPhillipeLoherEric R.LondinIsidoreRigoutsosAristeidis G.TelonisEwan A.GibbAnnaGoldenbergAziz M.MezliniKatherine A.HoadleyEricCollissonEricLanderBradley A.MurrayJulianHessMaraRosenbergLouisBergelsonHaileiZhangJuokChoGraceTiaoJaegilKimDimitriLivitzIgnatyLeshchinerBrendanReardonEliezerVan AllenAtanasKamburovRameenBeroukhimGordonSaksenaSteven E.SchumacherMichael S.NobleDavid I.HeimanNilsGehlenborgJaegilKimMichael S.LawrenceVolkanAdsayGloriaPetersenDavidKlimstraNabeelBardeesyMark D.M.LeisersonReanneBowlbyKatayoonKasaianInancBirolKaren L.MungallSaraSadeghiJohn N.WeinsteinPaul T.SpellmanYuexinLiuLaufey T.AmundadottirJoelTepperAatur D.SinghiRajivDhirDrwiegaPaulThomasSmyrkLizhiZhangPaulaKimJayBowenJessicaFrickJulie M.Gastier-FosterMarkGerkenKevinLauKristen M.LeraasTara M.LichtenbergNilsa C.RamirezJeremyRenkelMarkShermanLisaWisePeggyYenaErikZmudaJuliannShihAdrianAllyMirunaBalasundaramRebeccaCarlsenAndyChuEricChuahAmandaClarkeNoreenDhallaRobert A.HoltSteven J.M.JonesDarleneLeeYussanneMaMarco A.MarraMichaelMayoRichard A.MooreAndrew J.MungallJacqueline E.ScheinPayalSipahimalaniAngelaTamNinaThiessenKaneTseTinaWongDeniseBrooksJ. ToddAumanSaianandBaluTomBodenheimerD. NeilHayesAlan P.HoyleStuart R.JefferysCorbin D.JonesShaowuMengPiotr A.MieczkowskiLisle E.MoseCharles M.PerouAmy H.PerouJeffreyRoachYanShiJanae V.SimonsTaraSkellyMatthew G.SolowayDonghuiTanUmadeviVeluvoluJoel S.ParkerMatthew D.WilkersonAnilKorkutYasinSenbabaogluPatrickBurchRobertMcWilliamsKariChaffeeAnnObergWeiZhangMarie-ClaudeGingrasDavid A.WheelerLiuXiMoniqueAlbertJohnBartlettHarmanSekhonYeagerStephenZarenHowardMillerJudyAnneBreggiaRachna T.ShroffSudhaChudamaniJiaLiuLaxmiLollaRashiNareshToddPihlQiangSunYunhuWanYeWuSmithJenniferKevinRogginKarl-FriedrichBeckerMadhusmitaBeheraJosephBennettLoriBoiceEricBurksCarlos GilbertoCarlotti JuniorJohnChabotDanielaPretti da Cunha TirapelliJoseSebastião dos SantosMichaelDubinaJenniferEschbacherMeiHuangLoriHuelsenbeck-DillRogerJenkinsAlexeyKarpovRafaelKempVladimirLyadovShishirMaithelGeorgyManikhasEricMontgomeryHoutanNoushmehrAdeboyeOsunkoyaTaofeekOwonikokoOxanaPaklinaOlgaPotapovaSureshRamalingamW. KimrynRathmellKimberlyRieger-ChristCharlesSallerGaliyaSetdikovaAlexeyShabuninGabrielSicaTaoSuTravisSullivanPatSwansonKatherineTarvinMichaelTavobilovLeigh B.ThorneStefanUrbanskiOlgaVoroninaTimothyWangDanielCrainErinCurleyJohannaGardnerDavidMalleryScottMorrisJosephPaulauskisRobertPennyCandaceSheltonTroySheltonKlaus-PeterJanssenOliverBatheNathanBaharyJuliaSlotta-HuspeninaAmberJohnsHaninaHibshooshRosa F.HwangAntoniaSepulvedaAmieRadenbaughStephen B.BaylinMarioBerriosMoiz S.BootwallaAndreaHolbrookPhillip H.LaiDennis T.MaglinteSwapnaMahurkarTimothy J.TricheJr.David J.Van Den BergDaniel J.WeisenbergerLyndaChinRajuKucherlapatiMelanieKucherlapatiAngelikiPantaziPeterParkGordonSaksenaDougVoetPeiLinScottFrazerTimothyDefreitasSamMeierLyndaChinSun YoungKwonYong HoonKimSang-JaeParkSung-SikHanSeong HoonKimHarkKimEmmaFurthMargaretTemperoChrisSanderAndrewBiankinDavidChangPeterBaileyAnthonyGillJamesKenchSeanGrimmondAmberJohnsAustralian PancreaticCancer Genome Initiative (APGIRussellPostierRosemaryZunaHuguesSicotteJohn A.DemchokMartin L.FergusonCarolyn M.HutterKenna R.Mills ShawMargiShethHeidi J.SofiaRoyTarnuzzerZhiningWangLimingYangJiashan (Julia)ZhangInaFelauJean C.Zenklusen
We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.

Graphical abstract

Teaser

This TCGA study reveals the complex molecular landscape of PDAC, with a small number of tumors carrying multiple KRAS mutations, KRAS wild-type PDACs harboring alterations in other RAS pathway genes or alternate oncogenic drivers, and integrated RNA and protein subtypes indicating clinically significant subsets of disease.


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