Progression level of extracapsular spread and tumor budding for cervical lymph node metastasis of OSCC

Abstract

Objectives

The progression level of extracapsular spread (ECS) for cervical lymph node metastasis of oral squamous cell carcinoma (OSCC) was previously divided into three types, and their relationships with the prognosis of patients were re-examined.

Patients and methods

The Kaplan-Meier method was used to examine overall survival (OS) and relapse-free survival (RFS) curves. Prognosis factor for recurrence was analyzed with univariate and multivariate analysis.

Results

ECS was detected in 216 cases of OSCC and analyzed. The 5-year overall survival and RFS rates of patients with type C, which was microscopically defined as tumor invasion to perinodal fat or muscle tissue, were significantly poor at 40.6 and 37.8%, respectively. The results of a univariate analysis suggested that the prognosis of ECS in OSCC patients is associated with its progression level, particularly type C. The 5-year RFS rate of type C with tumor budding was significantly poor at 31.5%. Type C with tumor budding correlated with local and regional recurrence as well as distant metastasis. In a multivariate analysis, tumor budding was identified as an independent prognostic factor.

Conclusions

These results suggest that the progression level of ECS and tumor budding are useful prognostic factors in OSCC patients.

Clinical relevance

This study indicated that the progression level and tumor budding of ECS for cervical lymph node metastasis were useful prognostic factors in OSCC patients.

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Emerging techniques in assessment and treatment of muscle tension dysphonia.

Purpose of review: The purpose of this review is to summarize current evidence regarding treatment for muscle tension dysphonia (MTD) and to present recent advances in evaluation and management. Recent findings: It is generally accepted that voice therapy for MTD is effective, but current systematic reviews report limited evaluation specific to MTD patients with moderate evidence, at best, available to support voice therapy techniques. Individual studies are difficult to compare because of heterogeneity. Considerable work is underway to identify most important metrics to include in assessment, and to advance and define direct voice therapy approaches. Summary: Further standardization of assessment and treatment protocols for MTD will improve future research. Novel therapeutic techniques are under investigation. In small studies, these have found value in improving voice outcomes and measures compared with pretreatment values but have not met success greater than existing therapeutic methods. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Vocal tremor: where are we at?.

Purpose of review: Vocal tremor in movement disorders is often overlooked, although it has a significant impact on quality of life. Careful observation of tremor phenomenology allows for accurate diagnosis and tailored treatment. Recent findings: The central pathways associated with various vocal tremor-associated diseases have been further elucidated. Summary: Patients are likely to benefit from a combination of medical and interventional treatments delivered within a multidisciplinary setting Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Progression level of extracapsular spread and tumor budding for cervical lymph node metastasis of OSCC

Abstract

Objectives

The progression level of extracapsular spread (ECS) for cervical lymph node metastasis of oral squamous cell carcinoma (OSCC) was previously divided into three types, and their relationships with the prognosis of patients were re-examined.

Patients and methods

The Kaplan-Meier method was used to examine overall survival (OS) and relapse-free survival (RFS) curves. Prognosis factor for recurrence was analyzed with univariate and multivariate analysis.

Results

ECS was detected in 216 cases of OSCC and analyzed. The 5-year overall survival and RFS rates of patients with type C, which was microscopically defined as tumor invasion to perinodal fat or muscle tissue, were significantly poor at 40.6 and 37.8%, respectively. The results of a univariate analysis suggested that the prognosis of ECS in OSCC patients is associated with its progression level, particularly type C. The 5-year RFS rate of type C with tumor budding was significantly poor at 31.5%. Type C with tumor budding correlated with local and regional recurrence as well as distant metastasis. In a multivariate analysis, tumor budding was identified as an independent prognostic factor.

Conclusions

These results suggest that the progression level of ECS and tumor budding are useful prognostic factors in OSCC patients.

Clinical relevance

This study indicated that the progression level and tumor budding of ECS for cervical lymph node metastasis were useful prognostic factors in OSCC patients.

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Toward Biological Subtyping of Papillary Renal Cell Carcinoma With Clinical Implications Through Histologic, Immunohistochemical, and Molecular Analysis.

Papillary renal cell carcinoma (PRCC) has 2 histologic subtypes. Almost half of the cases fail to meet all morphologic criteria for either type, hence are characterized as PRCC not otherwise specified (NOS). There are yet no markers to resolve the PRCC NOS category. Accurate classification can better guide the management of these patients. In our previous PRCC study we identified markers that can distinguish between the subtypes. A PRCC patient cohort of 108 cases was selected for the current study. A panel of potentially distinguishing markers was chosen from our previous genomic analysis, and assessed by immunohistochemistry. The panel exhibited distinct staining patterns between the 2 classic PRCC subtypes; and successfully reclassified the NOS (45%) cases. Moreover, these immunomarkers revealed a third subtype, PRCC3 (35% of the cohort). Molecular testing using miRNA expression and copy number variation analysis confirmed the presence of 3 distinct molecular signatures corresponding to the 3 subtypes. Disease-free survival was significantly enhanced in PRCC1 versus 2 and 3 (P=0.047) on univariate analysis. The subtypes stratification was also significant on multivariate analysis (P=0.025; hazard ratio, 6; 95% confidence interval, 1.25-32.2). We propose a new classification system of PRCC integrating morphologic, immunophenotypical, and molecular analysis. The newly described PRCC3 has overlapping morphology between PRCC1 and PRCC2, hence would be subtyped as NOS in the current classification. Molecularly PRCC3 has a distinct signature and clinically it behaves similar to PRCC2. The new classification stratifies PRCC patients into clinically relevant subgroups and has significant implications on the management of PRCC. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Targeted Genomic Profiling Reveals Recurrent KRAS Mutations in Mesonephric-like Adenocarcinomas of the Female Genital Tract.

Mesonephric adenocarcinoma most commonly arises in the cervix and is presumed to be derived from normal or hyperplastic mesonephric remnants. It is characterized by recurrent KRAS mutations and lack of PIK3CA/PTEN alterations. Adenocarcinomas of the uterine corpus and ovary characterized by morphologic and immunophenotypic similarities to mesonephric adenocarcinoma have been reported. The pathogenesis of these tumors, which have been designated "mesonephric-like adenocarcinomas" is unknown, and it has been debated whether these represent mesonephric adenocarcinomas that arise in the endometrium/ovary or endometrioid adenocarcinomas that closely mimic mesonephric adenocarcinoma. The relationship at the molecular level between mesonephric adenocarcinomas and mesonephric-like adenocarcinomas is unknown. The aim of this study was to examine the molecular alterations in mesonephric-like adenocarcinomas to identify driver mutations and potential therapeutically targetable mutations, and to determine the relationship between mesonephric-like adenocarcinomas and mesonephric adenocarcinomas using targeted next-generation sequencing. Seven mesonephric-like adenocarcinomas (4 ovarian, 3 uterine corpus) underwent targeted next-generation sequencing to detect mutations, copy number variations and structural variants in exonic regions of 300 cancer genes, and 113 selected intronic regions across 35 genes. All 7 tumors (100%) harbored canonical activating KRAS mutations (4 G12D, 3 G12V). PIK3CA activating mutations were identified in 3 of 7 (43%) cases. There were no alterations in PTEN, ARID1A, or TP53 in any of the tumors. In copy number analysis, 5 of 7 (71%) tumors exhibited 1q gain, which was accompanied by 1p loss in 2 cases. In addition, 4 of 7 (57%) tumors had chromosome 10 gain, which was accompanied by gain of chromosome 12 in 3 cases. Mesonephric-like adenocarcinomas, similar to mesonephric adenocarcinomas, are characterized by recurrent KRAS mutations, gain of 1q, lack of PTEN mutations, and gains of chromosomes 10 and 12. PIK3CA mutations, which have not previously been identified in mesonephric adenocarcinoma, were found in 3 of 7 (43%) mesonephric-like adenocarcinomas in our study. Mesonephric-like adenocarcinomas exhibit strikingly similar molecular aberrations to mesonephric adenocarcinomas, but also frequently harbor PIK3CA mutations, demonstrating biological overlap with carcinomas of both mesonephric and Mullerian (endometrioid) differentiation. Given the previously documented association with endometriosis (ovarian neoplasms) and the prominent endometrial involvement (uterine corpus neoplasms), we believe these are best regarded as of Mullerian origin and representing adenocarcinomas which differentiate along mesonephric lines; as such, we propose the term mesonephric-like Mullerian adenocarcinoma. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Feasibility of Prostate PAXgene Fixation for Molecular Research and Diagnostic Surgical Pathology: Comparison of Matched Fresh Frozen, FFPE, and PFPE Tissues.

Advances in prostate cancer biology and diagnostics are dependent upon high-fidelity integration of clinical, histomorphologic, and molecular phenotypic findings. In this study, we compared fresh frozen, formalin-fixed paraffin-embedded (FFPE), and PAXgene-fixed paraffin-embedded (PFPE) tissue preparation methods in radical prostatectomy prostate tissue from 36 patients and performed a preliminary test of feasibility of using PFPE tissue in routine prostate surgical pathology diagnostic assessment. In addition to comparing histology, immunohistochemistry, and general measures of DNA and RNA integrity in each fixation method, we performed functional tests of DNA and RNA quality, including targeted Miseq RNA and DNA sequencing, and implemented methods to relate DNA and RNA yield and quality to quantified DNA and RNA picogram nuclear content in each tissue volume studied. Our results suggest that it is feasible to use PFPE tissue for routine robot-assisted laparoscopic prostatectomy surgical pathology diagnostics and immunohistochemistry, with the benefit of significantly improvedDNA and RNA quality and RNA picogram yield per nucleus as compared with FFPE tissue. For fresh frozen, FFPE, and PFPE tissues, respectively, the average Genomic Quality Numbers were 7.9, 3.2, and 6.2, average RNA Quality Numbers were 8.7, 2.6, and 6.3, average DNA picogram yields per nucleus were 0.41, 0.69, and 0.78, and average RNA picogram yields per nucleus were 1.40, 0.94, and 2.24. These findings suggest that where DNA and/or RNA analysis of tissue is required, and when tissue size is small, PFPE may provide important advantages over FFPE. The results also suggest several interesting nuances including potential avenues to improve RNA quality in FFPE tissues and confirm recent suggestions that some DNA sequence artifacts associated with FFPE can be avoided. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Cholangitis Lenta: A Clinicopathologic Study of 28 Cases.

Cholangitis lenta, also known as ductular cholestasis, cholangiolar cholestasis, or subacute nonsuppurative cholangitis, is an uncommon type of cholangitis characterized by ductular reaction with inspissated bile in dilated ductules. The literature on this unique entity has been limited to only a few studies based on a very limited number of cases, which importantly suggest an association with sepsis and/or intra-abdominal infection. The clinical, laboratory, and histologic features of 28 cases of cholangitis lenta are herein investigated. Twenty-five (89.3%) patients were liver transplant recipients. Most notably, the majority of patients showed clinical signs and symptoms of sepsis, and positive microbiology cultures were demonstrated in 24 (85.7%) patients. Significantly, 15 (53.6%) patients died during their hospitalization, ranging from 2 days to 5 months after the initial liver biopsy that showed histologic features of cholangitis lenta. Among the 13 discharged patients, including 2 who received retransplantation, 4 (14.3%) subsequently died of pneumonia, graft dysfunction, or fungal infection within 7 months to 9.3 years. Only 9 (32.1%) patients were alive at the last follow-up, with the follow-up time ranging from 3.8 to 10.4 years. Our data show that the finding of cholangitis lenta on liver biopsy is thus frequently associated with sepsis and with a high mortality rate. Therefore, accurate diagnosis of this condition on liver biopsy is imperative as it is an indication that the patient may have a potentially life threatening condition that requires immediate medical attention and management. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Recent Progress in Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia

Abstract

Purpose of Review

We reviewed recent diagnostic and therapeutic progress in chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML). We summarized recent genetic data that may guide future efforts towards implementing risk-adapted therapy based on mutational profile and improving disease control and survival of affected patients.

Recent Findings

Recent genetic data in CNL and aCML prompted modifications to the World Health Organization (WHO) diagnostic criteria, which have improved our understanding of how CNL and aCML are different diseases despite sharing common findings of peripheral granulocytosis and marrow myeloid hyperplasia. The overlap of recurrently mutated genes between aCML and CMML support considering CSF3R-T618I mutated cases as a distinct entity, either as CNL or CNL with dysplasia. Ongoing preclinical and clinical studies will help to further inform the therapeutic approach to these diseases.

Summary

Our understanding of CNL and aCML has greatly advanced over the last few years. This will improve clarity for the diagnosis of these diseases, provide a strategy for risk stratification, and guide risk-adapted therapy.

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Ten-year immune persistence and safety of the HPV-16/18 AS04-adjuvanted vaccine in females vaccinated at 15–55 years of age

Abstract

Women remain at risk of human papillomavirus (HPV) infection for most of their lives. The duration of protection against HPV-16/18 from prophylactic vaccination remains unknown. We investigated the 10-year immune response and long-term safety profile of the HPV-16/18 AS04-adjuvanted vaccine (AS04-HPV-16/18 vaccine) in females aged between 15 and 55 years at first vaccination. Females who received primary vaccination with three doses of AS04-HPV-16/18 vaccine in the primary phase-III study (NCT00196937) were invited to attend annual evaluations for long-term immunogenicity and safety. Anti-HPV-16/18 antibodies in serum and cervico-vaginal secretions (CVS) were measured using enzyme-linked immunosorbent assay (ELISA). Serious adverse events (SAEs) were recorded throughout the follow-up period. Seropositivity rates for anti-HPV-16 remained high (≥96.3%) in all age groups 10 years after first vaccination. It was found that 99.2% of 15–25-year olds remained seropositive for anti-HPV-18 compared to 93.7% and 83.8% of 26–45-year olds and 45–55-year olds, respectively. Geometric mean titers (GMT) remained above natural infection levels in all age groups. Anti-HPV-16 and anti-HPV-18 titers were at least 5.3-fold and 3.1-fold higher than titers observed after natural infection, respectively, and were predicted to persist above natural infection levels for ≥30 years in all age groups. At Year 10, anti-HPV-16/18 antibody titers in subjects aged 15–25 years remained above plateau levels observed in previous studies. Correlation coefficients for antibody titers in serum and CVS were 0.64 (anti-HPV-16) and 0.38 (anti-HPV-18). This study concluded that vaccinated females aged 15–55 years elicited sustained immunogenicity with an acceptable safety profile up to 10 years after primary vaccination, suggesting long-term protection against HPV.

The HPV-16/18 AS04-adjuvanted vaccine produced a sustained immune response in women aged 15–55 years at vaccination for up to 10 years, with an acceptable safety profile. Study results suggest that women in age groups not targeted by adolescent immunization and catch-up programs may still individually benefit from HPV vaccination.

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Inhibition of telomerase activity and induction of apoptosis by Rhodospirillum rubrum L-asparaginase in cancer Jurkat cell line and normal human CD4+ T lymphocytes

Abstract

Rhodospirillum rubrum L-asparaginase mutant _{E149R, V150P, F151T} (RrA) down-regulates telomerase activity due to its ability to inhibit the expression of telomerase catalytic subunit hTERT. The aim of this study was to define the effect of short-term and long-term RrA exposure on proliferation of cancer Jurkat cell line and normal human CD4⁺ T lymphocytes. RrA could inhibit telomerase activity in dose- and time-dependent manner in both Jurkat and normal CD4⁺ T cells. Continuous RrA exposure of these cells resulted in shortening of telomeres followed by cell cycle inhibition, replicative senescence, and development of apoptosis. Complete death of Jurkat cells was observed at the day 25 of RrA exposure while normal CD4⁺ T cells died at the day 50 due to the initial longer length of telomeres. Removal of RrA from senescent cells led to a reactivation of hTERT expression, restoration telomerase activity, re-elongation of telomeres after 48 h of cultivation, and survival of cells. These findings demonstrate that proliferation of cancer and normal telomerase-positive cells can be limited by continuous telomerase inhibition with RrA. Longer telomeres of normal CD4⁺ T lymphocytes make such cells more sustainable to RrA exposure that could give them an advantage during anti-telomerase therapy. These results should facilitate further investigations of RrA as a potent anti-telomerase therapeutic protein.

Long-term exposure to Rhodospirillum rubrum L-asparaginase (RrA) induced telomere shortening and eventual growth arrest and apoptosis in vitro. Telomerase inhibition using RrA may be considered as a promising approach for cancer treatment.

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Validation of 3D documentation of palatal soft tissue shape, color, and irregularity with intraoral scanning

Abstract

Objectives

The purpose of this study was to assess the feasibility of 3D intraoral scanning for documentation of palatal soft tissue by evaluating the accuracy of shape, color, and curvature.

Materials and methods

Intraoral scans of ten participants' upper dentition and palate were acquired with the TRIOS® 3D intraoral scanner by two observers. Conventional impressions were taken and digitized as a gold standard. The resulting surface models were aligned using an Iterative Closest Point approach. The absolute distance measurements between the intraoral models and the digitized impression were used to quantify the trueness and precision of intraoral scanning. The mean color of the palatal soft tissue was extracted in HSV (hue, saturation, value) format to establish the color precision. Finally, the mean curvature of the surface models was calculated and used for surface irregularity.

Results

Mean average distance error between the conventional impression models and the intraoral models was 0.02 ± 0.07 mm (p = 0.30). Mean interobserver color difference was − 0.08 ± 1.49° (p = 0.864), 0.28 ± 0.78% (p = 0.286), and 0.30 ± 1.14% (p = 0.426) for respectively hue, saturation, and value. The interobserver differences for overall and maximum surface irregularity were 0.01 ± 0.03 and 0.00 ± 0.05 mm.

Conclusions

This study supports the hypothesis that the intraoral scan can perform a 3D documentation of palatal soft tissue in terms of shape, color, and curvature.

Clinical relevance

An intraoral scanner can be an objective tool, adjunctive to the clinical examination of the palatal tissue.

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Seasonal Rhythms: The Role of Thyrotropin and Thyroid Hormones

Thyroid , Vol. 0, No. 0.


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Thyroid Storm: A Japanese Perspective

Thyroid , Vol. 0, No. 0.


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Projecting Survival in Papillary Thyroid Cancer: A Comparison of the Seventh and Eighth Editions of the American Joint Commission on Cancer/Union for International Cancer Control Staging Systems in Two Contemporary National Patient Cohorts

Thyroid , Vol. 0, No. 0.


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Validation of 3D documentation of palatal soft tissue shape, color, and irregularity with intraoral scanning

Abstract

Objectives

The purpose of this study was to assess the feasibility of 3D intraoral scanning for documentation of palatal soft tissue by evaluating the accuracy of shape, color, and curvature.

Materials and methods

Intraoral scans of ten participants' upper dentition and palate were acquired with the TRIOS® 3D intraoral scanner by two observers. Conventional impressions were taken and digitized as a gold standard. The resulting surface models were aligned using an Iterative Closest Point approach. The absolute distance measurements between the intraoral models and the digitized impression were used to quantify the trueness and precision of intraoral scanning. The mean color of the palatal soft tissue was extracted in HSV (hue, saturation, value) format to establish the color precision. Finally, the mean curvature of the surface models was calculated and used for surface irregularity.

Results

Mean average distance error between the conventional impression models and the intraoral models was 0.02 ± 0.07 mm (p = 0.30). Mean interobserver color difference was − 0.08 ± 1.49° (p = 0.864), 0.28 ± 0.78% (p = 0.286), and 0.30 ± 1.14% (p = 0.426) for respectively hue, saturation, and value. The interobserver differences for overall and maximum surface irregularity were 0.01 ± 0.03 and 0.00 ± 0.05 mm.

Conclusions

This study supports the hypothesis that the intraoral scan can perform a 3D documentation of palatal soft tissue in terms of shape, color, and curvature.

Clinical relevance

An intraoral scanner can be an objective tool, adjunctive to the clinical examination of the palatal tissue.

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Deep Learning based multi-omics integration robustly predicts survival in liver cancer

Identifying robust survival subgroups of hepatocellular carcinoma (HCC) will significantly improve patient care. Currently, endeavor of integrating multi-omics data to explicitly predict HCC survival from multiple patient cohorts is lacking. To fill in this gap, we present a deep learning (DL) based model on HCC that robustly differentiates survival subpopulations of patients in six cohorts. We build the DL based, survival-sensitive model on 360 HCC patients' data using RNA-seq, miRNA-seq and methylation data from TCGA, which predicts prognosis as good as an alternative model where genomics and clinical data are both considered. This DL based model provides two optimal subgroups of patients with significant survival differences (P=7.13e-6) and good model fitness (C-index=0.68). More aggressive subtype is associated with frequent TP53 inactivation mutations, higher expression of stemness markers (KRT19, EPCAM) and tumor marker BIRC5, and activated Wnt and Akt signaling pathways. We validated this multi-omics model on five external datasets of various omics types: LIRI-JP cohort (n=230, C-index=0.75), NCI cohort (n=221, C-index=0.67), Chinese cohort (n=166, C-index=0.69), E-TABM-36 cohort (n=40, C-index=0.77), and Hawaiian cohort (n=27, C-index=0.82). This is the first study to employ deep learning to identify multi-omics features linked to the differential survival of HCC patients. Given its robustness over multiple cohorts, we expect this workflow to be useful at predicting HCC prognosis prediction.

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Therapy for Chronic Myelomonocytic Leukemia in a New Era

Abstract

Chronic myelomonocytic leukemia (CMML) is a myeloid malignancy which shares clinical and morphologic features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs) and is classified by the WHO as an MDS/MPN. The defining feature of CMML is clonal hematopoiesis that results in peripheral monocytosis. The benefit of early treatment is currently unclear, and treatment may be held until the disease exhibits accelerated blast counts or the patient becomes symptomatic. Optimal treatments for CMML are not well defined. Conventional treatments include hydroxyurea, cytarabine, and hypomethylating agents. However, all treatment options are limited and, with the exception of allogeneic stem cell transplantation, are considered palliative. As we continue to learn about the genomics of CMML and about arising therapeutic targets and those under active clinical investigation, the future therapy of CMML will likely improve considerably. Here, we review the data available for conventional therapies and highlight emerging therapeutic strategies.

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Genetic Variations of DNA Repair Genes in Breast Cancer

Abstract

Genetic variations in DNA repair genes may affect DNA repair capacity therefore increase risk for cancer. In our study, we evaluted the relation between DNA repair gene polymorphisms XRCC1 rs1799782, rs25487, rs25489; XPC rs2228000, rs2228001; XPD rs1799793, rs13181; XRCC3 rs861539; RAD51B rs10483813, rs1314913 and breast cancer risk for 202 Turkish cases in total, in which 102 patients with breast cancer and 100 controls. Genotyping of the DNA samples was carried out by multiplex PCR and matrix-assisted laser desorption/ionization mass spectrometry with time of flight measurement (MALDI-TOF) using Sequenom MassARRAY 4 analyzer. Genotype and allele distributions were calculated between the groups. Odds ratios (ORs) and 95% confidence intervals (CIs) were reported. rs25487 AA genotype and A allele was found to be increased in the control group (respectively, OR 0.16 95% CI 0.02–1.06, p = 0.058; OR 1.55, 95% CI 1.01–2.36, p = 0.043) and rs861539 T allele was found to be decreased in the patient group (OR 1.53, 95% CI 1.01–2.30, p = 0.049). No association with breast cancer was found for the remaining SNPs. Our findings suggest that XRCC1 rs25487 AA genotype and A allele, XRCC3 rs861539 T allele may have protective effects in breast cancer for Turkish population.

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Treatment Advances in Spinal Muscular Atrophy

Abstract

Purpose of Review

Spinal muscular atrophy (SMA) is a genetic disorder of motor neurons in the anterior horns of the spinal cord and brainstem that results in muscle atrophy and weakness. SMA is an autosomal recessive disease linked to deletions of the SMN1 gene on chromosome 5q. Humans have a duplicate gene (SMN2) whose product can mitigate disease severity, leading to the variability in severity and age of onset of disease, and is therefore a target for drug development.

Recent Findings

Advances in preclinical and clinical trials have paved the way for novel therapeutic options for SMA patients, including many currently in clinical trials. In 2016, the first treatment for SMA has been approved in the USA, an antisense oligonucleotide that increases full-length protein product derived from SMN2.

Summary

The approval of a first treatment for SMA and the rapid advances in clinical trials provide the prospect for multiple approaches to disease modification. There are several other promising therapeutics in different stages of development, based on approaches such as neuroprotection, or gene therapy.

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Autism spectrum disorder and Li-Fraumeni syndrome: purely coincidental or mechanistically associated?

Abstract

Background

Autism spectrum disorders (ASDs) are neurodevelopmental disorders with impaired social interactions and communication and restrictive, repetitive patterns of behaviors, interests, and activities. A recent epidemiological study suggests that children with ASD might have an increased cancer risk.

Case presentation

The 14.5-year-old boy, previously diagnosed with ASD, was referred with persistent bone pain. Diagnostic work-up confirmed diagnosis of acute lymphoblastic leukemia (ALL); cytogenetic analysis revealed low hypodiploid karyotype with a mutation (c.733G>A, p.Gly245Ser, rs28934575) in TP53 in the leukemic blasts. By Sanger sequencing, the presence of this mutation in the germline was subsequently confirmed and, thus, diagnosis of Li-Fraumeni syndrome (LFS) was made. His family history was remarkable with two siblings with intellectual disability and a mother who has died of premenopausal breast cancer.

Conclusions

Some of the oncogenes and tumor suppressor genes causing cancer susceptibility syndromes overlap with those involved in autism. This functional overlap between autism and cancer is novel and particularly compelling. The surprising coincidence of LFS and ASD in our patient raises the question whether this is purely coincidental or mechanistically associated.

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Uptake Characteristics and Kinetics of Inorganic and Organic Phosphorus by Ceratophyllum demersum

Abstract

Submersed macrophytes take an unreplaceable role in stabilization of aquatic ecological system and purification of eutrophic water. It is becoming the focus of purifying water bodies around the world. This study investigated the inorganic and organic phosphorus (P) uptake characteristics in different P levels by Ceratophyllum demersum and P uptake kinetics of Ceratophyllum demersum through using ion depletion method. The results showed that the average daily P uptake by Ceratophyllum demersum increased significantly during the 30-day experimental period. P uptake abilities by Ceratophyllum demersum in different inorganic P (KH₂PO₄) levels were obviously enhanced with the increasing P concentration. Moreover, Ceratophyllum demersum could uptake and utilize β-glycerophosphate as P source no matter whether the systems were sterilized or not, which indicates that there was no microorganism dependence on the uptake of β-glycerophosphate by Ceratophyllum demersum. However, almost no P uptake was detected when using phytic acid as another kind of organic P source. The uptake ability of β-glycerophosphate P by Ceratophyllum demersum was much higher than that of inorganic P at the P level of 10 mg/L. The P uptake kinetics parameters were calculated according to the experimental data. The maximum absorption rate (I _max) of P by Ceratophyllum demersum was 54.94 μg P/g(dry weight)·h and the Michaelis constant (K _m) was 1.754 mg/L, which showed that the I _max of P by Ceratophyllum demersum was relatively low when compared with other emergent aquatic plants and the affinity of P with Ceratophyllum demersum was rather weak. Owing to its endurance to high P concentration and the excellent purifying capacity, Ceratophyllum demersum still can be used to control eutrophication of water bodies.

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Nitric Oxide (Donor/Induced) in Chemosensitization, Volume 1. 1st Edition

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Announcements

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Handbook of Supportive and Palliative Radiation Oncology

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Congenital and Acquired Bone Marrow Failure. 1st Edition

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Thyroid Cancer and Nuclear Accidents. 1st Edition

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Patient-Derived Mouse Models of Cancer. Patient-Derived Orthotopic Xenografts (PDOX)

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Book Reviews

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miR-223 and Stathmin-1 Expression in Non-tumor Liver Tissue of Patients with Hepatocellular Carcinoma

Aim: Overexpression of stathmin (STMN1) has been reported for several tumor entities. STMN1 expression correlated with the detection of mutant p53, also suggesting loss-of-function-dependent mechanisms for its accumulation in hepatocellular carcinoma (HCC) cells. On the other hand, miR-223 has been identified as one of the most down-regulated miRNAs in HCC, and its expression was shown to be negatively correlated with STMN1 expression. The aim of this study was to investigate the clinical significance of STMN1 and miRNA-223 expression. Patients and Methods: Fifty-six consecutive patients with HCC who underwent curative hepatectomy as initial treatment were enrolled. They were divided into two groups based on the STMN1 expression level: high (n=36) and low (n=20) gene-expression groups. We compared the clinicopathological factors between the groups with high and low expression in non-tumor tissues. Thirty out of 56 patients were also divided into groups with high (n=15) and low (n=15) miR-223 expression and compared the clinicopathological factors between the two groups. Results: There were no significant differences in patient background between high and low STMN1 expression groups. The incidence of multicentric (MC) recurrence in the high-expression group was significantly higher than in the low-expression group and high STMN1 expression was shown to be an independent risk factor for MC recurrence. There were also no significant differences in patient background between high and low miR-223 expression groups; however, the disease-free survival rate in the group with low expression was significantly worse. Furthermore, MC-related miRNAs identified by miRNA microarray clearly clustered patients into MC recurrence and non-recurrence groups. Conclusion: Both gene and miRNA expression profiles in non-tumor liver tissues could predict the risk for MC recurrence. Such molecular information may be useful in enabling better decision making for patients with HCC.

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Surgical Resection and Outcome of Synchronous and Metachronous Primary Lung Cancer in Breast Cancer Patients

Background/Aim: Women with breast cancer are at increased risk of subsequent primary malignancies, specifically lung cancer. The aim of this study was to report the frequency of lung cancer in patients with breast cancer, and patients' characteristics and surgical outcomes. Patients and Methods: We investigated 1,066 consecutive female patients undergoing surgical resection for breast cancer and 666 undergoing surgical resection for lung cancer. Results: Lung cancer with breast cancer was observed in 14 patients (1.3% of breast cancer and 2.1% of lung cancer cases; mean age=65 years), and 3/14 (21.4%) patients were smokers. Sixteen lung cancer lesions in 14 patients were adenocarcinomas and one was squamous cell carcinoma. All 14 patients were alive at the time of this report; 4/14 (28.6%) patients had recurrent breast cancer and 1/14 (7.1%) had recurrent lung cancer. In synchronous cases, 5/6 (83.3%) patients received concomitant surgery for both breast cancer and lung cancer. Patients' postoperative courses were uneventful. In metachronous cases, eight patients had lung cancer a mean of 33 months after breast cancer surgery. All eight patients received adjuvant therapies and 4/8 (50%) patients received adjuvant therapies for recurrent breast cancer, including chemotherapy, radiotherapy, hormonal therapy, and anti-HER2 therapy. All patients had early-stage lung adenocarcinoma and underwent surgical resection. Conclusion: Concomitant surgery for synchronous lung and breast cancer was feasible and safe. In metachronous cases, lung cancers tended to be detected within 3 years after surgery for breast cancer. Careful follow-up for postoperative breast cancer may contribute to the detection of early-stage lung cancer.

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The Association Between Chemotherapy Immediately Before Nivolumab and Outcomes Thereafter

Background/Aim: We investigated whether the efficacy and type of pre-nivolumab chemotherapy influence outcomes in non-small cell lung cancer patients following nivolumab treatment. Patients and Methods: In this multicenter study, 199 patients treated with nivolumab were retrospectively reviewed. We analyzed the relationships between the clinical response to nivolumab and to chemotherapy administered immediately beforehand. Results: Patients who achieved objective responses to pretreatments showed higher disease control rates with nivolumab than patients who did not (64% vs. 47%, p=0.03), as did those who achieved disease control with pretreatments (62% vs. 35%, p<0.001). Bevacizumab-pretreated patients tended to show better objective response rates with nivolumab (27% vs. 13%, p=0.06); the objective response rate to nivolumab was significantly higher in bevacizumab-pretreated patients who showed clinical responses (42% vs. 9.1%, p=0.02). Conclusion: Achievement of a clinical response to chemotherapy immediately before nivolumab, particularly when combined with bevacizumab, increases the likelihood of disease control post-nivolumab.

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Predictive Factors for Poor Progression-free Survival in Patients with Non-small Cell Lung Cancer Treated with Nivolumab

Background: Nivolumab has shown promising effects in patients with non-small-cell lung cancer (NSCLC) as a second- or later-line treatment. This study aimed to identify patients who would not experience any benefit from nivolumab treatment. Materials and Methods: In this study, data for 201 patients treated with nivolumab during 17 December 2015 to 31 July 2016 at three respiratory medical centers in Japan were retrospectively reviewed. We collected clinical data at the time of nivolumab treatment commencement. We investigated the relationship between progression-free survival (PFS) and patient characteristics. Results: In both univariate and multivariate analysis, performance status (PS) score ≥2, steroid use at baseline and lactate dehydrogenase (LDH) level >240 IU/l were significantly associated with poor PFS (all p<0.05). Conclusion: PS score ≥2, steroid use at baseline and a high LDH level were predictive of poor PFS in patients with NSCLC treated with nivolumab. Careful monitoring is recommended for treating such patients with nivolumab (UMIN-ID: UMIN000025908).

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A Proposal for Progression-Free Survival Assessment in Patients with Early Progressive Cancer

Background/Aim: Progression-free survival (PFS), which is evaluated in oncology clinical trials, is determined based on tumor progression evaluated according to an assessment schedule. There is possibly a bias in median PFS and hazard ratio (HR) for PFS depending on the assessment schedule referring to randomized controlled trials (RCTs) in patients with metastatic colorectal cancer. Materials and Methods: We re-analyzed the PFS in the FTD/TPI phase 2 trial by changing the assessment schedule. To assess biases in median PFS and HR for PFS resulting from different assessment schedules, we performed a computational simulation. Results: The reanalysis of FTD/TPI phase 2 trial and the simulation results showed that there were biases in median PFS and HR for PFS. Conclusion: In RCTs for early progressive cancer, median PFS is dependent on the assessment schedule; however, HR for PFS can be assessed without clinically-meaningful differences between assessment schedules, regardless of biomarker assumptions.

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Anti-inflammatory Effects of Enhanced Recovery Programs on Early-Stage Colorectal Cancer Surgery

Abstract

Background

Postoperative ileus (POI) is observed in 20–30% of patients undergoing colorectal cancer surgery, despite enhanced recovery programs (ERPs). Cyclooxygenase (COX)-2 is identified as a key enzyme in POI, but other arachidonic acid pathway enzymes have received little attention despite their potential as selective targets to prevent POI. The objectives were to compare the expression of arachidonic acid metabolism (AAM) enzymes (1) between patients who underwent colorectal cancer surgery and followed an ERP or not (NERP), (2) and between ERP patients who experimented POI or not and (3) to determine the ability of antagonists of these pathways to modulate contractile activity of colonic muscle.

Methods

This was a translational study. Main outcome measures were gastrointestinal motility recovery data, mRNA expressions of key enzymes involved in AAM (RT-qPCR) and ex vivo motility values of the circular colon muscle. Twenty-eight prospectively included ERP patients were compared to eleven retrospectively included NERP patients that underwent colorectal cancer surgery.

Results

ERP reduced colonic mucosal COX-2, microsomal prostaglandin E synthase (mPGES1) and hematopoietic prostaglandin D synthase (HPGDS) mRNA expression. mPGES1 and HPGDS mRNA expression were significantly associated with ERP compliance (respectively, r2 = 0.25, p = 0.002 and r2 = 0.6, p < 0.001). In muscularis propria, HPGDS mRNA expression was correlated with GI motility recovery (p = 0.002). The pharmacological inhibition of mPGES1 increased spontaneous ex vivo contractile activity in circular muscle (p = 0.03).

Conclusion

The effects of ERP on GI recovery are correlated with the compliance of ERP and could be mediated at least in part by mPGES1, HPGDS and COX-2. Furthermore, mPGES1 shows promise as a therapeutic target to further reduce POI duration among ERP patients.

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Clinical and Radiological Discrimination of Solitary Pulmonary Lesions in Colorectal Cancer Patients

Abstract

Objectives

The lung is one of the most common organs of metastasis from colorectal cancer (CRC), and we have encountered lung cancer patients with a history of CRC. There have been few studies regarding methods used to discriminate between primary lung cancer (PLC) and pulmonary metastasis from CRC (PM-CRC) based only on preoperative findings. We retrospectively investigated predictive factors discriminating between these lesions in patients with a history of CRC.

Methods

Between 2006 and 2015, 117 patients with a history of CRC (44 patients with 47 PLC and 73 patients with 102 PM-CRC) underwent subsequent or concurrent resection of pulmonary lesions. We compared the clinical and radiological characteristics of 100 patients with solitary lesions (43 PLC and 57 PM-CRC). Using univariate and multivariate analyses, we examined predictive factors for discrimination of these two lesions.

Results

All tumors with findings of ground-glass opacity (GGO) were PLC (n = 19). In a multivariate analysis of 81 radiologically solid tumors, two factors were found to be significant independent predictors of PLC: a history of stage I CRC and presence of pleural indentation. All tumors in 26 patients with either GGO or both a stage I CRC history and pleural indentation were PLC, while most tumors in patients without all three factors were PM-CRC (43/44; 97.7%).

Conclusions

The presence or absence of GGO, pathological CRC stage, and pleural indentation could be useful factors to distinguish between PLC and PM-CRC.

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Clinical vignettes inadequate to assess impact of implicit bias: concerning limitations of a systematic review

Abstract

We are writing in response to Dehon et al's article "A Systematic Review of the Impact of Physician Implicit Racial Bias on Clinical Decision Making"¹ in the August 2017 issue of Academic Emergency Medicine. As members of SAEM's Academy of Diversity and Inclusion in Emergency Medicine, we believe it is imperative to pursue research on the impact of bias and discrimination on clinical practice and healthcare outcomes. While we commend Dr. Dehon and her colleagues for their effort to assess the impact of implicit bias on clinical decision-making, we do not think that the evidence reviewed supports the breadth of their conclusions.

This article is protected by copyright. All rights reserved.

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Study Identifies Crucial Characteristic of High-Risk HPV

By comparing the genomes of women infected with a high-risk type of human papillomavirus (HPV), researchers have found that a precise DNA sequence of a viral gene is associated with cervical cancer.

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Sap From Garden Plants Can Burn Eyes

Gardeners caring for plants in the Euphorbia genus should be careful about handling the toxic sap, according to a new report.
Reuters Health Information

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Is Age a Risk Factor for Lymph Node Positivity in Melanoma?

Certain patients with thin melanomas aren't recommended for sentinel lymph node biopsy, but a study suggests that they should be.
Medscape Dermatology

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Immediate Biopsy for Suspicious Oral Lesions, Says ADA

Biopsy and histologic assessment of suspicious mucosal lesions in the mouth continue to be the cornerstone for early cancer detection recommended by the American Dental Association.
Medscape Medical News

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Anxiety and Fear of Recurrence Despite a Good Prognosis: An Interview Study with Differentiated Thyroid Cancer Patients

Thyroid , Vol. 0, No. 0.


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MiR-203a-3p suppresses cell proliferation and metastasis through inhibiting LASP1 in nasopharyngeal carcinoma

miR-203a-3p was reported as a tumor suppressor and disregulated in many malignancies including nasopharyngeal carcinoma (NPC). However, its function in tumor growth and metastasis in NPC has rarely been reported.

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An Interesting Case of Pyoderma Gangrenosum with Immature Hystiocytoid Neutrophils

Abstract

We present a unique case of a 36-year-old male who developed more than twenty Pyoderma gangrenosum ulcers demonstrating on histopathology a dense inflammatory infiltrate composed of histiocytoid mononuclear immature cells with a strong positivity for myeloperoxidase and Leder stain, suggesting a myeloid lineage in the absence of a concomitant myeloproliferative disorder. Histiocytoid Sweet syndrome is now recognized as a histological subtype of Sweet syndrome. Although Pyoderma gangrenosum and Sweet syndrome belong to the spectrum of neutrophilic diseases, to the best of our knowledge, this is the first case of a "Histiocytoid Pyoderma gangrenosum" encompassing immature granulocytes in the absence of leukemia cutis.

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Adult reference intervals for IgG subclasses with Siemens immunonephelometric assays in Chinese population

To determine the adult reference intervals for the Siemens IgG subclass reagents.

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Plastic Surgery Videos Need Strict Ethics Standards, Doctors Argue

Some plastic surgeons have gained large social media followings by sharing theatrical videos of surgery with entertainment, rather than education, in mind. Now experts are proposing ethics guidelines to ensure that the content of plastic surgery videos on social media isn't harmful to patients.
Reuters Health Information

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Las Vegas Faced a Massacre. Did It Have Enough Trauma Centers?

Hospitals view adding trauma care as a potential profit tool, but experts say more centers do not necessarily improve the system's ability to respond to a mass casualty event.
Kaiser Health News

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Stopping Long-term Aspirin Linked to CV-Event Spike

The elevated risk appeared shortly after patients stopped aspirin and did not appear to diminish over time, the investigators report.
Medscape Medical News

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Reaction to 'Old' Tattoo Ink Mimics Lymphoma

An unusual case of tattoo pigment hypersensitivity caused widespread lymphadenopathy 15 years later, but without a skin reaction.
Medscape Medical News

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Abnormal intrinsic brain functional network dynamics in Parkinson’s disease

Abstract

Parkinson's disease is a neurodegenerative disorder characterized by nigrostriatal dopamine depletion. Previous studies measuring spontaneous brain activity using resting state functional magnetic resonance imaging have reported abnormal changes in broadly distributed whole-brain networks. Although resting state functional connectivity, estimating temporal correlations between brain regions, is measured with the assumption that intrinsic fluctuations throughout the scan are stable, dynamic changes of functional connectivity have recently been suggested to reflect aspects of functional capacity of neural systems, and thus may serve as biomarkers of disease. The present work is the first study to investigate the dynamic functional connectivity in patients with Parkinson's disease, with a focus on the temporal properties of functional connectivity states as well as the variability of network topological organization using resting state functional magnetic resonance imaging. Thirty-one Parkinson's disease patients and 23 healthy controls were studied using group spatial independent component analysis, a sliding windows approach, and graph-theory methods. The dynamic functional connectivity analyses suggested two discrete connectivity configurations: a more frequent, sparsely connected within-network state (State I) and a less frequent, more strongly interconnected between-network state (State II). In patients with Parkinson's disease, the occurrence of the sparsely connected State I dropped by 12.62%, while the expression of the more strongly interconnected State II increased by the same amount. This was consistent with the altered temporal properties of the dynamic functional connectivity characterized by a shortening of the dwell time of State I and by a proportional increase of the dwell time pattern in State II. These changes are suggestive of a reduction in functional segregation among networks and are correlated with the clinical severity of Parkinson's disease symptoms. Additionally, there was a higher variability in the network global efficiency, suggesting an abnormal global integration of the brain networks. The altered functional segregation and abnormal global integration in brain networks confirmed the vulnerability of functional connectivity networks in Parkinson's disease.

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Oncology Research Program

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NCCN News

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Bladder Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on systemic therapy for muscle-invasive urothelial bladder cancer, as substantial revisions were made in the 2017 updates, such as new recommendations for nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. The complete version of the NCCN Guidelines for Bladder Cancer addresses additional aspects of the management of bladder cancer, including non–muscle-invasive urothelial bladder cancer and nonurothelial histologies, as well as staging, evaluation, and follow-up.

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Serving "a la CAR-T": Value-Based Pricing and Gene Therapy

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Distress and Financial Distress in Adults With Cancer: An Age-Based Analysis

Background: Although financial distress is commonly recognized in patients with cancer, it may be more prevalent in younger adults. This study sought to evaluate disparities in overall and financial distress in patients with cancer as a function of age. Methods: This was a single-center cross-sectional study of patients with solid malignancies requiring cancer therapy. The patient questionnaire included demographics, financial concerns, and measures of overall and financial distress. Data analyses compared patients in 3 age groups: young (<50 years), middle-aged (50–64 years), and elderly (≥65 years). Results: The cohort included 119 patients (median age, 62 years; 52% female; 84% white; 100% insured; 36% income ≥$75,000). Significant financial concerns included paying rent/mortgage (P=.003) and buying food (P=.032). Impact of Event Scale (IES) results revealed significant distress in 73% young, 64% middle-aged, and 44% elderly patients. The mean Distress Thermometer (DT) score was 6.1 (standard deviation [SD], 2.9) for young patients, 5.4 (SD, 2.6) for middle-aged, and 4.4 (SD, 3.3) for elderly patients. Young patients were more likely than elderly patients to have a higher IES distress score (P=.016) and DT score (P=.048). The mean InCharge score was lowest (indicating greatest financial distress) in the young group and progressed with age: 5.0 (SD, 1.9), 5.7 (SD, 2.7), and 7.4 (SD, 1.9), respectively (P<.001). Multivariable analyses revealed that the relationship between financial distress and overall distress was strongest in the middle-age group; as the DT increased by 1 point, the InCharge scores decreased by 0.52 (P<.001). Conclusions: Overall and financial distress are more common in young and middle-aged patients with cancer. There are several factors, including employment, insurance, access to paid sick leave, children, and education, that affect younger and middle-aged adults and are less of a potential stressor for elderly individuals.

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Implementation Framework for NCCN Guidelines

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Urothelial Carcinoma of the Bladder and the Rise of Immunotherapy

With the advent of platinum-based chemotherapy, survival rates for metastatic urothelial carcinoma have plateaued, giving way to the modern immunotherapy paradigm. Although immunotherapy as an effective treatment dates back to the live, attenuated bacillus Calmette-Guérin vaccine, the recent impact of immune checkpoint inhibitors targeting programmed death/programmed death-ligand 1 (PD-1/PD-L1) coupled with the promise of both anti–cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) antibodies and indoleamine-2, 3-dioxygenase-1 (IDO-1) inhibitors have provided a resurgence. To date, pembrolizumab, a PD-1 inhibitor, has been granted full FDA approval based on its high antitumor activity, tolerability, and efficacy, with notable prolonged durable responses in the second-line setting. Nivolumab (a PD-1 inhibitor) and atezolizumab, durvalumab, and avelumab (PD-L1 inhibitors) have also gained accelerated drug approval in the second-line setting. In addition, atezolizumab and pembrolizumab have been approved for platinum-ineligible patients in the first-line setting. Effective 2-drug combinations reported include nivolumab plus the CTLA-4 antibody ipilimumab and pembrolizumab plus the IDO-1 inhibitor epacadostat. Further expansion of immunotherapy will hinge in part on the ability to define responders versus nonresponders through the use of biomarkers like PD-L1 or mutational load. Clinical trials with immunotherapy for metastatic disease as single agents or in combination are ongoing. This review explores the rise of immunotherapy and presents the current treatments and challenges posed with development of biomarkers, and provides a summary of ongoing phase III clinical trials.

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To the Editor: Predictive Markers and Precision Medicine

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Pathologic Complete Response After Neoadjuvant Chemotherapy and Long-Term Outcomes Among Young Women With Breast Cancer

Purpose: Breast cancer in young women is associated with an aggressive tumor biology and higher risk of recurrence. Pathologic complete response (pCR) after neoadjuvant therapy has been shown to be a surrogate marker for disease-free survival (DFS) and overall survival (OS), but the association between pCR and survival outcomes in young women with breast cancer is not well described. Methods: This study included women aged ≤40 years at diagnosis who received neoadjuvant chemotherapy (NAC) for stage II–III invasive breast cancer between 1998 and 2014 at Massachusetts General Hospital. Outcomes were compared between patients who achieved pCR (ypT0/is, ypN0) and those with residual disease. Results: A total of 170 young women were included in the analytical data set, of which 53 (31.2%) achieved pCR after NAC. The 5-year DFS rate for patients with and without pCR was 91% versus 60%, respectively (P<.01), and the OS rate was 95% versus 75%, respectively (P<.01). Among patients with pCR, no difference was seen in OS irrespective of baseline clinical stage (P=.6), but among patients with residual disease after NAC, a significant difference in OS based on baseline clinical stage was observed (P<.001). Conclusions: Our results suggest pCR after NAC is strongly associated with significantly improved DFS and OS in young women with breast cancer, and perhaps even more so than baseline stage. However, the significantly higher mortality for patients who did not attain pCR highlights the need for better therapies, and the neoadjuvant trial design could potentially serve as an efficient method for rapid triage and escalation/de-escalation of therapies to improve outcomes for young women with breast cancer.

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EGFR-Mutant Non-Small Cell Lung Cancer in the Era of Precision Medicine: Importance of Germline EGFR T790M Testing

With the rapid development of precision medicine, next-generation sequencing (NGS) has provided the ability to uncode tumors at the DNA level. Identifying EGFR mutations and other molecular changes has become more crucial in the management of non–small cell lung cancer (NSCLC) than ever before. Although the histologic subtypes in patients with advanced NSCLC remain valid in determining treatment options, the detection of specific molecular signatures such as de novo T790M with sensitizing EGFR mutations could be more useful than the histologic subtype itself. Germline T790M mutation should be suspected and tested for when multiple biopsies show de novo T790M mutations or when de novo T790M is found in patients with a family history of lung cancer. This case report presents a 60-year-old woman with bilateral NSCLC with 3 different distinct histologic diagnoses. Evaluating the molecular profile using NGS completely changed the diagnosis, prognosis, and management of this rare presentation of NSCLC.

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A Population-Based Assessment of Emergency Department Observation Status for Older Adults With Cancer

Background: Hospitals' use of observation status for patients with cancer presenting to the emergency department (ED) is not well understood. This model of care delivery may be a viable alternative to inpatient admission for patients with cancer presenting with certain conditions. Our objective was to assess the use of observation status among Medicare beneficiaries with and without cancer. Methods: Population-based SEER-Medicare data were used to assess differences in the use of observation status between Medicare beneficiaries aged ≥66 years with and without cancer using a matched analysis (n=151,183 per cohort). We assessed the ratio of observation unit use to inpatient admission, between cancer and noncancer cohorts, and for patients diagnosed with breast, colon, lung, and prostate cancers. Poisson regression models were used to calculate observation rate estimates and 95% CIs while adjusting for selected patient characteristics. Results: When considering the volume of hospitalizations, observation status is used less frequently among beneficiaries with cancer than those without (43 vs 69 observation status visits per 1,000 inpatient admissions, respectively). The estimated observation rate per 1,000 inpatient admissions was higher for beneficiaries aged <75 years versus those aged ≥75 years, those with a Charlson comorbidity index of 0 vs 1 or ≥2, and those without a prior hospitalization versus those with ≥1 prior hospitalizations. Patients with breast and prostate cancers had higher adjusted and unadjusted observation rates per 1,000 inpatient admissions compared with those with colon and lung cancers. Conclusions: Observation status is used proportionately less for beneficiaries with cancer than those without. There may be opportunities to develop standards for ED staff to manage certain conditions for patients with cancer in observation status, and to reserve hospital resources for those who need it most.

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NCCN Guidelines Insights: Myeloproliferative Neoplasms, Version 2.2018

Myeloproliferative neoplasms (MPNs) are a group of heterogeneous disorders of the hematopoietic system that include myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). PV and ET are characterized by significant thrombohemorrhagic complications and a high risk of transformation to MF and acute myeloid leukemia. The diagnosis and management of PV and ET has evolved since the identification of mutations implicated in their pathogenesis. These NCCN Guideline Insights discuss the recommendations outlined in the NCCN Guidelines for the risk stratification, treatment, and special considerations for the management of PV and ET.

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Clinical Significance of Histologic Variants of Bladder Cancer

Pathologists have identified many "histologic variants" of bladder cancer (BCA): histologic patterns that differ from conventional urothelial carcinoma (transitional cell carcinoma). Several of these are biologically aggressive, and their identification may aid in clinical decision-making. This article reviews several histologic variants and their value in deciding management of cT1 disease and predicting response to neoadjuvant chemotherapy (NAC). Diagnostic issues are also addressed, such as interobserver variability among pathologists. For example, although stage cT1 conventional urothelial carcinoma is usually managed conservatively, cT1 micropapillary carcinoma has high mortality following conservative management, and early cystectomy may reduce mortality. Similarly, plasmacytoid and small cell cancers are remarkably aggressive, and those diagnosed as stage cT1 at transurethral resection are likely understaged; conservative management thus greatly risks undertreatment. As an example of response, NAC dramatically reduces mortality in patients with small cell BCA, and is thus the standard of care, even in stage cT1 disease. Although identification of histologic variants may inform on optimal management, diagnostic issues challenge their incorporation into clinical practice. For example, interobserver reproducibility is only moderate for the diagnosis of micropapillary BCA. Studies have identified specific histologic issues underlying this diagnostic irreproducibility, and ongoing work aims to remedy this issue. In summary, histologic variants are emerging as potentially useful biomarkers in the management of BCA. Although issues remain unresolved, pathologists and treating physicians will benefit from understanding these variants and their prognostic and therapeutic implications.

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The Senior Toronto Oncology Panel (STOP) Study: Research Participation for Older Adults With Cancer and Caregivers

Background: Patient engagement in research may lead to better-designed studies and improved health outcomes. The objectives of this study were to identify the research priorities of older adults with cancer (OAWCs) and their caregivers and examine how to engage these individuals in research teams and what supports are needed. Methods: We conducted 3 public meetings and 7 focus groups to delineate research priorities and the supports needed to facilitate integration of OAWCs and their caregivers on research teams. Results: A total of 33 older adults and 19 caregivers attended a public meeting and 27 older adults and 17 caregivers participated in a focus group. Most of the OAWCs and their caregivers had never participated in research before. Three themes were identified from the focus groups: (1) motivation to be on a team; (2) ability to make meaningful contributions; and (3) logistical considerations to facilitate engagement. Most participants were motivated to be a research team member and be involved in all steps of research if it could benefit them or future patients and caregivers. OAWCs and their caregivers were highly motivated to improve outcomes. Required logistics included flexibility regarding time and location, accessibility to computer technology, transportation support, materials worded in lay language, and attending/having short training sessions, as well as the presence of peer support. Conclusions: OAWCs and their caregivers are very motivated and willing to participate in research and to be research team members. Logistics and the social aspects of being on a team are important.

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Admission or Observation? Population Health Is Here

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Development, Validation, and Dissemination of a Breast Cancer Recurrence Detection and Timing Informatics Algorithm

Abstract

Background

This study developed, validated, and disseminated a generalizable informatics algorithm for detecting breast cancer recurrence and timing using a gold standard measure of recurrence coupled with data derived from a readily available common data model that pools health insurance claims and electronic health records data.

Methods

The algorithm has two parts: to detect the presence of recurrence and to estimate the timing of recurrence. The primary data source was the Cancer Research Network Virtual Data Warehouse (VDW). Sixteen potential indicators of recurrence were considered for model development. The final recurrence detection and timing models were determined, respectively, by maximizing the area under the ROC curve (AUROC) and minimizing average absolute error. Detection and timing algorithms were validated using VDW data in comparison with a gold standard recurrence capture from a third site in which recurrences were validated through chart review. Performance of this algorithm, stratified by stage at diagnosis, was compared with other published algorithms. All statistical tests were two-sided.

Results

Detection model AUROCs were 0.939 (95% confidence interval [CI] = 0.917 to 0.955) in the training data set (n = 3370) and 0.956 (95% CI = 0.944 to 0.971) and 0.900 (95% CI = 0.872 to 0.928), respectively, in the two validation data sets (n = 3370 and 3961, respectively). Timing models yielded average absolute prediction errors of 12.6% (95% CI = 10.5% to 14.5%) in the training data and 11.7% (95% CI = 9.9% to 13.5%) and 10.8% (95% CI = 9.6% to 12.2%) in the validation data sets, respectively, and were statistically significantly lower by 12.6% (95% CI = 8.8% to 16.5%, P < .001) than those estimated using previously reported timing algorithms. Similar covariates were included in both detection and timing algorithms but differed substantially from previous studies.

Conclusions

Valid and reliable detection of recurrence using data derived from electronic medical records and insurance claims is feasible. These tools will enable extensive, novel research on quality, effectiveness, and outcomes for breast cancer patients and those who develop recurrence.

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Tumor localization may change the type of adjuvant treatment in gastric cancer

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Reply to Tumor localization may change the type of adjuvant treatment in gastric cancer

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Antibiotic therapy, supportive treatment and management of immunomodulation-inflammation response in community acquired pneumonia: review of recommendations

Community-acquired pneumonia is a common and serious disease, with high rates of morbidity and mortality. Management and treatment of community-acquired pneumonia are described in three main documents: the 200...

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Reconstruction of a near total ear amputation with a neurosensorial radial forearm free flap prelaminated with porous polyethylene implant and delay procedure

When an auricular defect is caused by high-energy trauma that causes damage to the surrounding tissues, the patient may be not a candidate for reconstruction with local flaps and free tissue transfer may be necessary. Here we present a case of total auricular reconstruction in a 27 year-old man who had total loss of the left ear and traumatized temporal skin and fascia. A radial forearm flap prelaminated by a porous polyethylene implant was employed. A "printed" ear made of silicone, based on the patient's CT-scan of the contralateral ear, was used for intraoperative molding of the future reconstruction. Prolonged prelamination time and surgical delay (three months) were performed to reduce edema, distortion and loss of definition of the framework after revascularization. After subsequent integration and neovascularization of the added tissue, the prelaminated flap was transferred. Flap reinnervation was also performed by direct coaption of the great auricular nerve to the lateral antebrachial cutaneous nerve. The flap fully survived and there were no complications in the early postoperative period. Between 3 and 6 months, the patient returned to normal ranges in terms of warmth and cold, and recovered the discriminative facial sensibility. After one year the auricular reconstruction was intact and satisfactory aesthetic results were achieved. This method may offer a satisfactory solution for a difficult problem and may be considered for acquired total ear defects.

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miR-200c-3p spreads invasive capacity in human oral squamous cell carcinoma microenvironment

Abstract

Oral squamous cell carcinoma (OSCC) constitutes over 90% of all cancers in the oral cavity. The prognosis for patients with invasive OSCC is poor; therefore, it is important to understand the molecular mechanisms of invasion and subsequent metastasis not only to prevent cancer progression but also to detect new therapeutic targets against OSCC. Recently, extracellular vesicles—particularly exosomes—have been recognized as intercellular communicators in the tumor microenvironment. As exosomic cargo, deregulated microRNAs (miRNAs) can shape the surrounding microenvironment in a cancer-dependent manner. Previous studies have shown inconsistent results regarding miR-200c-3p expression levels in OSCC cell lines, tissues, or serum—likely because of the heterogeneous characters of the specimen materials. For this reason, single-cell clone analyses are necessary to effectively assess the role of exosome-derived miRNAs on cells within the tumor microenvironment. The present study utilized integrated microarray profiling to compare exosome-derived miRNA and exosome-treated cell-derived mRNA expression. Data were acquired from noninvasive SQUU-A and highly invasive SQUU-B tongue cancer cell clones derived from a single patient to determine candidate miRNAs that promote OSCC invasion. Matrigel invasion assays confirmed that hsa-miR-200c-3p was a key pro-invasion factor among six miRNA candidates. Consistently, silencing of the miR-200c-3p targets, CHD9 and WRN, significantly accelerated the invasive potential of SQUU-A cells. Thus, our data indicate that miR-200c-3p in exosomes derived from a highly invasive OSCC line can induce a similar phenotype in non-invasive counterparts. This article is protected by copyright. All rights reserved

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Biography—Hidenori Inohara

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Preface

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Serum tau and neurological outcome in cardiac arrest

Abstract

Objective: To test serum tau as a predictor of neurological outcome after cardiac arrest.

Methods: We measured the neuronal protein tau in serum at 24, 48, and 72 h after cardiac arrest in 689 patients in the prospective international Target Temperature Management trial. The main outcome was poor neurological outcome, defined as Cerebral Performance Category 3-5 at 6 months.

Results: Increased tau was associated with poor outcome at 6 months after cardiac arrest (median 38.5 [IQR 5.7-245] ng/L in poor versus 1.5 [0.7-2.4] ng/L in good outcome, for tau at 72 h, p<0.0001). Tau improved prediction of poor outcome compared to using clinical information (p<0.0001). Tau cut-offs had low false positive rates (FPR) for good outcome while retaining high sensitivity for poor outcome. For example, tau at 72 h had FPR 2% (95% CI 1-4%) with sensitivity 66% (95% CI 61-70%). Tau had higher accuracy than serum NSE (the area under the receiver operating characteristic curve was 0.91 for tau versus 0.86 for NSE at 72 hours, p=0.00024). During follow-up (up to 956 days), tau was significantly associated with overall survival. The accuracy to predict outcome by serum tau was equally high for patients randomized to 33°C and 36°C targeted temperature after cardiac arrest.

Interpretation: Serum tau is a promising novel biomarker for prediction of neurological outcome in patients with cardiac arrest. It may be significantly better than serum NSE, which is recommended in guidelines and currently used in clinical practice in several countries to predict outcome after cardiac arrest. This article is protected by copyright. All rights reserved.

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Pooled analysis of the HLA-DRB1 by smoking interaction in Parkinson's disease

ABSTRACT

Objective: Inflammatory response plays an important role in Parkinson's disease (PD). Previous studies have reported an association between human leukocyte antigen (HLA)-DRB1 and the risk of PD. There has also been growing interest in investigating whether inflammation-related genes interact with environmental factors such as smoking to influence PD risk. We performed a pooled analysis of the interaction between HLA-DRB1 and smoking in PD in three population-based case-control studies from Denmark and France.

Methods: We included 2,056 cases and 2,723 controls from three PD studies (Denmark, France) that obtained information on smoking through interviews. Genotyping of the rs660895 polymorphism in the HLA-DRB1 region was based on saliva or blood DNA samples. To assess interactions, we used logistic regression with product terms between rs660895 and smoking. We performed random-effects meta-analysis of marginal associations and interactions.

Results: Both carrying rs660895-G (AG vs. AA: OR= 0.81; GG vs. AA: OR= 0.56; p-trend=0.003) and ever smoking (OR=0.56, p<0.001) were inversely associated with PD. A multiplicative interaction was observed between rs660895 and smoking using codominant, additive (interaction parameter=1.37, p=0.005), and dominant (interaction parameter=1.54, p=0.001) genetic models without any heterogeneity (I²=0.0%): the inverse association of rs660895-(AG+GG) with PD seen in never smokers (OR=0.64, p<0.001) disappeared among ever smokers (OR=1.00, p=0.99). Similar interactions were observed when we investigated light and heavy smokers separately.

Interpretation: Our study provides the first evidence that smoking modifies the previously reported inverse association of rs660895-G with PD, and suggests that smoking and HLA-DRB1 are involved in common pathways, possibly related to neuroinflammation. This article is protected by copyright. All rights reserved.

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Mechanical and hypoxia stress can cause chondrocytes apoptosis through over-activation of endoplasmic reticulum stress

Publication date: December 2017
Source:Archives of Oral Biology, Volume 84
Author(s): Ziwei Huang, Min Zhou, Qian Wang, Mengjiao Zhu, Sheng Chen, Huang Li
ObjectiveTo examine the role of mechanical force and hypoxia on chondrocytes apoptosis and osteoarthritis (OA)-liked pathological change on mandibular cartilage through over-activation of endoplasmic reticulum stress (ERS).MethodsWe used two in vitro models to examine the effect of mechanical force and hypoxia on chondrocytes apoptosis separately. The mandibular condylar chondrocytes were obtained from three-week-old male Sprague–Dawley rats. Flexcell 5000T apparatus was used to produce mechanical forces (12%, 0.5Hz, 24h vs 20%, 0.5Hz, 24h) on chondrocytes. For hypoxia experiment, the concentration of O2 was down regulated to 5% or 1%. Cell apoptosis rates were quantified by annexin V and propidium iodide (PI) double staining and FACS analysis. Quantitative real-time PCR and western blot were performed to evaluate the activation of ERS and cellular hypoxia. Then we used a mechanical stress loading rat model to verify the involvement of ERS in OA-liked mandibular cartilage pathological change. Histological changes in mandibular condylar cartilage were assessed via hematoxylin & eosin (HE) staining. Immunohistochemistry of GRP78, GRP94, HIF-1α, and HIF-2α were performed to evaluate activation of the ERS and existence of hypoxia. Apoptotic cells were detected by the TUNEL method.ResultsTunicamycin, 20% mechanical forces and hypoxia (1% O2) all significantly increased chondrocytes apoptosis rates and expression of ERS markers (GRP78, GRP94 and Caspase 12). However, 12% mechanical forces can only increase the apoptotic sensitivity of chondrocytes. Mechanical stress resulted in OA-liked pathological change on rat mandibular condylar cartilage which included thinning cartilage and bone erosion. The number of apoptotic cells increased. ERS and hypoxia markers expressions were also enhanced. Salubrinal, an ERS inhibitor, can reverse these effects in vitro and in vivo through the down-regulation of ERS markers and hypoxia markers.ConclusionWe confirmed that mechanical stress and local hypoxia both contributed to the chondrocytes apoptosis. Mechanical stress can cause OA-like pathological change in rat mandibular condylar cartilage via ERS activation and hypoxia existed in the meantime. Both mechanical forces and hypoxia can induce ERS and cause chondrocytes apoptosis only if the stimulate was in higher level. Salubrinal can protect chondrocytes from apoptosis, and relieve OA-liked pathological change on mandibular condylar cartilage under mechanical stress stimulation.



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The Occipital Artery as an Alternative Donor for Low-Flow Bypass to Anterior Circulation After Internal Carotid Artery Occlusion Failure prior to Exenteration for an Atypical Cavernous Sinus Meningioma

Publication date: January 2018
Source:World Neurosurgery, Volume 109
Author(s): Shunya Hanakita, Stéphanie Lenck, Moujahed Labidi, Kentaro Watanabe, Damien Bresson, Sébastien Froelich
BackgroundIn skull base tumors involving the cavernous sinus, indications for aggressive resection are sparse and must be carefully examined because of their invasiveness. With careful evaluation, techniques including internal carotid artery sacrifice with or without extracranial-intracranial bypass may still be an option in some cases. Moreover, previous surgery with the sacrifice of potential donor vessels requires adjusting the revascularization strategy. We describe an occipital artery–middle cerebral artery bypass before skull base tumor resection.Case DescriptionA 47-year-old woman with a recurrent cavernous sinus meningioma was referred to our department. Because of tumor recurrence after radiotherapy and its rapid progression, radical resection, including part of the cavernous sinus, was planned. A balloon test occlusion was performed and showed good tolerance. An endovascular internal carotid artery occlusion was performed. The patient eventually experienced motor deficits and aphasia after surgery. Therefore, bypass surgery using an occipital artery–middle cerebral artery anastomosis was performed. The patient showed no exacerbation of symptoms after bypass surgery and subsequently underwent tumor resection.ConclusionsThe reliability of balloon test occlusion in the management of giant aneurysms may not be similarly applicable to skull base tumors. If hypoperfusion symptoms occur after occlusion of the internal carotid artery, a surgical revascularization procedure should be considered because of the risk of ischemic stroke following tumor resection. For patients whose superficial temporal artery is not available, the occipital artery can be a valuable alternative donor for low-flow bypass.



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Intraoperative Visualization of a Spinal Arachnoid Cyst Using Pyoktanin Blue

Publication date: January 2018
Source:World Neurosurgery, Volume 109
Author(s): Soichiro Takamiya, Toshitaka Seki, Kazuyoshi Yamazaki, Toru Sasamori, Kiyohiro Houkin
BackgroundSpinal arachnoid cysts (SACs) are filled with cerebrospinal fluid, and they include the arachnoid membrane, making it difficult to distinguish the walls of the cyst from the arachnoid membrane and excise the cyst as a lump. Here we report a technique for the intraoperative visualization of SACs, involving the use of pyoktanin blue.MethodsFour patients with spinal intradural arachnoid cysts underwent total excision of the cysts between October 2016 and April 2017. In 1 case, magnetic resonance imaging revealed the cyst clearly, but in the other cases, the cysts were unclear. All cysts were injected with 1% pyoktanin blue (Wako Pure Chemical Industries, Osaka, Japan) diluted 500 times with physiological saline before excision. When it was difficult to distinguish the cyst from the normal arachnoid membrane, 1% pyoktanin blue diluted 1000 times with physiological saline was injected into both the cyst and the subarachnoid space, and the spread of the stain was observed.ResultsThe cysts were better visualized after pyoktanin blue injection than before injection. When it was difficult to distinguish the cyst from the normal arachnoid space, pyoktanin blue injection was useful for judging the cyst space. There were no perioperative complications, and the patients' symptoms improved partially or completely after treatment.ConclusionsOur technique of pyoktanin blue injection into SACs could make their excision easy and safe.



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Accuracy of Pedicle Screw Insertion Among 3 Image-Guided Navigation Systems: Systematic Review and Meta-Analysis

Publication date: January 2018
Source:World Neurosurgery, Volume 109
Author(s): Jin Peng Du, Yong Fan, Qi Ning Wu, Dai Hua Wang, Jing Zhang, Ding Jun Hao
BackgroundMany retrospective studies of pedicle screw placement have revealed that intraoperative navigation systems provide higher accuracy rates and safety than do free-hand techniques. The accuracy of various image-guided navigation systems has been studied; however, differences have not been well defined due to the lack of adequate evidence-based comparative studies.ObjectiveA meta-analysis was conducted to focus on the variation in pedicle screw insertion among 3 navigation systems: a 3-dimensional fluoroscopy-based navigation system (3D FluoroNav), a 2-dimensional fluoroscopy-based navigation system (2D FluoroNav), and a conventional computed tomography navigation system (CT Nav).MethodsWe screened for comparative studies on different pedicle screw insertion navigation systems published through January 2017 using the Cochrane Library, Ovid, Web of Science, PubMed, and EMBASE databases.ResultsFrom 125 papers that were identified, 10 articles were finally chosen. The present comparative study included 8 retrospective clinical studies, 1 prospective clinical trial, and 1 randomized controlled cadaveric study. The prevalence rate of pedicle violation in the 3D FluoroNav group was significantly lower than the rates of the 2D FluoroNav group (relative risk [RR] 95%, confidence interval [CI]: 0.16–0.61, P < 0.01) and the CT Nav group (RR 95%, CI: 0.42–0.90, P = 0.01), and the rate of the CT Nav group was significantly lower than that of the 2D FluoroNav group (RR 95%, CI: 0.29–0.81, P < 0.01).ConclusionSignificant differences exist among CT Nav, 3D FluoroNav, and 2D FluoroNav. Our review suggests that 3D FluoroNav may be superior to the other 2 methods in reducing pedicle violation and that clinicians should consider 3D FluoroNav as a better choice.



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Pleomorphic fibroma of the skin with MDM2 immunoreactivity: a potential diagnostic pitfall

Abstract

Pleomorphic fibroma is a rare benign cutaneous neoplasm characterized by spindle-shaped cells and multinucleated giant cells scattered throughout collagenous stroma. These morphologic features can lead to diagnostic confusion, including atypical lipomatous tumor as one consideration. In contrast to atypical lipomatous tumor, previous studies have found pleomorphic fibroma to be negative for MDM2 immunohistochemical staining and MDM2 gene amplification. Here, we present a case of pleomorphic fibroma of skin with nuclear MDM2 immunoreactivity in the absence of MDM2 gene amplification, underscoring the superiority of fluorescence in situ hybridization as a diagnostic test in this differential diagnosis. The RB1 locus is also explored for differential diagnosis with pleomorphic / spindle cell lipoma and related entities.

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Efficient interplay effect mitigation for proton pencil beam scanning by spot-adapted layered repainting evenly spread out over the full breathing cycle

Publication date: Available online 4 October 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Per Rugaard Poulsen, John Eley, Ulrich Langner, Charles B. Simone, Katja Langen
PurposeTo develop and implement a practical repainting method for efficient interplay effect mitigation in proton pencil beam scanning (PBS).MethodsA new flexible repainting scheme with spot-adapted numbers of repaintings evenly spread out over the whole breathing cycle (here assumed to be 4s) was developed. Twelve fields from five thoracic and upper abdominal PBS plans were delivered three times with the new repainting scheme to an ion chamber array on a motion stage: once static and twice with 4s,3cm peak-to-peak sinusoidal motion with delivery started at maximum inhale and maximum exhale. For comparison, all dose measurements were repeated with no repainting and with 8 repaintings. For each motion experiment, the 3%/3mm gamma pass rate was calculated using the motion-convolved static dose as reference. Simulations were first validated with the experiments and then used to extend the study to 0-5cm motion magnitude, 2-6s motion periods, patient-measured liver tumor motion, and 1-6 fraction treatments. The effect of the proposed method was evaluated for the five clinical cases by 4D dose reconstruction in the planning 4DCT scan. The target homogeneity index, HI=(D2-D98)/Dmean, of a single fraction delivery was reported.ResultsThe gamma pass rates were 59.6±9.7% (no repainting), 76.5±10.8% (8 repaintings), and 92.4±3.8% (new repainting scheme). Simulations reproduced the experimental gamma pass rates with 1.3% root-mean-square error and demonstrated largely improved gamma pass rates with the new repainting scheme for all investigated motion scenarios. One- and two-fraction deliveries with the new repainting scheme had similar gamma pass rates as 3-4 and 6-fraction deliveries with 8 repaintings. The mean HI for the five test cases was 14.2% (no repainting), 13.7% (8 repaintings), 12.0% (new repainting scheme), and 11.6% (4D dose without interplay effects).ConclusionsA novel repainting strategy for efficient interplay effect mitigation was proposed, implemented, and shown to outperform conventional repainting in experiments, simulations and dose reconstructions. This strategy may allow for safe and more optimal clinical delivery of thoracic and abdominal proton PBS and better facilitate hypofractionated and stereotactic treatments.



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Consensus Contouring Guidelines for Post-Operative Completely Resected Cavity Stereotactic Radiosurgery (SRS) for Brain Metastases

Publication date: Available online 4 October 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Hany Soliman, Mark Ruschin, Lilyana Angelov, Paul D. Brown, Veronica L.S. Chiang, John P. Kirkpatrick, Simon S. Lo, Anita Mahajan, Kevin S. Oh, Jason P. Sheehan, Scott G. Soltys, Arjun Sahgal
PurposeCavity stereotactic radiosurgery (SRS) is an emerging treatment option after surgical resection of brain metastases. No guidelines for contouring the surgical cavity volume have been reported. The aim of this study was to propose contouring guidelines based on consensus contours generated by 10 international experts.MethodsTen post-operative completely resected cases with varying clinical scenarios and locations within the brain were selected. For each case, 10 experts independently contoured the surgical cavity clinical target volume (CTV). All the contours were analyzed and agreement was calculated using the Simultaneous Truth and Performance Level Estimation (STAPLE) with the kappa statistic. A follow-up survey was also completed by each investigator in order to summarize their contouring rationale based on a number of different clinical scenarios. Both the results from the survey and consensus STAPLE contours were summarized to establish contouring guidelines.ResultsThere was a high level of agreement between the expert CTV contours (mean sensitivity=0.75, mean specificity=0.98), and the mean kappa was 0.65. The agreement was statistically significant at p<0.001 for all cases. Based on these results and analyses of the survey answers, recommendations for CTV include: fusion of the pre-operative MRI to aid in volume delineation, contouring the entire surgical tract regardless of the preoperative location of the tumor, the CTV should be extended 5-10mm along the dura overlying the bone flap to account for microscopic disease extension in cases with preoperative dural contact, and a margin of up to 5mm into the adjacent sinus is sufficient when there is pre-operative venous sinus contact.ConclusionsConsensus contouring guidelines for post-operative completely resected cavity SRS treatment were established based on expert contours and clinical practice. However, in the absence of clinical data supporting the recommendations in this paper, these guidelines serve as a baseline for further study and refinement.



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Ipilimumab and early signs of pulmonary toxicity in patients with metastastic melanoma: a prospective observational study

Abstract

Ipilimumab, an immune checkpoint inhibitor, is approved for treatment metastastic melanoma and is a promising agent against other malignancies. There is some preliminary evidence from case reports that ipilimumab treatment may be associated with pulmonary side effects. However, data from prospective studies on ipilimumab-related pulmonary toxicity are still scarce. Serial spirometries and measurements of CO-diffusion capacity (DLCO) in patients with metastatic melanoma before and during treatment with ipilimumab were performed. A reduction from baseline of forced vital capacity (FVC) of ≥ 10%, or ≥ 15% of DLCO was defined as clinically meaningful and indicative for pulmonary toxicity. Of 71 patients included in this study, a clinically meaningful lung function decline was registered in 6/65 (9%), 5/44 (11%), and 9/38 (24%) patients after 3, 6, and 9 weeks of treatment initiation, respectively. Even after adjusting for age, concomitant melanoma treatment, progressive pulmonary metastases, and baseline pulmonary function values, mean ± SD DLCO decreased significantly during follow-up (−4.3% ± 13.6% from baseline, p = 0.033). Only 7% of patients reported respiratory symptoms. Clinically manifest ipilimumab-related pneumonitis was diagnosed only in one patient (1.4%). DLCO decline maybe an early indicator of subclinical pulmonary drug toxicity. Therefore, routine pulmonary function testing including DLCO measurement during treatment might help for risk stratification to screen for ipilimumab-related pneumonitis.

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Medication-Related Osteonecrosis of the Posterior Maxilla: Surgical Treatment Using a Combined Transnasal Endoscopic and Intraoral Approach, our experience with seven consecutive patients

Abstract

Upper jaw MRONJ if not correctly treated can lead to serious complication.

Upper jaw MRONJ is frequently associated with maxillary sinusitis, the disease can spread to other paranasal sinuses.

Combined approach is the most reliable procedure to treat odontogenic sinusitis; although MRONJ associated sinusitis is considered odontogenic there is no report in literature describing combined approach to treat MRONJ-induced sinusitis.

Buccal fat pad represents the best reconstructive option to close the bony defect.

BFPF does not allow rehabilitation through dental implant since it is adipose tissue and not bone tissue. However, guidelines do not recommend implant-supported prosthetic rehabilitation in patients with history of MRONJ so conventional dental rehabilitation should be carried out.

This article is protected by copyright. All rights reserved.

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Molecular identification of chromoblastomycosis clinical isolates in Guangdong

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Multi-azole-resistant strains of Cryptococcus neoformans var. grubii isolated from a FLZ-resistant strain by culturing in medium containing voriconazole

Abstract

A Cryptococcus neoformans var. grubii strain, NUBS14020, was the first fluconazole (FLZ)-resistant strain isolated from a feline cryptococcosis. Subsequent work demonstrated that multi-azole-resistant strains are readily isolated from FLZ-resistant strains by culturing in medium containing voriconazole (VRZ). The resulting clones were assessed for mutation and expression of known target genes, including the loci encoding lanosterol 14-α demethylase (ERG11), an ATP-binding cassette (ABC) transporter (AFR1), or a multidrug efflux pump (MEP); mutation and/or overexpression of these genes is known to be associated with azole resistance. We also examined the interaction between an efflux blocker (FK506, calcineurin inhibitor) and VRZ in the multi-azole-resistant strains. The ERG11 genes from multi-azole-resistant strains encoded a protein with a G344S substitution. Expression levels of AFR1, ERG11, and MEP in the multi-azole-resistant strains were not higher than those in the VRZ-susceptible parent strain (NUBS14020) when cultured in Sabourad's dextrose broth containing VRZ. Synergistic effects between FK506 and VRC were observed in all of the multi-azole-resistant strains. The minimal inhibitory concentrations (MICs) of the combination of VRZ and FK506 in multi-azole-resistant strains were 4 to 8 times lower that the MICs of VRZ alone. To the best of our knowledge, this work represents the first report that multi-azole-resistant strains of C. neoformans encode a G344S substitution in Erg11p. Further investigation will be needed to determine the mechanism of multi-azole resistance in C. neoformans, given that feline cryptococcosis due to multi- azole-resistant strains is readily transmitted from cats to humans.

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Erratum: Molecular identification of chromoblastomycosis clinical isolates in Guangdong

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In vitro susceptibility of Sporothrix brasiliensis : Comparison of yeast and mycelial phases

Abstract

Sporothrix brasiliensis has emerged as an important cause of sporotrichosis, particularly associated with feline and zoonotic cases. Owing to the paucity of data on antifungal activity against this species, the present study aimed to evaluate the in vitro susceptibility of clinical isolates of S. brasiliensis in the mycelial and yeast phases to itraconazole (ITZ), terbinafine (TRB), and amphotericin B (AMB). Thirty-five isolates from an outbreak of feline sporotrichosis in Southern Brazil were used. All of them were assessed in the yeast and filamentous phases using the broth microdilution technique in accordance with the respective reference protocols M27-A3 and M38-A2 of the Clinical and Laboratory Standards Institute (CLSI). In our study, TRB was the most active antifungal against both the filamentous and yeast phases, showing GM of the MIC of 0.343 μg/ml and 0.127 μg/ml, respectively. In the yeast phase, the GM of the MIC for TRB was significantly lower than that for both ITZ (P = .009) and AMB (P < .001). However, in the filamentous phase, the GM of the MIC for TRB was significantly lower than that of AMB (P < .001), but not different from that of ITZ (P = .091). AMB was the antifungal with the highest GM of the MIC for both phases (1.486 μg/ml for the filamentous phase and 0.660 μg/ml for the yeast). Our results may contribute to a better understanding of antifungal susceptibility profiles of clinical isolates of S. brasiliensis in the mycelial and yeast phases in further studies.

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