Gene expression signatures modulated by epidermal growth factor receptor activation and their relationship to cetuximab resistance in head and neck squamous cell carcinoma.

BACKGROUND: Aberrant activation of signaling pathways downstream of epidermal growth factor receptor (EGFR) has been hypothesized to be one of the mechanisms of cetuximab (a monoclonal antibody against EGFR) resistance in head and neck squamous cell carcinoma (HNSCC). To infer relevant and specific pathway activation downstream of EGFR from gene expression in HNSCC, we generated gene expression signatures using immortalized keratinocytes (HaCaT) subjected to ligand stimulation and transfected with EGFR, RELA/p65, or HRASVal12D. RESULTS: The gene expression patterns that distinguished the HaCaT variants and conditions were inferred using the Markov chain Monte Carlo (MCMC) matrix factorization algorithm Coordinated Gene Activity in Pattern Sets (CoGAPS). This approach inferred gene expression signatures with greater relevance to cell signaling pathway activation than the expression signatures inferred with standard linear models. Furthermore, the pathway signature generated using HaCaT-HRASVal12D further associated with the cetuximab treatment response in isogenic cetuximab-sensitive (UMSCC1) and -resistant (1CC8) cell lines. CONCLUSIONS: Our data suggest that the CoGAPS algorithm can generate gene expression signatures that are pertinent to downstream effects of receptor signaling pathway activation and potentially be useful in modeling resistance mechanisms to targeted therapies

Does Metabolism of (S)-N-[1-(3-Morpholin-4-ylphenyl)ethyl]-3-phenylacrylamide Occur at the Morpholine Ring? Quantum Mechanical and Molecular Dynamics Studies

The mechanism of Cytochrome P450 3A4 mediated metabolism of (S)-N- [1-(3-morpholin-4ylphenyl)ethyl]-3-phenylacrylamide and its difluoro analogue have been investigated by density functional QM calculations aided with molecular mechanics/molecular dynamics simulations. In this article, we mainly focus on the metabolism of the morpholine ring of substrates 1 and 2. The reaction proceeds via a hydrogen atom abstraction from the morpholine ring by Compound I on a doublet potential energy surface. A transition state was observed at an O-H distance of 1.46 Å for 1 while 1.38 Å for 2. Transition state for the rebound mechanism was not observed. The energy barrier for the hydrogen atom abstraction from 1 was found to be 7.01 kcal/mol in gas phase while 19.53 kcal/mol when the protein environment was emulated by COSMO. Similarly the energy barrier for substrate 2 was found to be 11.07 kcal/mol in gas phase while it was reduced to 12.99 kcal/mol in protein environment. Our previous study reported energy barriers for phenyl hydroxylation of 7.4 kcal/mol. Large energy barriers for morpholine hydroxylation indicates that hydroxylation at the phenyl ring may be preferred over morpholine. MD simulations in protein environment indicated that hydrogen atom at C4 position of phenyl ring remains in closer proximity to oxyferryl oxygen of the heme moiety as compared to morpholine hydrogen and hence greater chance to metabolize at phenyl ring

ハイ アスペルギローマ ジュツゴ ハイロウ ニ タイシテ PushampSlideホウ ト ロープウェイホウ オ オウヨウ シタ EWS ニヨル キカンシ ジュウテンジュツ ガ ユウヨウ デアッタ 1レイ

Background : Bronchial occlusion using endobronchial Watanabe Spigot（EWS）is reported to be useful for treatment of secondary intractable pneumothorax and thoracic empyema, peripheral bronchial fistula. However, the methods of the bronchial occlusion are sometimes difficult and EWS sometimes fall off from plugged bronchus. Case : A ４４ year old man presented hemosputum. He was diagnosed with Aspergilloma. We performed a resection of the right upper lobe and S６ partial resection. Air leak appeared at postoperative day ３. We performed EWS embolization with an application of push & slide method and the ropeway method, and the persistent air leak disappeared. Conclusion : Our method is useful when the bronchial occlusion is difficult

Feasibility of methotrexate discontinuation following tocilizumab and methotrexate combination therapy in patients with long-standing and advanced rheumatoid arthritis: a 3-year observational cohort study

Objectives: Methotrexate (MTX) is associated with extensive side effects, including myelosuppression, interstitial pneumonia, and infection. It is, therefore, critical to establish whether its administration is required after achieving remission with tocilizumab (TCZ) and MTX combination therapy in patients with rheumatoid arthritis (RA). Therefore, the aim of this multicenter, observational, cohort study was to evaluate the feasibility of MTX discontinuation for the safety of these patients. Methods: Patients with RA were administered TCZ, with or without MTX, for 3 years; those who received TCZ+MTX combination therapy were selected. After remission was achieved, MTX was discontinued without flare development in one group (discontinued [DISC] group, n = 33) and continued without flare development in another group (maintain [MAIN] group, n = 37). The clinical efficacy of TCZ+MTX therapy, patient background characteristics, and adverse events were compared between groups. Results: The disease activity score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) at 3, 6, and 9 months was significantly lower in the DISC group (P < .05, P < .01, and P < .01, respectively). Further, the DAS28-ESR remission rate at 6 and 9 months and Boolean remission rate at 6 months were significantly higher in the DISC group (P < .01 for all). Disease duration was significantly longer in the DISC group (P < .05). Furthermore, the number of patients with stage 4 RA was significantly higher in the DISC group (P < .01). Conclusions: Once remission was achieved, MTX was discontinued in patients who responded favorably to TCZ+MTX therapy, despite the prolonged disease duration and stage progression

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016)

Background and purposeThe Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in February 2017 and published in the Journal of JSICM, [2017; Volume 24 (supplement 2)] https://doi.org/10.3918/jsicm.24S0001 and Journal of Japanese Association for Acute Medicine [2017; Volume 28, (supplement 1)] http://onlinelibrary.wiley.com/doi/10.1002/jja2.2017.28.issue-S1/issuetoc.This abridged English edition of the J-SSCG 2016 was produced with permission from the Japanese Association of Acute Medicine and the Japanese Society for Intensive Care Medicine.MethodsMembers of the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine were selected and organized into 19 committee members and 52 working group members. The guidelines were prepared in accordance with the Medical Information Network Distribution Service (Minds) creation procedures. The Academic Guidelines Promotion Team was organized to oversee and provide academic support to the respective activities allocated to each Guideline Creation Team. To improve quality assurance and workflow transparency, a mutual peer review system was established, and discussions within each team were open to the public. Public comments were collected once after the initial formulation of a clinical question (CQ) and twice during the review of the final draft. Recommendations were determined to have been adopted after obtaining support from a two-thirds (> 66.6%) majority vote of each of the 19 committee members.ResultsA total of 87 CQs were selected among 19 clinical areas, including pediatric topics and several other important areas not covered in the first edition of the Japanese guidelines (J-SSCG 2012). The approval rate obtained through committee voting, in addition to ratings of the strengths of the recommendation, and its supporting evidence were also added to each recommendation statement. We conducted meta-analyses for 29 CQs. Thirty-seven CQs contained recommendations in the form of an expert consensus due to insufficient evidence. No recommendations were provided for five CQs.ConclusionsBased on the evidence gathered, we were able to formulate Japanese-specific clinical practice guidelines that are tailored to the Japanese context in a highly transparent manner. These guidelines can easily be used not only by specialists, but also by non-specialists, general clinicians, nurses, pharmacists, clinical engineers, and other healthcare professionals

Confirmation of the 8th edition of the AJCC/UICC TNM staging system for HPV-mediated oropharyngeal cancer in Japan

Background: Several studies have demonstrated that the 7th edition of the AJCC/UICC TNM staging classification system does not consistently distinguish between prognostic subgroups for human papillomavirus (HPV)-mediated oropharyngeal squamous cell carcinoma (OPSCC). The 8th edition of the AJCC/UICC TNM staging came into effect for use with HPV-mediated OPSCC on or after January 1, 2017. This study confirms that the 8th edition of the AJCC/UICC TNM staging system for HPV- mediated OPSCC accurately reflects disease outcomes. Patients and methods:We retrospectively analyzed 195 patients with OPSCC treated at Hokkaido University Hospital, Sapporo, Japan between 1998 and 2015. HPV status was evaluated by immunohistochemical analysis of p16. Results: Of the 195 OPSCC patients, 111 (56.9%) were p16 positive, and 84 (43.1%) were p16 negative. The 3-year overall survival rate (OS) was significantly lower in the p16-negative patients with stage III-IV in comparison with those with stage I-II (55.0% vs 93.1%, p<0.01). The 3-year OS did not differ significantly between stage I-II and stage III-IV in the p16-positive patients (86.7% vs 87.7%). According to the 8th edition of the AJCC/UICC TNM staging system, stage I-II and stage III could be differentiated on the basis of the 3-year OS in the p16-positive patients (90.9% vs 70.2%, p<0.01). Conclusions: The 7th edition of the AJCC/UICC TNM staging system is suitable for use with p16-negative patients; however, it does not effectively discriminate between p16-positive patients. Therefore, the 8th edition of the AJCC/UICC TNM staging system is more suitable for HPV-mediated OPSCC in Japan

Reliability and Validity of Speech Evaluation in Adductor Spasmodic Dysphonia

Objectives. In order to establish a reliable diagnostic tool for adductor spasmodic dysphonia (ADSD), it is necessary to determine the proper terms representing its characteristic voice symptoms and to relate them to objective measures such as acoustic parameters or speech perturbation. The aim of this study was to evaluate speech in patients with ADSD by perceptual evaluations and acoustic measures, and to examine the reliability and validity of the measures by comparison with normal controls. Methods. Twenty-four patients with ADSD and 24 healthy volunteers matched to the ADSD patients with regard to age and sex participated in the study. Speech materials, consisting of three short sentences, were constructed from serial voiced syllables to elicit abductor voice breaks. Three otolaryngologists specializing in phoniatrics rated the degree of voice symptoms using a visual analog scale (VAS). VAS sheets with five 100-mm horizontal lines were given to each rater. The ends of the lines were labeled normal versus severe, and the five lines were labeled as overall severity and each of the four voice symptoms; strangulation, interruption, tremor and strained speech. Nine words were selected from the speech materials for acoustic analysis, and abnormal acoustic events were classified into one of the three categories; percentage of frequency shifts, percentage of aperiodic segments, or percentage of phonation breaks. Acoustic measures were performed by a speech-language-hearing therapist specializing in voice disorders and five healthy university students. To evaluate the intra- and inter-rater/measurer reliability of the VAS scores or acoustic measures, Pearson r correlations were calculated. To examine the validity of perceptual evaluations and acoustic measures, the sensitivity, specificity, positive predictive value and negative predictive value were calculated. Results. Pearson r correlation coefficients for overall severity showed the highest intra- and inter-rater reliability, and reliability coefficients for one of the four voice symptoms, strangulation (r = 0.816-0.937), were slightly higher than those for the other symptoms. For acoustic events, intra-measurer reliabilities were r = 0.645 (frequency shifts), r = 0.969 (aperiodic segments), and r = 1.0 (phonation breaks), and inter-measurer reliability ranged from r = 0.102 to r = 1.0 (average r = 0.861). The Pearson r correlation coefficient for phonation breaks was higher than those for the other acoustic events. Perceptual evaluation using VAS showed high sensitivity (91.7 %) and specificity (100 %), and acoustic analysis showed low sensitivity (70.8 %) and high specificity (100 %). Eight of the 24 patients were judged to be within normal limits by one or both evaluation methods. Conclusions. Both perceptual evaluation and acoustic measures alone were found to be likely to miss true ADSD patients. It is important to obtain a range of speech materials and to use a combination of perceptual evaluation and acoustic measures based on our understanding of the advantages and disadvantages of both methods

Lymph node metastasis in the suprasternal space from thyroid papillary cancer

The suprasternal space is a narrow space between the superficial and deep layers of the investing layers of the deep cervical fascia above the manubrium of the sternum. The suprasternal space has been paid little attention as a space with the potential for lymph node metastasis from both thyroid cancer and head and neck cancer. We experienced 2 patients who were found to have a lymph node in the suprasternal space preoperatively. Both of them had well-differentiated thyroid papillary carcinomas and level III and IV lymph node metastases as well as metastasis in the suprasternal space. We have not previously dissected the suprasternal space prophylactically in other patients with thyroid papillary cancer, but no patient has developed metastasis in this space to date. The suprasternal space is not usually dissected in atients with thyroid cancer. However, suprasternal space metastasis has been reported to occur occasionally in patients with lymph node metastases in levels III and IV. We consider that dissection of the suprasternal space, which is not routinely performed, should be done when preoperative examination suggests lymph node metastasis in the suprasternal space as dissection of this space is less invasive, easy to achieve, and is not time consuming. Greater attention should be paid to the suprasternal space as an area with the otential for lymph node metastasis from thyroid cancer

Oncocytoma of the Parotid Gland with Facial Nerve Paralysis

Parotid gland tumor with facial nerve paralysis is strongly suggestive of a malignant tumor. However, several case reports have documented benign tumors of the parotid gland with facial nerve paralysis. Here, we report a case of oncocytoma of the parotid gland with facial nerve paralysis. A 61-year-old male presented with pain in his right parotid gland. Physical examination demonstrated the presence of a right parotid gland tumor and ipsilateral facial nerve paralysis of House–Brackmann (HB) grade III. Due to the facial nerve paralysis, a malignant tumor of the parotid gland was suspected and right parotidectomy was performed. Oncocytoma was confirmed histopathologically. The facial nerve paralysis was resolved 2 months after surgery. During the follow-up period (one and a half years), no recurrence was observed. As the tumor showed a distinctive dumbbell shape and increased somewhat due to inflammation (i.e., infection), the facial nerve was pinched by the enlarged tumor. Ischemia and strangulation of the nerve were considered to be the cause of the facial nerve paralysis associated with the benign tumor in this case