OtoRhinoLaryngology News: 10/16/17

Δευτέρα 16 Οκτωβρίου 2017

Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14 C-microtracer and therapeutic dose in cancer patients

Abstract

Introduction

Niraparib (Zejula™) is a poly(ADP-ribose) polymerase inhibitor recently approved by the US Food and Drug Administration for the maintenance treatment of patients with recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. The pivotal phase III clinical trial has shown improved progression-free survival in patients receiving niraparib compared with those receiving placebo.

Purpose

Since niraparib is administered orally, it is of interest to investigate the oral bioavailability (F _po) of this novel compound, which is the aim of this study.

Methods

Six patients received an oral therapeutic dose of 300 mg niraparib, followed by a 15-min intravenous infusion of 100 µg ¹⁴C-niraparib with a radioactivity of approximately 100 nCi. The niraparib therapeutic dose was measured in plasma using a validated liquid chromatography–tandem mass spectrometry method, whereas the total ¹⁴C-radioactivity and ¹⁴C-niraparib plasma levels were measured by accelerator mass spectrometry and a validated high performance liquid chromatography assay with AMS.

Results

The F _po of niraparib was determined to be 72.7% in humans.

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Population pharmacokinetics of trastuzumab emtansine in previously treated patients with HER2-positive advanced gastric cancer (AGC)

Abstract

Purpose

Ado-trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising trastuzumab conjugated via a stable thioether linker to DM1, a highly potent cytotoxic agent. A population pharmacokinetics (PK) analysis was performed to characterize T-DM1 PK and evaluate the impact of patient characteristics on T-DM1 PK in previously treated patients with HER2-positive advanced gastric cancer (AGC).

Methods

Following T-DM1 weekly or every three weeks dosing, T-DM1 concentration measurements (n = 780) were collected from 136 patients in the GATSBY (NCT01641939) study and analyzed using nonlinear mixed effects modeling. The influence of demographic, baseline laboratory, and disease characteristics on T-DM1 PK was examined.

Results

T-DM1 PK was best described by a two-compartment model with parallel linear and nonlinear (Michaelis–Menten) elimination from the central compartment. The final population model estimated linear clearance (CL) of 0.79 L/day, volume of distribution in the central compartment (V _c) of 4.48 L, distribution clearance (Q) of 0.62 L/day, volume of distribution in the peripheral compartment (V _p) of 1.49 L, nonlinear CL of 2.06 L/day, and KM of 1.63 μg/mL. Parameter uncertainty was low to moderate for fixed effects, except KM (estimated with poor precision). Patients with high body weight and low baseline trastuzumab concentrations had significantly faster linear CL; those with higher body weight had significantly larger V _c.

Conclusions

In a HER2-positive AGC population, T-DM1 PK was best described by a two-compartment model with parallel linear and nonlinear elimination. Baseline body weight and trastuzumab concentration were identified as significant covariates for T-DM1 PK in a HER2-positive AGC population.

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Cholecystokinin receptor antagonist alters pancreatic cancer microenvironment and increases efficacy of immune checkpoint antibody therapy in mice

Abstract

Advanced pancreatic ductal adenocarcinoma (PDAC) has typically been resistant to chemotherapy and immunotherapy; therefore, novel strategies are needed to enhance therapeutic response. Cholecystokinin (CCK) has been shown to stimulate growth of pancreatic cancer. CCK receptors (CCKRs) are present on pancreatic cancer cells, fibroblasts, and lymphocytes. We hypothesized that CCKR blockade would improve response to immune checkpoint antibodies by promoting influx of tumor-infiltrating lymphocytes (TILs) and reducing fibrosis. We examined the effects of CCKR antagonists or immune checkpoint blockade antibodies alone or in combination in murine models of PDAC. Monotherapy with CCKR blockade significantly decreased tumor size and metastases in SCID mice with orthotopic PDAC, and in C57BL/6 mice, it reduced fibrosis and induced the influx of TILs. Immune-competent mice bearing syngeneic pancreatic cancer (Panc02 and mT3-2D) that were treated with the combination of CCK receptor antagonists and immune checkpoint blockade antibodies survived significantly longer with smaller tumors. Tumor immunohistochemical staining and flow cytometry demonstrated that the tumors of mice treated with the combination regimen had a significant reduction in Foxp3+ T-regulatory cells and an increase in CD4+ and CD8+ lymphocytes. Masson's trichrome stain analysis revealed 50% less fibrosis in the tumors of mice treated with CCKR antagonist compared to controls and compared to checkpoint antibody therapy. CCKR antagonists given with immune checkpoint antibody therapy represent a novel approach for improving survival of PDAC. The mechanism by which this combination therapy improves the survival of PDAC may be related to the decreased fibrosis and immune cells of the tumor microenvironment.

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Editorial Board

Publication date: October 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, Volume 124, Issue 4

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Society Page

Information for Readers

The insufficient integration of medicine into clinical dental education: a missed opportunity or an ethical dilemma?

Publication date: October 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, Volume 124, Issue 4
Author(s): Jeffrey Bennett

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3-D computed tomography measurement of mandibular growth after costochondral grafting in growing children with temporomandibular joint ankylosis and jaw deformity

Publication date: October 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, Volume 124, Issue 4
Author(s): Jieyun Zhao, Dongmei He, Chi Yang, Chuan Lu, Yihui Hu, Dong Huang, Edward Ellis
ObjectiveThe aim of this study was to evaluate the long-term results after costochondral grafting (CCG) in growing children with temporomandibular joint ankylosis and jaw deformity by 3-dimensional computed tomography (CT) measurement.Study DesignPatients with unilateral TMJ ankylosis and jaw deformity treated by CCG from 2010 to 2014 were evaluated. Their CT data within 1 week after operation and after at least 2 years of follow-up were analyzed using ProPlan CMF 1.4 software. Maximal incisal opening (MIO), condyle–ramus heights, chin deviation, and growth of CCG were measured and compared before and after the operation and at the last follow-up. SPSS 17.0 software was used for statistical analysis.ResultsSeven patients were included in the study. The mean follow-up period was 46.4 months. Five of 7 patients treated with this protocol experienced good mouth opening and symmetric mandibular growth. One patient achieved good mouth opening but not symmetric growth, and 1 patient experienced ankylosis again.ConclusionsCCG can be a reliable method to treat temporomandibular joint ankylosis with jaw deformity in growing children. Continued growth occurs in the children, but long-term outcomes require further investigation.

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Comparative analysis of imaging techniques for diagnostic accuracy of peri-implant bone defects: a meta-analysis

Publication date: October 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, Volume 124, Issue 4
Author(s): Lauren Oliveira Lima Bohner, Eduardo Mukai, Elisa Oderich, André Luís Porporatti, Camila Pacheco-Pereira, Pedro Tortamano, Graziela De Luca Canto
ObjectiveThe aim of this study was to systematically review the literature regarding diagnostic accuracy of imaging techniques in detecting peri-implant bone defects.Study DesignThe search was performed in 8 electronic databases from April to May 2016 and updated in September 2016. Studies that assessed imaging techniques to detect peri-implant bone defects were analyzed.ResultsThe search yielded 680 articles published from 1991 to 2016. Of these, 12 studies were considered eligible for this review. The selected studies evaluated the use of cone beam computed tomography (CBCT), intraoral radiography (IR), computed tomography, and panoramic radiography. The sensitivity for CBCT was 59%, whereas the specificity was 67%. For IR, the sensitivity was 60%, and the specificity was 59%. Area under the curve values in receiver operating characteristic (ROC) analysis were 69% for CBCT and 63% for IR. For CBCT, the highest value for positive predictive value was 0.94, negative predictive value was 0.98, positive likelihood ratio was 21.3, and negative likelihood ratio was 1.28. For IR, the highest positive predictive value was 1.0, negative predictive value 1.0, positive likelihood ratio 50.0, and negative likelihood ratio 0.70. The highest diagnostic odds ratio was 80 for CBCT and 4.45 for IR. No conclusion could be drawn for additional techniques.ConclusionsBoth CBCT and IR showed a clinically acceptable performance for assessing peri-implant bone defects.

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Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14 C-microtracer and therapeutic dose in cancer patients

Abstract

Introduction

Purpose

Since niraparib is administered orally, it is of interest to investigate the oral bioavailability (F _po) of this novel compound, which is the aim of this study.

Methods

Results

The F _po of niraparib was determined to be 72.7% in humans.

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Population pharmacokinetics of trastuzumab emtansine in previously treated patients with HER2-positive advanced gastric cancer (AGC)

Abstract

Purpose

Methods

Results

Conclusions

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Cholecystokinin receptor antagonist alters pancreatic cancer microenvironment and increases efficacy of immune checkpoint antibody therapy in mice

Abstract

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DDR2 and IFITM1 Are Prognostic Markers in Gallbladder Squamous Cell/Adenosquamous Carcinomas and Adenocarcinomas

Abstract

This study was conducted to investigate the expressions of DDR2 and IFITM1 and their clinical and pathological significances in the rare type squamous cell/adenosquamous carcinomas (SC/ASC) and ordinary adenocarcinomas (AC) of gallbladder cancers. DDR2 and IFITM1 expression was examined in 69 SC/ASCs and 146 ACs using EnVision immunohistochemistry. Results showed that the percentage of positive DDR2 and IFITM1 expression was significantly higher in SC/ASC patients with high TNM stage, lymph node metastasis, invasion, and no resection surgery compared to patients with low TNM stages, no lymph node metastasis, no invasion, and resection surgery (P < 0.05 or P < 0.01). The positive rate of DDR2 was significantly higher in SC/ASC patients with large tumor sizes than patients with small tumor sizes (p < 0.05). The percentage of positive DDR2 and IFITM1 expressions was significantly higher in AC patients with high TNM stages that didn't receive resection surgery compared to patients with low TNM stages that did receive resection surgery (P < 0.05 or P < 0.01). The positive rate of IFITM1 was significantly higher in AC patients with lymph node metastasis and invasion than in patients without metastasis and invasion (p < 0.05). Positive DDR2 and IFITM1 expression was closely associated with a decreased overall survival in SC/ASC and AC patients (P < 0.05 or P < 0.01). AUC analysis showed that DDR2 and IFITM1 was sensitive and specific for the diagnosis of SC/ASC (AUC = 0.740 and AUC =0.733, respectively) and AC (AUC = 0.710 and AUC =0.741, respectively). In conclusion, positive DDR2 and IFITM1 expression is a marker for the clinical severity, poor prognosis, and diagnosis of gallbladder SC/ASC and AC.

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Is There a Link between Defects of Thyroid Hormonogenesis and Morphogenesis?

Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 389-391.

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Most Low-Risk Papillary Thyroid Cancers Remain Stable During Active Surveillance

Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 368-370.

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Ultrasound Has a Role in Predicting Tumor Invasiveness in Follicular Variant of Papillary Thyroid Carcinoma

Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 371-374.

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Hypothyroidism in the Differential Diagnosis of Hyponatremia — A Clinical Pearl in Peril

Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 395-397.

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A 10-Gene Classifier Can Accurately Diagnose Malignant Versus Benign Cytologically Indeterminate Thyroid Nodules

Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 375-377.

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Mortality May Be Higher in Older Patients Whose Levels of TSH and Free T4 Are More Variable

Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 385-388.

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Tumor-Volume–Doubling Time of Pulmonary Metastases in Follicular-Cell–Derived Thyroid Carcinoma May Allow More Appropriate Selection of Patients for Multikinase Inhibitor Therapy

Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 378-381.

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Exposure to Flame Retardants Is Inconsistently Associated with Papillary Thyroid Cancer

Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 392-394.

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Subclinical Hyperthyroidism with Serum TSH

Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 382-384.

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Thyroid Cancer Tumor Board: To Surveil or Not to Surveil? That Is the Question

Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 398-400.

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Issue Information

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Correction to: Functional and quality of life outcomes after partial glossectomy: a multi-institutional longitudinal study of the head and neck research network

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Topical propranolol improves epistaxis in patients with hereditary hemorrhagic telangiectasia - a preliminary report

Abstract

Background

Severe epistaxis is often difficult to control in patients with hereditary hemorrhagic telangiectasia (HHT). Propranolol has been shown to have antiangiogenic properties in vitro and in vivo and is commonly used to treat hemangiomas. We present our experience with topical nasal propranolol for the treatment of moderate to severe epistaxis in patients with HHT.

Methods

Retrospective case series. Six patients with HHT were treated with 0.5 cm³ of 1.5% propranolol gel, applied to each nostril twice daily for at least 12 weeks. Outcome measures were epistaxis severity score (ESS), hemoglobin level, and number of blood transfusions prior to and while on treatment. Local and systemic side effects were recorded.

Results

The mean duration of treatment was 30 ± 5.6 weeks. A significant improvement in the ESS was found in all patients, with a mean decrease from 6.4 ± 2.1 at treatment onset to 3.5 ± 1.7 at 12 weeks (p = 0.028). Hemoglobin level increased significantly from 8.4 ± 3.1 to 11.0 ± 1.8 g/dL at 12 weeks (p = 0.043). The mean number of blood transfusions decreased from 4.5 ± 4.9 before treatment to 2.5 ± 2.9 at 12 weeks and 0.3 ± 0.8 at 24 weeks, but the difference did not reach statistical significance (p = 0.109 for both). No significant side effects of treatment were recorded.

Conclusions

These preliminary results suggest that topical propranolol may be effective for the treatment of epistaxis in patients with HHT. A prospective controlled trial is required to confirm our findings.

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Paradigm shift in head and neck oncology patient management

Abstract

Objective

This article describes a paradigm shift in what is considered to be good care for patients living with and after (head and neck) cancer. HNO patients often experience severe and difficult physical and psychosocial problems due to the nature and location of the disease. Many disciplines are involved in their treatment, so their voice is only one amongst many others in the decision making process. For this patient group it seems complicated to put the concept of Shared Decision Making into practice. As a step in this direction, patient reported outcomes which ask patients to select the disconcerting issues and symptoms can be used as a basis for referral, supportive care and treatment decision making. We need to provide more tailored and personalized information that is specific to individual circumstances, preferences and concerns and focuses more on the impact of treatment and access to help and support. Follow up of these patients should be concentrated on both medical and emotional aspects.

Practice implications

A shift in the way caregivers provide their information contributes to a more profound involvement of patients in treatment decisions.

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A filamentous bacteriophage targeted to carcinoembryonic antigen induces tumor regression in mouse models of colorectal cancer

Abstract

Colorectal cancer is a deadly disease, which is frequently diagnosed at advanced stages, where conventional treatments are no longer effective. Cancer immunotherapy has emerged as a new form to treat different malignancies by turning-on the immune system against tumors. However, tumors are able to evade antitumor immune responses by promoting an immunosuppressive microenvironment. Single-stranded DNA containing M13 bacteriophages are highly immunogenic and can be specifically targeted to the surface of tumor cells to trigger inflammation and infiltration of activated innate immune cells, overcoming tumor-associated immunosuppression and promoting antitumor immunity. Carcinoembryonic antigen (CEA) is highly expressed in colorectal cancers and has been shown to promote several malignant features of colorectal cancer cells. In this work, we targeted M13 bacteriophage to CEA, a tumor-associated antigen over-expressed in a high proportion of colorectal cancers but largely absent in normal cells. The CEA-targeted M13 bacteriophage was shown to specifically bind to purified CEA and CEA-expressing tumor cells in vitro. Both intratumoral and systemic administration of CEA-specific bacteriophages significantly reduced tumor growth of mouse models of colorectal cancer, as compared to PBS and control bacteriophage administration. CEA-specific bacteriophages promoted tumor infiltration of neutrophils and macrophages, as well as maturation dendritic cells in tumor-draining lymph nodes, suggesting that antitumor T-cell responses were elicited. Finally, we demonstrated that tumor protection provided by CEA-specific bacteriophage particles is mediated by CD8⁺ T cells, as depletion of circulating CD8⁺ T cells completely abrogated antitumor protection. In summary, we demonstrated that CEA-specific M13 bacteriophages represent a potential immunotherapy against colorectal cancer.

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Quantification of altered tissue turnover in a liquid biopsy: a proposed precision medicine tool to assess chronic inflammation and desmoplasia associated with a pro-cancerous niche and response to immuno-therapeutic anti-tumor modalities

Abstract

Immuno-therapy has begun to revolutionize cancer treatment. However, despite the significant progress achieved in regard to the duration of clinical benefits, a substantial number of patients do not respond to these therapies. To improve the outcome of patients receiving immuno-therapy, there is a need for novel biomarkers that can predict and monitor treatment. Tumor microenvironment alterations, more specifically the state of chronic inflammation and desmoplasia (tumor fibrosis), are important factors to consider in this context. Here, we discuss the potential for quantification of altered tissue turnover in a liquid biopsy as a proposed precision medicine tool to assess chronic inflammation and desmoplasia in the immuno-oncology (IO) setting. We highlight the need for novel non-invasive biomarkers in IO and the importance of addressing tumor microenvironment alterations. We focus on desmoplasia and extracellular matrix (ECM) remodeling, and how the composition of the ECM defines T-cell permissiveness in the tumor microenvironment and opens up the possibility for associated liquid biopsy biomarkers. Moreover, we address the importance of the assessment of chronic inflammation, primarily macrophage activity, in a liquid biopsy.

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Characterization of arthralgia induced by PD-1 antibody treatment in patients with metastasized cutaneous malignancies

Abstract

Background

PD-1 antibodies (PD1ab) are increasingly used in metastatic melanoma and other malignancies. Arthralgia is an underestimated side effect of PD-1 antibody treatment with unknown cause. Our aim was to characterize PD1ab-induced arthralgia.

Patients and methods

We retrospectively included patients with metastatic cutaneous malignancies treated with pembrolizumab or nivolumab ± ipilimumab at the National Center for Tumor Diseases (Heidelberg) between 01/2013 and 09/2016. Arthralgia was characterized by laboratory diagnostics, imaging, and if indicated, rheumatologic consultation.

Results

26 of 195 patients (13.3%) developed arthralgia. The median onset of symptoms was 100 days (7–780 days). Most frequently, arthralgia involved large joints (shoulders, knees) in a predominantly symmetrical pattern. Only two patients were seropositive for rheumatoid factor and/or anti-citrullinated protein antibodies. Ten patients developed the clinical picture of arthritis, with seven of them showing synovitis in MRI or PET/CT. Five patients showed inflammation in joints pre-damaged by osteoarthritis. In 11 patients arthralgia could not be specified. The majority of patients was satisfactorily treated with non-steroidal anti-inflammatory drugs (NSAIDs), 23.1% required additional low-dose corticosteroids and only 7.6% of our patients received further immunosuppressive treatment. Patients with arthralgia showed a better treatment response and improved PFS and OS.

Conclusion

Arthralgia is frequent during PD1ab treatment. The clinical picture varies between synovitis of predominantly large joints, progressive osteoarthritis and arthralgia without evident joint damage. Vast majority of cases can be satisfactorily managed by NSAID and/or low-dose corticosteroids.

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Safety of shortened infusion times for combined ipilimumab and nivolumab

Abstract

Background

Combined ipilimumab and nivolumab induces encouraging response rates in patients with unresectable or metastatic melanoma. However, the approved protocol for dual checkpoint inhibition (3 mg/kg ipilimumab over 90 min and 1 mg/kg nivolumab over 60 min) is time-intensive and several trials have shown that both single agents can be safely administered at faster infusion rates.

Aim

To investigate whether combined checkpoint inhibition with 3 mg/kg ipilimumab and 1 mg/kg nivolumab can be safely administered over 30 min per agent.

Patients and methods

We reviewed the rate of infusion-related reactions (IRRs) in the first 12 months of our single-institution experience using shortened infusion times for combined checkpoint inhibition with ipilimumab and nivolumab.

Results

Between May 24, 2016 and June 10, 2017, a total of 46 melanoma patients received 100 shortened cycles of combined 3 mg/kg ipilimumab and 1 mg/kg nivolumab. One patient (2.2%; 1/46) had a questionable reaction after administration of 1 mg/kg nivolumab over 30 min, but none of the other patients had a bona fide IRR.

Conclusions

Shortened infusion times for combined ipilimumab and nivolumab treatment are safe, thereby facilitating a more efficient use of outpatient facilities and enhancing patient's convenience.

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Tumor-infiltrating immune cells as potential biomarkers predicting response to treatment and survival in patients with metastatic melanoma receiving ipilimumab therapy

Abstract

Monoclonal antibodies targeting immune checkpoints are gaining ground in the treatment of melanoma and other cancers, and considerable effort is made to identify biomarkers predicting the efficacy of these therapies. Our retrospective study was performed on surgical tissue samples (52 lymph nodes and 34 cutaneous/subcutaneous metastases) from 30 patients with metastatic melanoma treated with ipilimumab. Using a panel of 11 antibodies against different immune cell types, intratumoral immune cell densities were determined and evaluated in relation to response to ipilimumab treatment and disease outcome. For most markers studied, median immune cell densities were at least two times higher in lymph node metastases compared to skin/subcutaneous ones; therefore, the prognostic and predictive associations of immune cell infiltration were evaluated separately in the two groups of metastases as well as in all samples as a whole. Higher prevalence of several immune cell types was seen in lymph node metastases of the responders compared to non-responders, particularly FOXP3⁺ cells and CD8⁺ T lymphocytes. In subcutaneous or cutaneous metastases, on the other hand, significant difference could be observed only in the case of CD16 and CD68. Associations of labeled cell densities with survival were also found for most cell types studied in nodal metastases, and for CD16⁺ and CD68⁺ cells in skin/s.c. metastatic cases. Our results corroborate the previous findings suggesting an association between an immunologically active tumor microenvironment and response to ipilimumab treatment, and propose new potential biomarkers for predicting treatment efficacy and disease outcome.

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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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Immunological classification of renal cell carcinoma patients based on phenotypic analysis of immune check-point molecules

Abstract

Objectives

To clarify comprehensive immunological signature patterns of tumour tissue-infiltrating lymphocytes in patients with renal cell carcinoma and show its clinical significance.

Materials and methods

We investigated the surface marker expressions of tumour tissue-infiltrating lymphocytes quantitatively and classified them based on their functional populations. We extracted 109 sets of tumour tissue-infiltrating lymphocytes from 80 patients who underwent surgical resection of renal cell carcinoma, of which 44 tumour tissue-infiltrating lymphocytes were multiply extracted from 15 patients. Each tumour tissue-infiltrating lymphocyte was characterised on the basis of functional T-cell populations using ten surface marker expressions measured by flow cytometry.

Results

All sets of the tumour tissue-infiltrating lymphocytes were classified into three groups, which correlated significantly with Fuhrman grade (OR 0.253, 95% CI 0.094–0.678, P = 0.006). Importantly, both overall metastasis-free survival (HR 0.449, 95% CI 0.243–0.832, P = 0.011) and recurrence-free survival (HR 0.475, 95% CI 0.238–0.948, P = 0.035) of the patients with the higher marker expressions were significantly inferior to those of the patients with the lower marker expressions by multivariate analysis. Six specific genes for this classification identified by microarray analysis verified our results using the TCGA KIRC data set. In addition, we discovered the presence of intra-tumoural diversity in the classification of 3 (20%) of the 15 patients.

Conclusions

This study showed that the presence of classable diversity in the immunological signature of tumour tissue-infiltrating lymphocytes correlated with prognosis and tumour aggressiveness that was observed even within individual tumours in some patients with renal cell carcinoma.

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Rectal Cancer in Asian vs. Western Countries: Why the Variation in Incidence?

Opinion statement

Colorectal cancer (CRC) is the third most common cancer worldwide. CRC has been thought to be less common in Asia compared to Western countries. However, the incidence rates of CRC in Asia are high and there is an increasing trend in the Asian population. Furthermore, colorectal cancer accounts for the greatest number of all incidences of CRC in Asia. The increasing adoption of a Western lifestyle, particularly in dietary habits, is likely the most important factor contributing to the rapid increase in colon cancer incidence; it is noteworthy that trends for rectal cancer were flat. The etiology of colon and rectal cancer is a bit different. The risks of distal colon and rectal cancers are more likely to be related to environmental factors, such as polluted surface water sources, alcohol consumption, and habitual smoking. The lack of great change in the incidence of rectal cancer might be due to weaker associations with such lifestyle factors. Therefore, it has been hypothesized that proximal and distal sections of the colon and rectum are two different organs in terms of function and genetic background. It may mean differences in differential sensitivities and exposures to carcinogens. However, despite the decrease in whole incidence, the CRC incidence in young adults in Western countries are reversely increasing, especially in rectal cancer, due to reasons largely unknown. Although the treatment algorithm is different between Asia and western countries, globally, the survival rate for patients with rectal cancer has risen during the past 10 years. Screening contributes a great deal to reducing the incidence and improving survival. Most countries in Asia, such as China, need nationwide registration and screening systems to provide better data.

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Reply to the Letter by S. Sorscher Regarding “Implications of BRAF Mutations in dMMR Colorectal Cancers”

Abstract

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Sentinel Lymph Node Biopsy in Endometrial Cancer: a New Standard of Care?

Opinion statement

Lymph node status is one of the most important factors in determining prognosis and the need for adjuvant treatment in endometrial cancer (EMCA). Unfortunately, full lymphadenectomy bears significant surgical and postoperative risks. The majority of patients with clinical stage I disease will not have metastatic disease; thus, a full lymphadenectomy only increases morbidity in this population of patients. The use of the sentinel lymph node (SLN) biopsy has emerged as an alternative to complete lymphadenectomy in EMCA. By removing the highest yield lymph nodes, the SLN biopsy has the same diagnostic ability as lymphadenectomy while minimizing morbidity. The sensitivity of sentinel lymph node identification with robotic fluorescence imaging for detecting metastatic endometrial and cervical cancer (FIRES) trial published this year is the largest prospective, multi-institution trial investigating the accuracy of the SLN biopsy for endometrial and cervical cancer. Results of this trial found an excellent sensitivity (97.2%) and false negative rate (3%) with the technique. The conclusions from the FIRES trial and those of a recent meta-analysis are that SLN biopsy has an acceptable diagnostic accuracy in detecting lymphatic metastases, and can replace lymphadenectomy for this diagnostic purpose. There remains controversy surrounding the SLN biopsy in high-risk disease and the use of adjuvant therapy in the setting of low volume disease detected with ultrastaging. Current data suggests that the technique is accurate in high-risk disease and that the increased detection of metastasis helps guide adjuvant therapy such that oncologic outcomes are likely not affected by forgoing a full lymphadenectomy. Further prospective study is needed to investigate the impact of low volume metastatic disease on oncologic outcomes and the need for adjuvant therapy in these patients.

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Management of Atypical Renal Cell Carcinomas

Opinion statement

Non-clear cell renal cell carcinoma (RCC) encompasses a diverse group of diseases, with research yielding different histologic findings and genetic profiles with each distinct subgroup. Simply mirroring the management techniques of clear cell RCC and borrowing from its growing armamentarium of therapeutic agents, while somewhat productive at first, but will ultimately be limiting. Further investigation into the molecular pathogenesis of disease, similarities and differences between specific subtypes, and mechanisms of resistance to therapeutics will help identify new targets, stimulate development of novel agents, and improve clinical trial offerings for non-clear cell RCC (nccRCC). As nccRCC has been largely excluded from past trials, there will be a need for future trials to be designed either to evaluate nccRCC specifically, or to include nccRCC as a prespecified subgroup. Multi-center collaborative trials should be supported, as many of the nccRCC subtypes are rare and remain underrepresented even within the construct of trials that only enroll nccRCC. Given the absence of clear molecular targets at present, patients with metastatic nccRCC should be offered and encouraged enrollment on clinical studies whenever possible.

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Enabling Development of Paediatric Medicines in Europe: 10 Years of the EU Paediatric Regulation

Abstract

The year 2017 marks the tenth anniversary of entry into force of the Paediatric Regulation in the European Union (EU). This law aimed to stimulate the development of paediatric medicines and provide more information on their use, as a response to the lack of evidence and approval of medicines for children. The European Medicines Agency (EMA) has had a central role in the implementation of the Regulation. Pharmaceutical companies need to submit a paediatric investigation plan (PIP) to the EMA's Paediatric Committee (PDCO) for every new medicine, unless an exemption (waiver) is granted. The plans, which describe the development of drugs for children, must be agreed well in advance of the request for marketing authorization of the medicine. Deferrals of studies can be granted to allow approval in adults before the completion of paediatric studies. Between January 2007 and December 2016, a total of 273 new medicines and 43 additional pharmaceutical forms appropriate for use in children were authorized in the EU, and 950 PIPs were agreed by the EMA. In addition, 486 waivers of the development of a medicine in one or more medical conditions were agreed. The Paediatric Regulation has had a very positive impact on paediatric drug development, as exemplified by a comparison of two periods of 3 years before and after entry into force of the Regulation. We conclude that the Regulation has resulted in more medicines for children and more information on the pediatric use of medicines in the EU being available to clinicians.

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Palivizumab Prophylaxis Against Respiratory Syncytial Virus Infection in Children with Immunocompromised Conditions or Down Syndrome: A Multicenter, Post-Marketing Surveillance in Japan

Abstract

Objective

The aim of this study was to assess the safety and effectiveness of palivizumab for the prevention of lower respiratory tract infection (LRI) caused by respiratory syncytial virus (RSV) in children with immunocompromised conditions or Down syndrome.

Methods

In this multicenter, post-marketing surveillance study (December 2013 to December 2015), children aged ≤24 months with immunocompromised conditions or Down syndrome (without hemodynamically significant congenital heart disease) receiving palivizumab immunoprophylaxis during two RSV seasons were observed until 30 days after the final palivizumab injection. Safety [adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), serious ADRs (SADRs)] and effectiveness (frequency, incidence, and duration of hospitalization due to RSV infections) were assessed.

Results

Of 304 patients receiving palivizumab, 167 (54.9%) had immunocompromised conditions, and 138 (45.4%) had Down syndrome; 260 (85.5%) completed palivizumab immunoprophylaxis. The annual mean (±standard deviation) number of doses was 5.3 (±2.4) per season. Overall, 220 AEs occurred in 99 patients (32.6%), including 89 SAEs in 53 patients (17.4%). Of these, 33 AEs in 25 patients (8.22%) were considered ADRs, and 13 ADRs in 11 patients (3.62%) were considered SADRs. In four patients, five SADRs (nephroblastoma and asthma in the same patient, septic shock, device-related infection, and drug-induced liver injury) were previously unreported; however, none were considered drug-related. During the observation period, five RSV infections occurred and two patients required hospitalization.

Conclusion

Palivizumab was generally safe and effective for the prevention of LRI caused by RSV in newborns, infants, and children with immunocompromised conditions or Down syndrome up to the age of 24 months.

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Pericardial effusion-induced subcutaneous edema in the trunk and lower limbs after percutaneous drainage for carcinomatous pericarditis: report of a case

Abstract

The recurrence of gastric cancer is rarely associated with cardiac tamponade induced by carcinomatous pericarditis. We encountered a patient in whom cancer recurred as carcinomatous pericarditis 9 years after surgery for advanced gastric cancer. Furthermore, pericardial effusion caused marked subcutaneous edema in her trunk and lower limbs after percutaneous pericardial drainage was applied to treat cardiac tamponade. A 49-year-old woman presented with lower limb edema and exertional dyspnea 9 years after distal gastrectomy for advanced gastric cancer. Chest computed tomography and ultrasonography showed bilateral pleural effusion and pericardial effusion. Pericardial drainage and thoracocentesis were performed, and her symptoms of respiratory distress remitted. Class V adenocarcinoma was detected on cytology from both effusions, and was diagnosed as the recurrence of gastric cancer. After systemic chemotherapy, she was admitted for the aggravation of dyspnea because of recurrent retention of pericardial effusion. Pericardiocentesis was repeated. The pericardial effusion became subcutaneously retained in the trunk below the puncture site over the lower limbs via the drainage route. Edema in the trunk below the abdomen and lower limbs gradually aggravated over time. The skin extended and became sclerotic because of severe edema, liquid leaked from abdominal skin injuries, and the condition became similar to skin lymphorrhea in lymphedema. Neoplastic cardiac tamponade due to gastric cancer has an extremely low incidence and a poor prognosis. We encountered a patient in whom pericardial effusion caused subcutaneous edema in the trunk and lower limbs after percutaneous pericardial drainage was applied to treat carcinomatous pericarditis associated with gastric cancer.

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Gemcitabine and docetaxel in a patient with primary ovarian leiomyosarcoma: a case report and review of literature

Abstract

Primary ovarian leiomyosarcoma (POLMS) is extremely rare, and optimal therapy for this disease is unknown. A 40-year-old woman presented at a local hospital with abdominal pain. Tumor resection of the left ovary was performed. The pathological diagnosis was leiomyoma of the left ovary. Nine months after surgery, she developed of severe back pain and a subcutaneous tumor on her left shoulder. Magnetic resonance imaging and computed tomography revealed left ovarian tumor recurrence, pelvic bone metastasis, and multiple liver masses. Biopsy of the subcutaneous tumor on her left shoulder demonstrated metastatic leiomyosarcoma. The previously resected left ovarian tumor was re-examined, and the tumor was found to be a leiomyosarcoma. The patient received gemcitabine 800 mg/m² and docetaxel 60 mg/m² (GD therapy), administered at 3-week intervals. After three cycles of GD therapy, the patient experienced dyspnea and was diagnosed with mild interstitial pneumonia. Oral corticosteroid therapy resulted in complete symptom improvement. Thereafter, the dosage of GD was decreased, and after 13 cycles of GD therapy, radiofrequency ablation was performed twice for liver metastases. The tumors have shrunk by 65.5% after 23 cycles of GD. She remains alive after undergoing 24 cycles of GD. GD therapy may be effective for POLMS.

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How effective is collagen resorbable membrane placement after partially impacted mandibular third molar surgery on postoperative morbidity? A prospective randomized comparative study

Abstract

Background

Collagen membranes have some benefits include promoting wound healing through isolation, clot stabilization, wound stability, and hemostasis, enhancing primary wound coverage through its chemotactic ability to attract fibroblasts, and augmenting flap thickness by providing a collagenous scaffold. The purpose of this study was to compare primary and secondary healing and collagen membrane-based primary healing after surgical removal of partial impacted mandibular third molars, evaluating the incidence of postoperative complications and analyzing the swelling, mouth opening, and pain.

Methods

This was a prospective, randomized controlled study. Patients were randomly assigned to three groups: the SC (Secondary closure) group, the PC (Primary closure) group, and the MBPC (membrane based primary closure) group. Data were collected on pain, mouth opening, swelling, and complications experienced by the patients.

Results

There was no statistically significant difference between the groups for the pain (p > 0.05), relatively. The swelling recorded on postoperative days 2 and 7 was lower in the SC group than in the PC (p = 0.046 and 0.00) and in MBPC (p = 0.005 and 0.002) groups, respectively. Mouth opening showed a statistically significant difference between the three groups at day 2 (p = 0.00). Wound dehiscence was shown in 6 patients in the PC (20%) group and 2 patients in the MBPC (6.7%) group. Dry socket was observed 3 patients in the SC group (10%), 2 patients in the PC group (6.7%), and no dry socket in the MBPC group. No cases of infection or postoperative bleeding were encountered.

Conclusions

The secondary closure provides a marked advantage over the primary closure in terms of swelling and mouth opening. However, the absence of alveolitis in the primary closure using the collagen membrane and minimal wound dehiscence, suggests that membrane use may support primary healing in terms of wound healing.

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Outcome measures for oral health based on clinical assessments and claims data: feasibility evaluation in practice

Abstract

Background

It is well known that treatment variation exists in oral healthcare, but the consequences for oral health are unknown as the development of outcome measures is still in its infancy. The aim of this study was to identify and develop outcome measures for oral health and explore their performance using health insurance claims records and clinical data from general dental practices.

Methods

The Dutch healthcare insurance company Achmea collaborated with researchers, oral health experts, and general dental practitioners (GDPs) in a proof of practice study to test the feasibility of measures in general dental practices. A literature search identified previously described outcome measures for oral healthcare. Using a structured approach, identified measures were (i) prioritized, adjusted and added to after discussion and then (ii) tested for feasibility of data collection, their face validity and discriminative validity. Data sources were claims records from Achmea, clinical records from dental practices, and prospective, pre-determined clinical assessment data obtained during routine consultations.

Results

In total eight measures (four on dental caries, one on tooth wear, two on periodontal health, one on retreatment) were identified, prioritized and tested. The retreatment measure and three measures for dental caries were found promising as data collection was feasible, they had face validity and discriminative validity. Deployment of these measures demonstrated variation in clinical practices of GDPs. Feedback of this data to GDPs led to vivid discussions on best practices and quality of care. The measure 'tooth wear' was not considered sufficiently responsive; 'changes in periodontal health score' was considered a controversial measure. The available data for the measures 'percentage of 18-year-olds with no tooth decay' and 'improvement in gingival bleeding index at reassessment' was too limited to provide accurate estimates per dental practice.

Conclusions

The evaluated measures 'time to first restoration', 'distribution of risk categories for dental caries', 'filled-and-missing score' and 'retreatment after restoration', were considered valid and relevant measures and a proxy for oral health status. As such, they improve the transparency of oral health services delivery that can be related to oral health outcomes, and with time may serve to improve these oral health outcomes.

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Magnitude of Muscle Strength and Mass Adaptations Between High-Load Resistance Training Versus Low-Load Resistance Training Associated with Blood-Flow Restriction: A Systematic Review and Meta-Analysis

Abstract

Background

Low-load resistance training (< 50% of one-repetition maximum [1RM]) associated with blood-flow restriction (BFR-RT) has been thought to promote increases in muscle strength and mass. However, it remains unclear if the magnitude of these adaptations is similar to conventional high-load resistance training (> 65% 1RM; HL-RT).

Objective

To compare the effects of HL- versus BFR-RT on muscle adaptations using a systematic review and meta-analysis procedure.

Methods

Studies were identified via electronic databases based on the following inclusion criteria: (a) pre- and post-training assessment of muscular strength; (b) pre- and post-training assessment of muscle hypertrophy; (c) comparison of HL-RT vs. BFR-RT; (d) score ≥ 4 on PEDro scale; (e) means and standard deviations (or standard errors) are reported from absolute values or allow estimation from graphs. If this last criterion was not met, data were directly requested from the authors.

Results

The main results showed higher increases in muscle strength for HL- as compared with BFR-RT, even when considering test specificity, absolute occlusion pressure, cuff width, and occlusion pressure prescription. Regarding the hypertrophic response, results revealed similar effects between HL- and BFR-RT, regardless of the absolute occlusion pressure, cuff width, and occlusion pressure prescription.

Conclusions

Based on the present data, maximum muscle strength may be optimized by specific training methods (i.e., HL-RT) while both HL- and BFR-RT seem equally effective in increasing muscle mass. Importantly, BFR-RT is a valid and effective approach for increasing muscle strength in a wide spectrum of ages and physical capacity, although it may seem particularly of interest for those individuals with physical limitations to engage in HL-RT.

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Aclaración sobre la evaluación de la obstrucción nasal mediante rinomanometría y escalas subjetivas y medición del éxito terapéutico médico y quirúrgico

Publication date: Available online 14 October 2017
Source:Acta Otorrinolaringológica Española
Author(s): Francisco Larrosa, Isam Alobid

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Migración digestiva y expulsión espontánea de un tubo de derivación salivar de Montgomery

Publication date: Available online 14 October 2017
Source:Acta Otorrinolaringológica Española
Author(s): Pablo Torrico Román

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Myopericytoma of the tongue base: A case report

Publication date: Available online 16 October 2017
Source:Acta Otorrinolaringológica Española
Author(s): Stefano Rubino, Rita De Berardinis, Daniele Colombo, Alessandro De Padova

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Diagnóstico y tratamiento de la otitis media secretora infantil: recomendaciones CODEPEH

Publication date: Available online 13 October 2017
Source:Acta Otorrinolaringológica Española
Author(s): Faustino Núñez-Batalla, Carmen Jáudenes-Casaubón, Jose Miguel Sequí-Canet, Ana Vivanco-Allende, Jose Zubicaray-Ugarteche
La incidencia y prevalencia de la otitis media secretora infantil (OMS) son elevadas, sin embargo, existen evidencias de que solo una minoría de profesionales sigue las recomendaciones de las guías para su manejo clínico. Con objeto de mejorar el diagnóstico y el tratamiento de la OMS, para prevenir y/o reducir sus consecuencias sobre el desarrollo del niño, la Comisión para la Detección Precoz de la Hipoacusia (CODEPEH) ha realizado una amplia revisión de la literatura científica sobre la materia y ha elaborado un documento de recomendaciones para una correcta actitud clínica ante la OMS, abordando métodos diagnósticos y tratamiento médico y quirúrgico. Entre otros, no usar ninguna medicación, especialmente corticoides y antibióticos, siendo la espera vigilada la primera medida a tomar durante 3 meses. Si persiste la OMS, el otorrinolaringólogo valorará el tratamiento quirúrgico. En niños que presentan comorbilidades de diversa entidad, el impacto de la OMS es superior por lo que hay que actuar de forma inmediata, sin espera vigilada.The incidence and the prevalence rates of otitis media with effusion (OME) are high. However, there is evidence that only a minority of professionals follow the recommendations provided in clinical practice guidelines. For the purpose of improving diagnosis and treatment of OME in children to prevent and/or reduce its impact on children's development, the Commission for the Early Detection of Deafness (CODEPEH) has deeply reviewed the scientific literature on this field and has drafted a document of recommendations for a correct clinical reaction to of OME, including diagnosis and medical and surgical treatment methodology. Among others, medication, in particular antibiotics and corticoids, should not be prescribed and 3 months of watchful waiting should be the first adopted measure. If OME persists, an ENT doctor should assess the possibility of sugical treatment. The impact of OME in cases of children with a comorbidity is higher, so it requires immediate reaction, without watchful waiting.

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Clustering of prevention behaviours in patients with high-risk primary melanoma

Abstract

Objective

Because melanoma patients are at high risk of further disease, we aimed to study their melanoma prevention behaviours.

Methods

In a large cohort of patients newly diagnosed with high-risk melanoma in Queensland, Australia, we assessed clustering of preventive behaviours using latent class analysis. We assessed associated factors with prevalence proportion ratios (PPRs) and 95% confidence intervals (CIs) estimated by Poisson regression, and also if preventive behaviour was associated with better tumour prognosis at diagnosis.

Results

Among 789 primary melanoma patients (57% male; 21% with previous melanoma), we identified 4 different behaviour clusters: "no/ low prevention" (34% of cohort), "sun protection only" (25%), "skin checks only" (25%) and "sun protection and skin checks" (16%). Prevalence of clusters differed between males and females and also the component behaviours. Preventive behaviours were associated with having skin that burned and past cutaneous cancer, and for males, combined sun protective and skin checking behaviour was associated with higher education and non-smoking. In patients with no past history of cutaneous cancer, males in the "skin checks only" cluster had significantly reduced chances of a thick (poor prognosis) melanoma (PPR = 0.79, 95% CI 0.68, 0.91) and females in the "sun protection and skin checks" cluster were significantly less likely to have an ulcerated melanoma (PPR = 0.85, 95% CI 0.74, 0.98) compared with the "no/ low prevention" cluster.

Conclusion

These findings allow tailoring of preventive advice to melanoma patients to reduce their risk of future primary and recurrent disease.

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Issue Information

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Diagnostic pathology of early systemic cancer: ERBB2 gene amplification in single disseminated cancer cells determines patient survival in operable esophageal cancer

Abstract

Early metastatic dissemination and evolution of disseminated cancer cells (DCCs) outside the primary tumor is one reason for the failure of adjuvant therapies because it generates molecular geno- and phenotypes different from primary tumors which still underlie therapy decisions. Since ERBB2 amplification in esophageal DCCs but not in primary tumor cells predict outcome, we aimed to establish an assay with diagnostic reliability for single DCCs or circulating tumor cells (CTCs). For this we evaluated copy number alterations of more than 600 single DCCs from multiple cancer types to define reference regions suitable for quantification of target regions, such as ERBB2. We then compared ERBB2 quantitative PCR (qPCR) measurements with fluorescent in situ hybridization (FISH) data of various breast cancer cell lines and identified the aberration-calling threshold. The method was applied to two independent cohorts of esophageal cancer patients from Hamburg (n = 59) and Düsseldorf (n = 53). We found a high correlation between the single cell qPCR assay and the standard FISH assay (R = 0.98) and significant associations between amplification and survival for both patient cohorts (Hamburg (HH), p = 0.033; Düsseldorf (D), p = 0.052; pooled HH+D, p = 0.002) when applied to DCCs of esophageal cancer patients. Detection of a single ERBB2-amplified DCC was the most important risk factor for death from esophageal cancer (relative risk = 4.16; 95% CI = 1.887- 9.184; p < 0.001). In our study, we detected ERBB2-amplified cells in 7% of patients. These patients could benefit from anti-ERBB2 targeting therapies. This article is protected by copyright. All rights reserved.

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The impact of socioeconomic status on stage specific prostate cancer survival and mortality before and after introduction of PSA test in Finland

Abstract

Socioeconomic status (SES) has an impact on prostate cancer (PCa) outcomes. Men with high SES have higher incidence and lower mortality of PCa versus lower SES males. PCa cases diagnosed in Finland in 1985-2014 (N=95076) were identified from the Finnish Cancer Registry. Information on education level (EL) was obtained from Statistics Finland. EL was assessed with three-tiered scale: basic, upper secondary and higher education. PCa stage at diagnosis was defined as localized, metastatic or unknown. Years of diagnosis 1985-1994 were defined as pre-PSA period and thereafter as post-PSA period. We report PCa-specific survival (PCSS) and relative risks (RR) for PCa specific mortality (PCSM) among cancer cases in Finland, where healthcare is 100% publicly reimbursed and inequality in healthcare services low. Men with higher EL had markedly better 10-year PCSS: 68% vs 63% in 1985-1994 and 90% vs 85% in 1995-2004 compared to basic EL in localized PCa. The RR for PCSM among men with localized PCa and higher EL compared to basic EL was 0.76(95%confidence interval (CI) 0.66-0.88) in 1985-1994 and 0.61(95%CI 0.53-0.70) in 1995-2004. Variation in PCSS and PCSM between EL categories was evident in metastatic PCa, too. The difference in PCSM between EL categories was larger in the first 10-year post-PSA period than before that but decreased thereafter in localized PCa, suggesting PSA testing became earlier popular among men with high EL. In summary, higher SES/EL benefit PCa survival both in local and disseminated disease and the effect of EL was more pronounced in early post-PSA period. This article is protected by copyright. All rights reserved.

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The human PKP2/Plakophilin-2 gene is induced by Wnt/β-catenin in normal and colon cancer-associated fibroblasts

Abstract

Colorectal cancer results from the malignant transformation of colonic epithelial cells. Stromal fibroblasts are the main component of the tumour microenvironment, and play an important role in the progression of this and other neoplasias. Wnt/β-catenin signalling is essential for colon homeostasis, but aberrant, constitutive activation of this pathway is a hallmark of colorectal cancer. Here we present the first transcriptomic study on the effect of a Wnt factor on human colonic myofibroblasts. Wnt3A regulates the expression of 1136 genes, of which 662 are upregulated and 474 are downregulated in CCD-18Co cells. A set of genes encoding inhibitors of the Wnt/β-catenin pathway stand out among those induced by Wnt3A, which suggests that there is a feedback inhibitory mechanism. We also show that the PKP2 gene encoding the desmosomal protein Plakophilin-2 is a novel direct transcriptional target of Wnt/β-catenin in normal and colon cancer-associated fibroblasts. PKP2 is induced by β-catenin/TCF through three binding sites in the gene promoter and one additional binding site located in an enhancer 20 kb upstream from the transcription start site. Moreover, Plakophilin-2 antagonizes Wnt/β-catenin transcriptional activity in HEK-293T cells, which suggests that it may act as an intracellular inhibitor of the Wnt/β-catenin pathway. Our results demonstrate that stromal fibroblasts respond to canonical Wnt signalling and that Plakophilin-2 plays a role in the feedback control of this effect suggesting that the response to Wnt factors in the stroma may modulate Wnt activity in the tumour cells. This article is protected by copyright. All rights reserved.

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A low frequency haplotype spanning SLX4/FANCP constitutes a new risk locus for early-onset breast cancer (

Abstract

Only a fraction of breast cancer (BC) cases can be yet explained by mutations in genes or genomic variants discovered in linkage, genome-wide association and sequencing studies. The known genes entailing medium or high risk for BC are strongly enriched for a function in DNA double strand repair. Thus, aiming at identifying low frequency variants conferring an intermediate risk, we here investigated 17 variants (MAF: 0.01-0.1) in 10 candidate genes involved in DNA repair or cell cycle control. In an exploration cohort of 437 cases and 1189 controls we show the variant rs3810813 in the SLX4/FANCP gene to be significantly associated with both BC (≤60 years; OR=2.6(1.6-3.9), p=1.6E-05) and decreased DNA repair capacity (≤60 years; beta=37.8(17.9-57.8) p=5.3E-4). BC association was confirmed in a verification cohort (N=2441). Both associations were absent from cases diagnosed >60 years and stronger the earlier the diagnosis. By imputation we show that rs3810813 tags a haplotype with 5 additional variants with the same allele frequency (R² > 0.9), and a pattern of association very similar for both phenotypes (cases <60 years p<0.001, the Bonferroni threshold derived from unlinked variants in the region). In young cases (≤60 years) carrying the risk haplotype, micronucleus test results are predictive for BC (AUC >0.9). Our findings propose a risk variant with high penetrance on the haplotype spanning SLX4/FANCP to be functionally associated to BC predisposition via decreased repair capacity and suggest this variant is carried by a fraction of these haplotypes that is enriched in early onset BC cases. This article is protected by copyright. All rights reserved.

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CCDC6: The identity of a protein known to be partner in fusion

Abstract

Coiled Coil Domain Containing 6 gene, CCDC6, was initially isolated as part of a tumorigenic DNA originated by the fusion of CCDC6 with the tyrosine kinase of RET receptor, following a paracentric inversion of chromosome 10. For a long time CCDC6 has been considered as an accidental partner of the RET protooncogene, providing the promoter and the first 101 aa necessary for the constitutive activation of the oncogenic Tyrosine Kinase (TK) RET in thyroid cells. With the advent of more refined diagnostic tools and bioinformatic algorithms, an exponential growth in fusion genes discoveries has allowed the identification of CCDC6 as partner of genes other than RET in different tumor types.

CCDC6 gene product has a proper role in sustaining the DNA damage checkpoints in response to DNA damage. The inactivation of CCDC6 secondary to chromosomal rearrangements or gene mutations could enhance tumor progression by impairing the apoptotic response upon the DNA damage exposure, contributing to the generation of radio- and chemo-resistance. Preclinical studies indicate that the attenuation of CCDC6 in cancer, while conferring a resistance to cisplatinum, sensitizes the cancer cells to the small molecule inhibitors of Poly (ADP-ribose) polymerase (PARP1/2) with a synthetic lethal effect.

Several CCDC6 mutations and gene rearrangements have been described so far in different types of cancer and CCDC6 may represent a possible predictive biomarker of tumor resistance to the conventional anticancer treatments. Nevertheless, the detection of a CCDC6 impairment in cancer patients may help to select, in future clinical trials, those patients who could benefit of PARP-inhibitors treatment alone or in combination with other treatments. This article is protected by copyright. All rights reserved.

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Identification of somatic genetic alterations in ovarian clear cell carcinoma with next generation sequencing

Abstract

Ovarian clear cell carcinoma (OCCC) is the most refractory subtype of ovarian cancer and more prevalent in Japanese than Caucasians (25% and 5% of all ovarian cancer, respectively). The aim of this study is to discover the genomic alterations that may cause OCCC and effective molecular targets for chemotherapy. Paired genomic DNAs of 48 OCCC tissues and corresponding non-cancerous tissues were extracted from formalin-fixed, paraffin embedded specimens collected between 2007 and 2015 at Tohoku University Hospital. All specimens underwent exome sequencing and the somatic genetic alterations were identified. We divided the cases into three clusters based on the mutation spectra. Clinical characteristics such as age of onset and endometriosis are similar among the clusters but one cluster shows mutations related to APOBEC activation, indicating its contribution to subset of OCCC cases. There are three hypermutated cases (showing 12-fold or higher somatic mutations than the other 45 cases) and they have germline and somatic mismatch repair gene alterations. The frequently mutated genes are ARID1A (66.7%), PIK3CA (50%), PPP2R1A (18.8%) and KRAS (16.7%). Somatic mutations important for selection of chemotherapeutic agents, such as BRAF, ERBB2, PDGFRB, PGR, and KRAS are found in 27.1% of OCCC cases, indicating clinical importance of exome analysis for OCCC. Our study suggests that the genetic instability caused by either mismatch repair defect or activation of APOBEC play critical roles in OCCC carcinogenesis. This article is protected by copyright. All rights reserved.

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Targeted Deep Sequencing of Effusion Cytology Samples is Feasible, informs Spatiotemporal Tumor Evolution, and has Clinical and Diagnostic Utility

Abstract

During the course of disease, many cancer patients eventually present with metastatic disease including peritoneal or pleural spread. In this context, cytology specimens derived from ascites or pleural effusion may help to differentiate malignant from benign conditions and sometimes yield diagnosis of a malignancy. However, even when supported by immunohistochemistry, cytological interpretation can be challenging, especially if tumor cellularity is low. Here, we investigated whether targeted deep sequencing of formalin-fixed and paraffin embedded (FFPE) cytology specimens of cancer patients is feasible, and has diagnostic and clinical impact. To this end, a cohort of 20 matched pairs was compiled, each comprising a cytology sample (FFPE cell block) and at least one biopsy/surgical resection specimen serving as benchmark. In addition, 5 non-malignant effusions were sequenced serving as negative-controls. All samples yielded sufficient libraries and were successfully subjected to targeted sequencing employing a semiconductor based next-generation sequencing platform. Using gene panels of different size and composition, including the Oncomine Comprehensive Panel, for targeted sequencing, somatic mutations were detected in the tissue of all 20 cases. Of these, 15 (75%) harbored mutations that were also detected in the corresponding cytology samples. In four of these cases (20%), additional private mutations were detected in either cytology or tissue samples, reflecting spatiotemporal tumor evolution. Of the five remaining cases, three (15%) showed wild type alleles in cytology material whereas tumor tissue had mutations in interrogated genes. Two cases were discordant, showing different private mutations in the cytology and in the tissue sample, respectively.

In summary, sequencing of cytology specimens (FFPE cell block) reflecting spatiotemporal tumor evolution is feasible and yields adjunct genetic information that may be exploitable for diagnostics and therapy. This article is protected by copyright. All rights reserved.

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Prevalence of Kaposi’s sarcoma-associated herpesvirus among intravenous drug users: a systematic review and meta-analysis

Abstract

Intravenous drug users (IDUs) have been demonstrated to be highly vulnerable to HIV/AIDS. Nevertheless, the prevalence of Kaposi's sarcoma associated herpesvirus (KSHV), an important co-infected agent with HIV, among this population remained obscure. We conducted a systematic review on the epidemiological features of KSHV among IDUs worldwide. Eligible studies were retrieved from 6 electronic databases (PubMed, EMBASE, Web of Science, CBM, CNKI and Wanfang). We calculated the pooled prevalence and 95% confidence interval (CI) overall and among subgroups using either random-effects model or fixed-effects model depending on between-study heterogeneity. The potential publication bias was assessed by the Egger's test. A meta-regression analysis was performed to explore the sources of heterogeneity. Finally, twenty-two studies with a total sample of 7881 IDUs were included in the analysis. The pooled prevalence of KSHV was 14.71% (95% CI 11.12%–19.46%) among IDUs. Specifically, KSHV prevalence was 10.86% (95% CI 6.95%–16.96%) in HIV-negative IDUs, and 13.56% (95% CI 10.57%–17.38%) in HIV-positive IDUs. Moreover, prevalence among IDUs from the three continents involved in the current study was similar: 16.10% (95%CI 7.73%–33.54%) in Asia; 14.22% (95%CI 8.96%–22.57%) in Europe and 14.06% (95%CI 11.38%–17.37%) in America. Globally, IDUs are at higher risk of the KSHV infection when compared with the general population, regardless of geographical region or HIV-infection status.

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Xeroderma pigmentosum complementation group D polymorphism toward lung cancer susceptibility survival and response in patients treated with platinum chemotherapy

Future Oncology, Ahead of Print.

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Epidermal nevus syndromes: New insights into whorls and swirls

Abstract

Knowledge of the molecular underpinnings of many epidermal nevi and epidermal nevus syndrome has expanded rapidly in recent years. In this review and update on epidermal nevus syndrome, we will cover recent genetic discoveries involving epidermal nevi, including nevus sebaceus, keratinocytic epidermal nevus, nevus comedonicus, congenital hemidysplasia with ichthyosiform nevus and limb defects syndrome, phakomatosis pigmentokeratotica, Becker's nevus, porokeratotic adnexal ostial nevus, inflammatory linear verrucous epidermal nevi, and cutaneous-skeletal hypophosphatemia syndrome. We will discuss how newly defined mutations relate to the biology reflected in the cutaneous patterns seen in these mosaic disorders and how new molecular data has informed our understanding of these diseases and shaped management decisions.

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Alopecic and aseptic nodule of the scalp in a girl

Abstract

Alopecic and aseptic nodule of the scalp is a rare entity characterized by the presence of nodules or cysts with sterile punctured material and negative cultures accompanied by nonscarring alopecia in the scalp of young men. We describe a case in which an 11-year-old girl presented with a nodular, fluctuant, round lesion on the vertex with localized alopecia. High-resolution ultrasound showed a hypoechoic lesion with increased flow on Doppler imaging and culture of the citrine-yellowish material obtained by puncture was negative. The patient showed complete clinical response to treatment with topical indomethacin.

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Hermansky-Pudlak syndrome: Report of two patients with updated genetic classification and management recommendations

Abstract

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder caused by mutations in one of nine genes involved in the packaging and formation of specialized lysosomes, including melanosomes and platelet-dense granules. The cardinal features are pigmentary dilution, bleeding diathesis, and accumulation of ceroid-like material in reticuloendothelial cells. Pulmonary fibrosis induced by tissue damage is seen in the most severe forms, and one subtype is characterized by immunodeficiency. We describe two patients with HPS type 1 and review the updated gene-based classification, clinical features, and recommendations for evaluation and follow-up.

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Correction to: Thyroid 2016;26:1343–1421. DOI: 10.1089/thy.2016.0229

Thyroid , Vol. 0, No. 0.

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The Role of Chemokines in Thyroid Carcinoma

Thyroid , Vol. 0, No. 0.

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CD4+ T Memory Stem Cells Correlate with Disease Progression in Chronically HIV-1-Infected Patients

Viral Immunology , Vol. 0, No. 0.

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Psychosocial and Executive Function Recovery Trajectories One Year after Pediatric Traumatic Brain Injury: The Influence of Age and Injury Severity

Journal of Neurotrauma , Vol. 0, No. 0.

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Changes in [18F]Fluorodeoxyglucose Activities in a Shockwave-Induced Traumatic Brain Injury Model Using Lithotripsy

Journal of Neurotrauma , Vol. 0, No. 0.

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The Effects of Glial Cell Line-Derived Neurotrophic Factor after Spinal Cord Injury

Journal of Neurotrauma , Vol. 0, No. 0.

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Preliminary Validation of the World Health Organization Disability Assessment Schedule 2.0 for Mild Traumatic Brain Injury

Journal of Neurotrauma , Vol. 0, No. 0.

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The Association between Dual-Task Gait after Concussion and Prolonged Symptom Duration

Journal of Neurotrauma , Vol. 0, No. 0.

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Body System Effects of a Multi-Modal Training Program Targeting Chronic, Motor Complete Thoracic Spinal Cord Injury

Journal of Neurotrauma , Vol. 0, No. 0.

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Optimizing Clinical Decision Making in Acute Traumatic Spinal Cord Injury

Journal of Neurotrauma Oct 2017, Vol. 34, No. 20: 2841-2842.

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Conversations with a Master Cancer Educator: Joseph F. O’Donnell, M.D.

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Regression of an intramedullary spinal cord metastasis with a checkpoint inhibitor: a case report

CNS Oncology, Ahead of Print.

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Psychosocial and Executive Function Recovery Trajectories One Year after Pediatric Traumatic Brain Injury: The Influence of Age and Injury Severity

Journal of Neurotrauma , Vol. 0, No. 0.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2ynVzIG

Changes in [18F]Fluorodeoxyglucose Activities in a Shockwave-Induced Traumatic Brain Injury Model Using Lithotripsy

Journal of Neurotrauma , Vol. 0, No. 0.

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The Effects of Glial Cell Line-Derived Neurotrophic Factor after Spinal Cord Injury

Journal of Neurotrauma , Vol. 0, No. 0.

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Preliminary Validation of the World Health Organization Disability Assessment Schedule 2.0 for Mild Traumatic Brain Injury

Journal of Neurotrauma , Vol. 0, No. 0.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2gfpUhG

The Association between Dual-Task Gait after Concussion and Prolonged Symptom Duration

Journal of Neurotrauma , Vol. 0, No. 0.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2ynfpnk

Body System Effects of a Multi-Modal Training Program Targeting Chronic, Motor Complete Thoracic Spinal Cord Injury

Journal of Neurotrauma , Vol. 0, No. 0.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2geIoix

Optimizing Clinical Decision Making in Acute Traumatic Spinal Cord Injury

Journal of Neurotrauma Oct 2017, Vol. 34, No. 20: 2841-2842.

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Psychological and lifestyle risk factors for asthma exacerbations and morbidity in children

Asthma is the most common childhood illness and disproportionately affects low-income, minority children who live in urban areas. A range of risk factors are associated with asthma morbidity and mortality, suc...

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Presence of mast cells and the expression of metalloproteinase 9 in the gingiva of ovariectomized rats with periodontal disease

Publication date: Available online 14 October 2017
Source:Journal of Oral Biology and Craniofacial Research
Author(s): Vanessa Ávila Sarmento Silveira, Renata Falchete do Prado, Yasmin Rodarte Carvalho, Horácio Faig-Leite
BackgroundThe host's answer has an important role in periodontal disease, and the mast cells have a prime role. Such cells seem to be influenced by estrogen deficiency. The objective was to evaluate the mast cells and the expression of metalloproteinase(MMP)-9 in periodontal disease induced in ovariectomized rats.MethodsFor that purpose, 36 rats were used; 18 ovariectomized (OVX) and another 18 Sham-operated (SHAM). After 60days the periodontal disease was induced by a ligature around the first lower right molars (group P). The opposite side was the control group (groupC). The euthanasia occurred 3, 7 and 14days after the placement of the ligature. The gingiva was removed and analyzed histochemically and immunohistochemically to quantify the mast cells and to analyze MMP 9 expression.ResultsBy comparing the groups SHAM-P and C and groups OVX-C and P, it was noted that mast cells from group C were higher than P in all experimental periods. When comparing groups SHAM-C and OVX-C, significant factors were not found. When comparing groups SHAM-P and OVX-P, there was an inclination for mast cells reduction with time. The MMP-9 expression was related to the presence of periodontitis.ConclusionsIt was concluded that periodontitis led to mast cells reduction and MMP-9 increase. The ovariectomy itself did not alter the MMP-9 expression and did not influence the presence of mast cells in rat papilla, however, when associated to inflammation led to a reduction of mast cells.

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Spontaneous isolated dissection of the superior mesenteric artery and aneurysm formation resulting from segmental arterial mediolysis: a case report

Spontaneous isolated dissection of the superior mesenteric artery (SMA) can lead to bowel ischemia, aneurysm rupture, or even death. Studies have suggested that mechanical or hemodynamic stress on the vascular...

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Is There a Link between Defects of Thyroid Hormonogenesis and Morphogenesis?

Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 389-391.

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Most Low-Risk Papillary Thyroid Cancers Remain Stable During Active Surveillance

Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 368-370.

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Ultrasound Has a Role in Predicting Tumor Invasiveness in Follicular Variant of Papillary Thyroid Carcinoma

Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 371-374.

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Hypothyroidism in the Differential Diagnosis of Hyponatremia — A Clinical Pearl in Peril

Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 395-397.

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A 10-Gene Classifier Can Accurately Diagnose Malignant Versus Benign Cytologically Indeterminate Thyroid Nodules

Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 375-377.

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Mortality May Be Higher in Older Patients Whose Levels of TSH and Free T4 Are More Variable

Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 385-388.

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Tumor-Volume–Doubling Time of Pulmonary Metastases in Follicular-Cell–Derived Thyroid Carcinoma May Allow More Appropriate Selection of Patients for Multikinase Inhibitor Therapy

Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 378-381.

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Exposure to Flame Retardants Is Inconsistently Associated with Papillary Thyroid Cancer

Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 392-394.

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Effects of continuous visual feedback during sitting balance training in chronic stroke survivors

Postural control deficits are common in stroke survivors and often the rehabilitation programs include balance training based on visual feedback to improve the control of body position or of the voluntary shif...

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Satisfaction with Life over Time in People with Burn Injury: A National Institute on Disability, Independent Living, and Rehabilitation Research Burn Model System Study

Publication date: Available online 16 October 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Dagmar Amtmann, Fraser D. Bocell, Kara McMullen, Alyssa M. Bamer, Kurt L. Johnson, Shelley Wiechman, Jeffrey C. Schneider
ObjectivesTo examine trajectories of satisfaction with life (SWL) of burn survivors over time and their clinical, demographic and other predictors.DesignLongitudinal survey.SettingN/A.ParticipantsIndividuals 18 and over who underwent burn-related surgery and met one of the following criteria: (1) > 10% total burn surface area (TBSA) burn and ≥ 65 years of age; (2) > 20% TBSA burn and 18 to 64 years of age; (3) electrical high voltage/lightning injury; or (4) burn injury to the hands, face, or feet. A total of 378 participants had data on all variables of interest and were included in the analyses.InterventionsN/A.Main Outcome MeasuresSatisfaction with Life ScaleResultsGrowth mixture modeling (GMM) identified two classes with different trajectories of SWL. The mean SWL of the unchanged class (n=224, 60%) was flat over two years with high initial SWL scores. The SWL of the dissatisfied class (n=154, 40%) was at the low end of average and got progressively worse over time.ConclusionsSWL after burn injury can be described by two different trajectories with substantially different outcomes. Older age, mental health and unemployment prior to injury predicted the membership in the dissatisfied class. Additional services could be provided to those at high risk for low SWL to achieve better outcomes.

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Effect of Upper limb Rehabilitation compared to No Upper limb Rehabilitation in Lung Transplant Recipients – A Randomized Controlled trial

Publication date: Available online 16 October 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): L.M. Fuller, D. El-Ansary, B.M. Button, M. Corbett, G. Snell, S. Marasco, A.E. Holland
Objectiveto investigate effects of a supervised UL exercise program (SULP) versus no supervised UL exercise program (NULP) after lung transplantation (LTX).DesignRandomized controlled trialSettingPhysiotherapy gymParticipantsPost LTX>18years, N=80InterventionAll participants underwent lower limb strength thrice weekly and endurance training. Participants randomised to supervised upper limb program (SULP) completed progressive UL strength training program using hand weights & adjustable pulley equipment.OutcomesOverall bodily pain rated on visual analogue scale (VAS). Shoulder flexion, abduction strength and HRQOL (SF36) were measured.MeasurementsAt baseline, 6 & 12 weeks & 6 months by blinded assessors.Results80 participants recruited,43 randomized to SULP and 37 to NULP. After 6 weeks of training, SULP(41) participants had less overall bodily pain on VAS than those NULP(36) (mean 2.1cm (SD 1.3) vs 3.8cm (SD1.7), p <0.001) and greater UL strength than NULP participants (peak force 8.4Nm (4.0) versus 6.7Nm (2.8) p = 0.037). At 12 weeks SULP participants had better HRQOL – bodily pain domain (76(17) vs 66(26), p=0.05) but at 6 months there was no difference between groups for any outcome. No serious adverse events reported.ConclusionUL rehabilitation results in short term improvements in pain and muscle strength following LTX, but no longer-term impacts were evident.

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Development of a computerized adaptive testing system of the Functional Assessment of Stroke

Publication date: Available online 16 October 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Gong-Hong Lin, Yi-Jing Huang, Shih-Chieh Lee, Sheau-Ling Huang, Ching-Lin Hsieh
ObjectiveTo develop a computerized adaptive testing system of the Functional Assessment of Stroke (CAT-FAS) to assess upper- and lower-extremity (UE/LE) motor function, postural control, and basic activities of daily living (BADL) with optimal efficiency and without sacrificing psychometric properties in patients with stroke.DesignSimulation study using the data from a previous study. Participants were assessed with the UE/LE subscales of the Fugl-Meyer Assessment (UE-FM/LE-FM), Postural Assessment Scale for Stroke patients (PASS), and Barthel Index (BI) at 14- and 30-day after stroke.SettingOne rehabilitation unit in a medical center.ParticipantsA total of 301 and 262 participants were assessed at 14 and 30 days after stroke, respectively.InterventionsNot applicable.Main Outcome MeasuresThe UE-FM, LE-FM, PASS, and BIResultsThe CAT-FAS adopting the optimal stopping rule (limited reliability increased < 0.010) had good Rasch reliability across the 4 domains (0.88–0.93) and needed few items for the whole administration (8.5 items on average). The concurrent validity (CAT-FAS vs. the original tests, Pearson's r = 0.91–0.95) and responsiveness (standardized response mean = 0.65–0.76) of the CAT-FAS were good in patients with stroke.ConclusionWe developed the CAT-FAS, and our results support that the CAT-FAS has sufficient efficiency, reliability, concurrent validity, and responsiveness in patients with stroke. The CAT-FAS can be used to simultaneously assess patients' functions of UE, LE, postural control, and BADL using, on average, no more than 10 items; this efficiency is very useful for reducing the assessment burdens of both clinicians and patients.

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An Akt3 splice variant lacking the serine 472 phosphorylation site promotes apoptosis and suppresses mammary tumorigenesis

The Akt pathway is a well-known promoter of tumor malignancy. Akt3 is expressed as two alternatively spliced variants, one of which lacks the key regulatory serine 472 phosphorylation site. Whereas the function of full-length Akt3 isoform (Akt3/+S472) is well-characterized, that of Akt3/-S472 isoform remains unknown. Despite being expressed at a substantially lower level than Akt3/+S472 in triple negative breast cancer cells, specific ablation of Akt3/-S472, enhanced, whereas overexpression, suppressed mammary tumor growth-consistent with a significant association with patient survival duration relative to Akt3/+S472. These effects were due to induction of apoptosis, which was mediated by Bim upregulation, leading to conformational activation of Bax and caspase-3 processing. Bim accumulation was caused by endocytosis of EGF receptors with concomitant ERK attenuation, which stabilizes BIM. These findings demonstrate an unexpected function of an endogenously expressed Akt isoform in promoting - as opposed to suppressing - apoptosis, underscoring that Akt isoforms may exert dissonant functions in malignancy.

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STK33 promotes growth and progression of pancreatic cancer as a critical downstream mediator of HIF-1{alpha}

The serine/threonine kinase STK33 has been implicated in cancer cell proliferation. Here we provide evidence of a critical role for STK33 in the pathogenesis and metastatic progression of pancreatic ductal adenocarcinoma (PDAC). STK33 expression in PDAC was regulated by the hypoxia-inducible transcription factor HIF-1α. In human PDAC specimens, STK33 was overexpressed and associated with poor prognosis. Enforced STK33 expression promoted PDAC proliferation, migration, invasion and tumor growth, whereas STK33 depletion exerted opposing effects. Mechanistic investigations showed that HIF-1α regulated STK33 via direct binding to a hypoxia response element in its promoter. In showing that dysregulated HIF-1α/STK33 signaling promotes PDAC growth and progression, our results suggest STK33 as a candidate therapeutic target to improve PDAC treatment.

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ATR is a therapeutic target in synovial sarcoma

Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterised by expression of SS18-SSX fusions, where treatment options are limited. To identify therapeutically actionable genetic dependencies in SS, we performed a series of parallel, high-throughput small interfering RNA (siRNA) screens and compared genetic dependencies in SS tumor cells to those in >130 non-SS tumour cell lines. This approach revealed a reliance of SS tumor cells upon the DNA damage response serine/threonine protein kinase ATR. Clinical ATR inhibitors (ATRi) elicited a synthetic lethal effect in SS tumor cells and impaired growth of SS patient-derived xenografts. Oncogenic SS18-SSX family fusion genes are known to alter the composition of the BAF chromatin-remodeling complex, causing ejection and degradation of wild-type SS18 and the tumor suppressor SMARCB1. Expression of oncogenic SS18-SSX fusion proteins caused profound ATRi sensitivity and a reduction in SS18 and SMARCB1 protein levels, but a SSX18-SSX1 Δ71-78 fusion containing a C-terminal deletion did not. ATRi sensitivity in SS was characterized by an increase in biomarkers of replication fork stress (increased γH2AX, decreased replication fork speed, and increased R-loops), an apoptotic response, and a dependence upon Cyclin E expression. Combinations of cisplatin or PARP inhibitors enhanced the anti-tumor cell effect of ATRi, suggesting that either single agent ATRi or combination therapy involving ATRi might be further assessed as candidate approaches for SS treatment.

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Administering xCT inhibitors based on circadian clock improves antitumor effects

Clock genes encoding transcription factors that regulate circadian rhythms may inform chrono-modulated chemotherapy, where time-dependent dose alterations might affect drug efficacy and reduce side effects. For example, inhibiting the essential cystine transporter xCT with sulfasalazine induces growth arrest in cancer cells. Although the anticancer effects of sulfasalazine have been studied extensively, its effects on transcriptional control of xCT expression have not been studied. Here we show that sulfasalazine administration during the period of increased xCT expression improves its anticancer effects, and that the Clock gene itself induces xCT expression and regulates its circadian rhythm. Our findings highlight the clinical potential of chrono-modulated chemotherapy and the importance of xCT-mediated transcriptional regulation in the utility of such strategies.

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Blocking myristoylation of Src inhibits its kinase activity and suppresses prostate cancer progression

Protein N-myristoylation enables localization to membranes and helps maintain protein conformation and function. N-myristoyltransferases (NMT) catalyze co- or post-translational myristoylation of Src family kinases and other oncogenic proteins, thereby regulating their function. In this study, we provide genetic and pharmacological evidence that inhibiting the N-myristoyltransferase NMT1 suppresses cell cycle progression, proliferation and malignant growth of prostate cancer cells. Loss of myristoylation abolished the tumorigenic potential of Src and its synergy with androgen receptor in mediating tumor invasion. We identified the myristoyl-CoA analog B13 as a small molecule inhibitor of NMT1 enzymatic activity. B13 exposure blocked Src myristoylation and Src localizaiton to the cytoplasmic membrane, attenuating Src-mediated oncogenic signaling. B13 exerted its antiinvasive and antitumor effects against prostate cancer cells with minimal toxic side-effects in vivo. Structural optimization based on structure-activity relationships enabled the chemical synthesis of LCL204 with enhanced inhibitory potency against NMT1. Collectively, our results offer a preclincal proof of concept for the use of protein myristoylation inhibitors as a strategy to block prostate cancer progression.

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Clinical significance of programmed cell death-ligand 1 expression and the immune microenvironment at the invasive front of colorectal cancers with high microsatellite instability

Abstract

Immunotherapy is reportedly effective in colorectal cancers (CRCs) with high microsatellite instability (MSI-H); however, the specific cell types that respond to immune checkpoint therapy are unclear. Herein, we aimed to examine the expression of programmed cell death-ligand 1 (PD-L1) and related proteins in MSI-H and microsatellite-stable (MSS) CRCs to investigate the immune microenvironment at the tumor's invasive front. The MSI status was retrospectively assessed in 499 patients undergoing surgical resection of primary CRC; of these, 48 were classified as MSI-H. Propensity score matching was performed, and tissues from 36 and 37 patients with MSI-H and MSS CRCs, respectively, were immunohistochemically evaluated for PD-L1, PD-1, CD8, and CD68. PD-L1 expression was evaluated separately for tumor cells (PD-L1 [T]) and tumor-infiltrating myeloid cells in the stroma (PD-L1 [I]). PD-L1 (T) was positive in only 5.4% and 36.1% of MSS and MSI-H CRCs, while PD-L1 (I) was positive in 27% and 72.2% of these CRCs, respectively. The PD-L1 (T) and PD-L1 (I) expression levels in MSI-H CRCs significantly correlated with poor differentiation, lymphatic invasion, and vascular invasion (P<0.05), and with early-stage adenocarcinoma and high budding grade (P<0.05), respectively. Significantly more PD-L1 (I), CD8-positive cells, and CD68-positive macrophages were present at the invasive front than in the central tumor in MSI-H CRCs (P<0.005). PD-L1 was expressed on both tumor cells and CD68/CD163-positive (M2) macrophages at the invasive front of MSI-H CRCs. In conclusion, PD-L1-positive tumor cells and M2-type tumor-associated macrophages may contribute to tumor invasion and immune escape at the invasive front. This article is protected by copyright. All rights reserved.

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The endothelial prostate-specific membrane antigen is highly expressed in gliosarcoma and visualized by [ 68 Ga]-PSMA-11 PET: a theranostic outlook for brain tumor patients?

gliomagliosarcomaPSMAtheranostics

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Objective measurement and clinical significance of IDO1 protein in hormone receptor-positive breast cancer

Abstract

Background

Immunostimulatory therapies targeting immune-suppressive pathways produce durable responses in advanced solid tumors. Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting oxidoreductase that catalyzes the degradation of tryptophan to kynurenine. IDO induces immune tolerance by downregulating CD8+ and effector CD4+ T cell responses. IDO1, the most active isoform, is expressed in diverse tumor types and can be targeted using small molecule inhibitors. We used an objective, in situ assay to measure IDO1 in a collection of hormone receptor-positive breast cancers (HR+ BC).

Methods

IDO1 protein was measured using quantitative immunofluorescence in 362 stage I-III HR+ BC represented in tissue microarrays. IDO1 levels were determined in the tumor and stroma, and stratified using median cut-point. Associations between IDO1, clinico-pathological features and CD3+, CD8+, CD20+ and FOXP3 tumor-infiltrating lymphocytes were examined using χ² and Mann-Whitney tests. Survival was studied using Kaplan-Meier estimator and a proportional hazards model. All tests were two-sided.

Results

IDO1 protein was observed in 76.2% of HR+ BC. There was no association between IDO1 and major clinico-pathological characteristics. Increased IDO1 correlated with decreased CD20+ infiltration (P = 0.0004) but not with CD3+, CD8+ or FOXP3 levels. Elevated IDO1 expression was associated with worse 20-year overall survival (log-rank P = 0.02, HR = 1.39, 95% C.I.: 1.05-1.82). IDO1 scores were independently associated with outcome in multivariable analysis.

Conclusions

IDO1 protein is expressed in the majority of HR+ BC and is an independent negative prognostic marker. Additionally, IDO1 expression is negatively associated with tumor B-cell infiltration. Measurement of IDO1 has the potential to identify a population that might derive benefit from IDO1 blockade.

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Αρχειοθήκη ιστολογίου

Δευτέρα 16 Οκτωβρίου 2017

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Conclusions

Abstract

Background

Methods

Results

Conclusions

Abstract

Background

Objective

Methods

Results