Evaluation of the 8th TNM classification on p16-positive oropharyngeal squamous cell carcinomas in the Netherlands, and the importance of additional HPV DNA-testing.

Abstract

Background

Oropharyngeal squamous cell carcinomas (OPSCCs) are traditionally caused by smoking and excessive alcohol consumption. However, in the last decades high-risk human papillomavirus (HR-HPV) infections play an increasingly important role in tumorigenesis. HPV-driven OPSCCs are known to have a more favorable prognosis, which has led to important and marked changes in the recently released TNM-8. In this edition, OPSCCs are divided based on p16-immunostaining, with p16-overexpression as surrogate marker for the presence of HPV. The aims of this study are to evaluate TNM-8 on a Dutch consecutive cohort of patients with p16-positive OPSCC and to determine the relevance of additional HPV DNA-testing.

Patients and methods

All OPSCC patients without distant metastases at diagnosis and treated with curative intent at VU University Medical Center (2000-2015) and Erasmus Medical Center (2000-2006) were included (N = 1,204). HPV-status was established by p16-immunostaining followed by HPV DNA-PCR on the p16-immunopositive cases. We compared TNM-7 and TNM-8 using the Harrell's C index.

Results

In total, 388 of 1,204 (32.2%) patients were p16-immunopositive. In these patients, TNM-8 had a markedly better predictive prognostic power than TNM-7 (Harrell's C index 0.63 versus 0.53). Of the 388 p16-positive OPSCCs, 48 tumors (12.4%) were HPV DNA-negative. This subgroup had distinct demographic, clinical and morphologic characteristics and showed a significantly worse five-year overall survival compared to the HPV DNA-positive tumors (P < 0.001).

Conclusions

TNM-8 has a better predictive prognostic power than TNM-7 in patients with p16-positive OPSCC. However, within p16-positive OPSCCs there is an HPV DNA-negative subgroup with distinct features and a worse overall survival, indicating the importance to perform additional HPV DNA-testing when predicting prognosis and particularly for selecting patients for de-intensified treatment regimens.

Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus IV paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy

Abstract

Background

Paclitaxel is currently only available as an intravenous (IV) formulation. DHP107 is a novel oral formulation of lipid ingredients and paclitaxel. DHP107 demonstrated comparable efficacy, safety, and pharmacokinetics to IV paclitaxel as second-line therapy in patients with advanced gastric cancer (AGC). DREAM is a multicenter, open-label, prospective, randomized phase III study of patients with histologically/cytologically confirmed, unresectable/recurrent AGC after first-line therapy failure.

Methods and materials

Patients were randomized 1:1 to DHP107 (200 mg/m² orally twice daily days 1, 8, 15 every 4 weeks) or IV paclitaxel (175 mg/m² day 1 every 3 weeks). Patients were stratified by Eastern Cooperative Oncology Group performance status, disease status, and prior treatment; response was assessed (Response Evaluation Criteria in Solid Tumors) every 6 weeks. Primary endpoint: non-inferiority of progression-free survival (PFS); secondary endpoints: overall response rate (ORR), overall survival (OS), and safety. For the efficacy analysis, sequential tests for non-inferiority were performed, first with a non-inferiority margin of 1.48, then with a margin of 1.25.

Results

Baseline characteristics were balanced in the 236 randomized patients (n=118 per arm). Median PFS (per-protocol) was 3.0 (95% CI, 1.7-4.0) months for DHP107 and 2.6 (95% CI, 1.8-2.8) months for paclitaxel (hazard ratio [HR]=0.85; 95% CI, 0.64-1.13). A sensitivity analysis on PFS using independent central review showed similar results (HR = 0.93; 95% CI, 0.70-1.24). Median OS (final analysis set) was 9.7 (95% CI, 7.1-11.5) months for DHP107 versus 8.9 (95% CI, 7.1-12.2) months for paclitaxel (HR = 1.04; 95% CI, 0.76-1.41). ORR was 17.8% for DHP107 (CR 4.2%; PR 13.6%) versus 25.4% for paclitaxel (CR 3.4%; PR 22.0%). Nausea, vomiting, diarrhea, and mucositis were more common with DHP107; peripheral neuropathy was more common with paclitaxel. Grade ≥3 adverse events were infrequent, most commonly neutropenia (42% versus 53%); febrile neutropenia was rare (5.9% versus 2.5%). No hypersensitivity reactions occurred with DHP107 (paclitaxel 2.5%).

Conclusions

DHP107 as second-line treatment for AGC was non-inferior to paclitaxel for PFS; other efficacy and safety parameters were comparable. DHP107 is the first oral paclitaxel with proven efficacy/safety for the treatment of AGC. ClinicalTrials.gov: NCT01839773.

Lifestyle factors and risk of sporadic colorectal cancer by microsatellite instability status: A systematic review and meta-analyses

Abstract

Introduction

The association of lifestyle factors with molecular pathological subtypes of colorectal cancer (CRC), such as microsatellite instability (MSI), could provide further knowledge about the colorectal carcinogenic process. The aim of this review was to evaluate possible associations between lifestyle factors and risk of sporadic CRC by MSI status.

Methods

PubMed and Web of Science were searched for studies investigating the association between alcohol, body mass index (BMI), dietary fiber, hormone replacement therapy (HRT), non-steroidal anti-inflammatory drugs (NSAIDs), physical activity, red meat, smoking, or statin use, with MSI-high (MSI-H) and microsatellite stable (MSS) CRC. Meta-analyses were performed to calculate summary relative risks (sRR).

Results

Overall, 31 studies reporting on the association between lifestyle factors and CRC according to MSI status were included in this review. Ever smoking was associated with MSI-H (sRR=1.62; 95%CI: 1.40-1.88) and MSS/MSI-Low CRC (sRR=1.10; 95%CI: 1.01-1.20), but the association was significantly stronger for MSI-H CRC. The use of HRT was associated with a 20% decrease (sRR=0.80; 95%CI: 0.73-0.89) in the risk of MSS CRC, but was not associated with MSI-H CRC. An increase in BMI per 5 kg/m² was equally associated with MSS and MSI-H CRC (sRR=1.22, in both cases), but was statistically significant for MSS CRC only (95%CI: 1.11-1.34 and 0.94-1.58, respectively). Limited evidence for associations between other lifestyle factors and CRC by MSI status exists.

Conclusions

Lifestyle factors, such as HRT and smoking are differentially associated with the risk of MSI-H and MSS CRC. Further research on associations of lifestyle factors and CRC subtypes is necessary to provide a better understanding of the CRC disease pathway.

RAS mutation analysis in circulating tumor DNA from patients with metastatic colorectal cancer: the AGEO RASANC prospective multicenter study.

Abstract

Background

RAS mutations are currently sought for in tumor samples, which takes a median of almost 3 weeks in western European countries. This creates problems in clinical situations that require urgent treatment and for inclusion in therapeutic trials that need RAS status for randomization. Analysis of circulating tumor DNA might help to shorten the time required to determine RAS mutational status prior to anti-EGFR antibody therapy for metastatic colorectal cancer. Here we compared plasma versus tissue RAS analysis in a large prospective multicenter cohort.

Patients and methods

Plasma samples were collected prospectively from chemotherapy-naive patients and analyzed centrally by next-generation sequencing (NGS) with the colon lung cancer V2 Ampliseq panel and by methylation digital polymerase chain reaction (WIF1 and NPY genes). Tumoral RAS status was determined locally, in parallel, according to routine practice. For a minimal kappa coefficient of 0.7, reflecting acceptable concordance (precision ± 0.07), with an estimated 5% of non-exploitable data, 425 subjects were necessary.

Results

From 07/2015 to 12/2016, 425 patients were enrolled. For the 412 patients with available paired plasma and tumor samples, the kappa coefficient was 0.71 [95% CI: 0.64-0.77] and accuracy was 85.2% [95% CI: 81.4-88.5]. In the 329 patients with detectable ctDNA (at least one mutation or one methylated biomarker), the kappa coefficient was 0.89 [95% CI: 0.84-0.94] and accuracy was 94.8% [95% CI: 91.9-97.0]. The absence of liver metastases was the main clinical factor associated with inconclusive circulating tumor DNA results (odds ratio = 0.11 [95% CI: 0.06-0.21]). In patients with liver metastases, accuracy was 93.5% with NGS alone and 97% with NGS plus the methylated biomarkers.

Conclusion

This prospective trial demonstrates excellent concordance between RAS status in plasma and tumor tissue from patients with colorectal cancer and liver metastases, thus validating plasma testing for routine RAS mutation analysis in these patients.

Trial registration

Clinicaltrials.gov, NCT02502656

The hard road to data interpretation: three or six months of adjuvant chemotherapy for patients with stage III colon cancer?

Abstract

Background

Six months of adjuvant oxaliplatin-based chemotherapy is standard for patients with stage III colon cancer following surgery. However, oxaliplatin is associated with peripheral neurotoxicity which worsens over treatment duration. Consequently, a shorter treatment duration, if equally effective would be extremely beneficial. A pooled analysis of data for 12,834 stage III colon cancer patients, from six randomised phase III trials of adjuvant therapy, the IDEA study, was performed and the results presented at the ASCO Annual Meeting 2017. To clarify the potential impact of these results on clinical practice ESMO decided to sponsor a special session at their 2017 Annual Meeting dedicated to achieving a more meaningful interpretation of the results.

Methods

Medical oncologists from Europe, the US and Asia selected for their involvement in the trials, together with an independent statistician and an independent clinician, were invited to provide their independent interpretations of the results, and contribute to a moderated panel discussion. The pooled analysis evaluated the non-inferiority of 3- versus 6-months of adjuvant FOLFOX/CAPOX therapy, but not the non-inferiority of 3-months CAPOX versus 6-months FOLFOX therapy.

Results

There was strong evidence of an interaction between the choice of regimen (CAPOX or FOLFOX) and duration of treatment. Patients were classified as either 'fighters' or 'fatalists', and 3 months CAPOX was considered standard for patients classified as fatalists, even if they had high-risk disease. However, patients classified as 'fighters' would only receive 3 months of CAPOX if they had low-risk disease but would always receive 6 months of CAPOX/FOLFOX if they had T4 disease. The panel was split on whether they would advocate 3 or 6 months CAPOX therapy based on high-risk N2 disease.

Conclusions

The main drivers of the duration of treatment were choice of regimen and patient attitude, with risk, based mainly on T4 stage, having less influence.

Management of metastatic retroperitoneal sarcoma: a consensus approach from the Transatlantic Retroperitoneal Sarcoma Working Group (TARPSWG)

Abstract

Introduction

Retroperitoneal sarcoma (RPS) is a rare disease accounting for 0.1-0.2% of all malignancies. Management of RPS is complex and requires multidisciplinary, tailored treatment strategies at all stages, but especially in the context of metastatic or multifocal recurrent disease. Due to the rarity and heterogeneity of this family of diseases, the literature to guide management is limited.

Methods

The Trans-Atlantic Retroperitoneal Sarcoma Working Group (TARPSWG) is an international collaboration of sarcoma experts from all disciplines convened in an effort to overcome these limitations. The TARPSWG has compiled the available evidence surrounding metastatic and multifocally recurrent RPS along with expert opinion in an iterative process to generate a consensus document regarding the complex management of this disease. The objective of this document is to guide sarcoma specialists from all disciplines in the diagnosis and treatment of multifocal recurrent or metastatic RPS.

Results

All aspects of patient assessment, diagnostic processes, local and systemic treatments, and palliation are reviewed in this document, and consensus recommendations provided accordingly. Recommendations were guided by available evidence, in conjunction with expert opinion where evidence was lacking.

Conclusions

This consensus document combines the available literature regarding the management of multifocally recurrent or metastastic RPS with the practical expertise of high-volume sarcoma centers from multiple countries. It is designed as a tool for decision-making in the complex multidisciplinary management of this condition and is expected to standardize management across centers, thereby ensuring that patients receive the highest quality care.

Ten-year retrospective clinicohistological study of cutaneous lupus erythematosus in Korea

Abstract

An understanding of the differences in clinical manifestations and laboratory abnormalities between subtypes of cutaneous lupus erythematosus (CLE) is still lacking. The purpose of this study was to analyze demographic, clinical and histological features of CLE according to three main presentation subsets: acute (ACLE), subacute (SCLE) and chronic (CCLE). A 10-year retrospective analysis was performed on data from patients who were diagnosed with CLE between March 2005 and September 2015 in a Korean tertiary referral dermatology clinic. We compared demographic data and clinical and histological findings between three different CLE groups. An overall sample of 220 patients with CLE consisted of 67 patients with ACLE, 25 patients with SCLE and 135 patients with CCLE. Patients with CCLE regardless of systemic lupus erythematosus (SLE) presence had lower prevalence of anemia, urinary abnormalities and elevated erythrocyte sedimentation rate. Furthermore, CCLE patients who only had skin lesions showed lower female predominance, lower extracutaneous manifestation, fewer laboratory and immunological abnormalities including low antinuclear antibody titers and the lowest positivity for C3, C4 and anti-dsDNA, anti-Ro, anti-Sm and anti-RNP antibodies, and more prominent perieccrine inflammation and dermal fibrosis in histological findings. Considering distinct cutaneous manifestations of LE, a comprehensive awareness of each CLE subtype is important for achieving a favorable prognosis through appropriate diagnosis and management. This study provides comparative clinical and histological profiles of patients with different CLE subtypes in Korea.

Unilateral telangiectasia macularis eruptiva perstans with an unusual clinical presentation

Pruritic arthropod bite-like papules in T-cell large granular lymphocytic leukaemia and chronic myelomonocytic leukaemia

Summary

T-cell large granular lymphocytic leukaemia (T-LGLL) is a clinically indolent mature T-cell neoplasm characterized by a monoclonal population of CD3+ CD8+ cytotoxic T cells, which usually presents as neutropenia, anaemia and thrombocytopenia. Chronic myelomonocytic leukaemia (CMML) is a clonal haematopoietic disorder with features of both a myeloproliferative neoplasm and myelodysplastic syndrome (MDS). Patients with CMML exhibit a persistent peripheral blood monocytosis in addition to myelodysplastic features. Because of the rarity of T-LGLL, its cutaneous manifestations are poorly documented, but include vasculitis, vasculopathy, persistent ulcerations, generalized pruritus and disseminated granuloma annulare. Various types of skin lesions have been observed in patients with CMML and reportedly occur in approximately 10% of cases. We report the extraordinary case of a patient with MDS who developed T-LGLL, and subsequently the MDS progressed to CMML. The patient then developed diffuse arthropod bite-like papules and intractable pruritus.

Involvement of spinal cannabinoid receptors in the antipruritic effects of WIN 55,212-2, a cannabinoid receptor agonist

Summary

Background

Cannabinoids have been used for their analgesic and euphoric effects for millennia, but recently the antipruritic effects of cannabis have been discovered. Considering the similarities between pain and itch sensations, we hypothesized that cannabinoid receptors may play a role in the antipruritic effects of cannabinoids.

Aim

To analyse the role of the spinal cannabinoid receptors, CB1 and CB2, in the antipruritic effects of the cannabinoid agonist WIN 55,212-2.

Methods

Male Balb/c mice weighing 20–30 g were used. Scratching behaviour in the mice was produced by injection of serotonin 5 μg/50 μL intradermally into the nape of the neck. Scratching of the site of injection by the hind paws was video-recorded for 30 min. After testing different doses of WIN 55,212-2 [1, 3 and 10 mg/kg intraperitoneally (IP)], the effects of the CB1 receptor antagonist, AM-251 [1 μg/mouse administered intrathecally (IT)] and the CB2 receptor antagonist AM-630 (4 μg/mouse IT) on the antipruritic effects of WIN 55,212-2 were studied using a rotarod apparatus.

Results

WIN 55,212-2 (1, 3 or 10 mg/kg IP) dose-dependently decreased serotonin-induced scratches. The receptor antagonist CB1 partially reversed the effects of WIN 55,212-2 (P < 0.05); whereas CB2 had no statistically significant effect. WIN 55,212-2 impaired motor function only at the highest dose given (10 mg/kg, P < 0.05).

Conclusions

Our findings support prior researches indicating that cannabinoids exert antipruritic effects. Moreover, our results show that the antipruritic effects of cannabinoids are partially mediated by spinal CB1 receptors.

Erythema elevatum diutinum-like vasculitis secondary to cocaine adulterated with levamisole

Asymptomatic hyperkeratotic plaque on the vulva of a patient with lichen sclerosus

Alternative activation of hedgehog pathway induced by ultraviolet B radiation: preliminary study

Summary

Background

There is still much ambiguity in studies of Sonic hedgehog (Shh) pathways and its dysregulation. Some studies concerning the role of the Shh pathway in basal cell carcinoma (BCC) have been conducted, but there is a lack of studies about Shh pathway dysregulation under the influence of ultraviolet (UV)B radiation.

Aim

To evaluate skin expression of Shh, Ptch1, Ptch2, Smo and Gli1 proteins in BCCs with and without the influence of UVB radiation.

Methods

In total, 34 healthy controls (HCs) and 42 patients with nodular BCC were recruited into the study. Patients were divided into five groups (A–E), depending on UVB dose received and BCC status. In all skin specimens, expression of Shh, Ptch1, Ptch2, Smo and Gli1 protein was evaluated.

Results

Comparing the BCC group with the HC group, there was significantly higher expression of Shh, Ptch1, Ptch2, Smo and Gli1 proteins. Expression of Ptch2, Smo and Gli1 was increased in response to UVB doses of 3 MED (minimal erythema dose), whereas expression of Ptch1 and Shh was unaffected.

Conclusion

The lack of change in expression of Shh and Ptch1 after exposure to UVB suggests that the Shh pathway may be activated through a noncanonical pathway under the influence of strong UVB doses.

Systemic allergic contact dermatitis associated with topical diltiazem and/or cinchocaine

Abstract

Topical anesthetics for the treatment of anal fissures or hemorrhoids are a frequent cause of allergic contact dermatitis (ACD) in the perianal region¹. Since 2009, a few cases have been reported also to the calcium channel blocker diltiazem^2,3,4 used as a first-line agent in the treatment of anal fissures. We present a case of ACD from diltiazem and/or cinchocaine followed by systemic contact dermatitis (SCD).

This article is protected by copyright. All rights reserved.

A retrospective case series of referrals to our psychodermatology clinic 2009-2016

Abstract

Psychodermatology is a relatively new subspecialty exploring the interaction between skin and the mind. Managing patients in this cohort can be challenging^1,2,3. The aetiology of psychocutaneous disease is often complex, ranging from solely functional skin-directed symptoms (psychogenic pruritis), to thought disorders manifesting in a cutaneous fashion (delusional parasitosis), to factitious disorders with cutaneous consequences (e.g. dermatitis artefacta). In addition, purely psychiatric conditions (i.e. substance misuse, depression or obsessive compulsive disorder), may occur alongside dermatological disease, further complicating successful management.

This article is protected by copyright. All rights reserved.

High Surface Area SnO2-Ta2O5 Composite for Visible Light Driven Photocatalytic Degradation of an Organic Dye

Abstract

SnO₂-Ta₂O₅ nanocomposite was synthesised by a facile co-precipitation method and further calcined to obtain crystalline powder. Phase formation, morphology, bandgap and photo-catalytic properties were analysed using powder X-ray diffraction, Scanning electron microscopy, UV-Vis diffused reflectance spectroscopy, BET surface area and Raman spectroscopy respectively. Effect of calcination temperature on the crystallinity of the composite was studied. The as prepared samples of SnO₂, Ta₂O₅ and SnO₂-10wt%Ta₂O₅ composite as well as the calcined composite sample were tested for photocatalytic activity for methylene blue dye degradation under visible light. Photocatalytic studies reveal that, the as prepared SnO₂-10wt%Ta₂O₅ composite showed the best photocatalytic activity for the degradation of Methylene Blue (MB) by harvesting visible light radiation efficiently. Further mineralisation of methylene blue, estimated by COD analysis, is found to have degraded with an efficiency of 91.6%. The study demonstrates that heterostructure of SnO₂-Ta₂O₅ nanocomposite could be applied in photocatalytic purification of organic pollutants.

This article is protected by copyright. All rights reserved.

Anti-photoaging Effect of Prunus yeonesis Blossom Extract via Inhibition of MAPK/AP-1 and Regulation of the TGF-βI/Smad and Nrf2/ARE Signaling Pathways

Abstract

Cherry blossoms have attracted attention as an ingredient with potential for use in skincare products. However, no skin photoaging-related research has been performed with this plant. In the present study, cherry blossom extract (CBE) at 1, 10, and 100 μg/mL was investigated for its skin anti-photoaging effects in UVB-irradiated normal human dermal fibroblasts (NHDF) cells in vitro. Our results showed that CBE markedly increased type I procollagen during UVB exposure via two pathways. Firstly, transcription activator protein-1 expression and MAP kinases were downregulated, consequently reducing the production of matrix metalloproteinase (MMP)-1 and MMP-3. Secondly, transforming growth factor TGF-βI secretion was upregulated by Smads. Application of CBE facilitated the nuclear translocation of Nrf2 against reactive oxygen species (ROS)-induced damage, which is essential for the coordinated induction of cytoptotective enzymes. Together, our findings suggest that CBE may be a promising ingredient for skin aging therapy and provide a novel approach for alleviating cutaneous aging.

This article is protected by copyright. All rights reserved.

Effects of Repeated UVA Irradiation on Human Skin Fibroblasts Embedded in 3D Tense Collagen Matrix

Abstract

Skin photoaging is caused by cumulative UVA exposure that leads to dermal matrix alterations associated with impaired fibroblast functions. In this study, we evaluated the effects of repeated UVA irradiation on mechanically stressed fibroblasts which were embedded in 3D tense collagen matrix. By comparison to 2D monolayer culture, we investigated the expressions of alpha smooth muscle actin (α-SMA) cytoskeleton and α2 subunit of integrin receptors, as well as the collagen metabolism, focusing to MMP-1 and collagen type I expressions. We found that UVA exposure reduces collagen levels in both culture conditions. However, concerning integrin α2 and α-SMA expression, UVA irradiation had no effect on 2D culture, whereas in tense 3D culture, it had an inhibitory effect. In UVA-irradiated 3D culture, fibroblasts acquired elongated shape and lost their dynamic interaction with collagen fibers through a decrease of integrin α2 and α-SMA. Fibroblast responses to UVA irradiation were different in 2D versus 3D environment, highlighting the importance of collagen environment in the regulation of mechanical activities. The behavior of fibroblast upon mechanical stimulation closely mimics stressed extracellular environment. The model of UVA-irradiated fibroblasts cultured in tense 3D collagen gel illustrated the in vivo situation of both mechanically stressed and photoaged human skin.

This article is protected by copyright. All rights reserved.

Validation of Questionnaire and Diary Measures of Time Outdoors Against an Objective Measure of Personal Ultraviolet Radiation Exposure

Abstract

Self-reported sun exposure is commonly measured using questionnaires or diaries, but there are limited data on their validity, particularly for population subgroups. This research aimed to compare self-reported sun exposure, measured as 1) habitual time outdoors over the past month on weekends and weekdays, and 2) a four-day diary measure, against objective measurement of personal ultraviolet radiation using polysulfone film dosimeters. From November 2015 to January 2016, 94 people (22-69 years and living in New South Wales, Australia) completed a questionnaire, 4-day diary and 4-day dosimeter measures of overall, weekday and weekend sun exposure. Spearman correlations and Bland-Altman plots were used to measure agreement. The overall weekly correlation was 0.57 (95% confidence interval [CI] 0.44, 0.68) between standard erythemal doses (SEDs) measured by dosimeter and time spent outdoors measured by questionnaire, 0.74 (95% CI 0.66-0.81) between dosimeter and diary, and 0.59 (95% CI 0.48-0.68) between questionnaire and diary measures. Validity was lower for younger people and weekend sun exposure. There was strong correlation between dosimeter and sun diary measures and moderate correlation between dosimeter and questionnaire measures. Daily measurement over a longer period may be required to accurately capture week-long sun exposure in all population subgroups.

This article is protected by copyright. All rights reserved.

Heat shock protein 90 inhibitor enhances apoptosis by inhibiting the AKT pathway in thermal-stimulated SK-MEL-2 human melanoma cell line

: Heat shock proteins (Hsps) are chaperone proteins, which are upregulated after various stresses. Hsp90 inhibitors have been investigated as adjuvant therapies for the treatment of melanoma. Thermal ablation could be a treatment option for surgically unresectable melanoma or congenital nevomelanocytic nevi, however, there is a limitation such as the possibility of recurrence.