Principles for identification of High Potency Category Chemicals for which the Dermal Sensitisation Threshold (DST) approach should not be applied

An essential step in ensuring the toxicological safety of chemicals used in consumer products is the evaluation of their skin sensitising potential. The sensitising potency, coupled with information on exposure levels, can be used in a Quantitative Risk Assessment (QRA) to determine an acceptable level of a given chemical in a given product. Where consumer skin exposure is low, a risk assessment can be conducted using the Dermal Sensitisation Threshold (DST) approach, avoiding the need to determine potency experimentally. Since skin sensitisation involves chemical reaction with skin proteins, the first step in the DST approach is to assess, on the basis of the chemical structure, whether the chemical is expected to be reactive or not. Our accompanying publication describes the probabilistic derivation of a DST of 64 μg/cm² for chemicals assessed as reactive. This would protect against 95% of chemicals assessed as reactive, but the remaining 5% would include chemicals with very high potency. Here we discuss the chemical properties and structural features of high potency sensitisers, and derive an approach whereby they can be identified and consequently excluded from application of the DST.     

Extension of the Dermal Sensitisation Threshold (DST) approach to incorporate chemicals classified as reactive

The evaluation of chemicals for their skin sensitising potential is an essential step in ensuring the safety of ingredients in consumer products. Similar to the Threshold of Toxicological Concern, the Dermal Sensitisation Threshold (DST) has been demonstrated to provide effective risk assessments for skin sensitisation in cases where human exposure is low. The DST was originally developed based on a Local Lymph Node Assay (LLNA) dataset and applied to chemicals that were not considered to be directly reactive to skin proteins, and unlikely to initiate the first mechanistic steps leading to the induction of sensitisation. Here we have extended the DST concept to protein reactive chemicals. A probabilistic assessment of the original DST dataset was conducted and a threshold of 64 μg/cm² was derived. In our accompanying publication, a set of structural chemistry based rules was developed to proactively identify highly reactive and potentially highly potent materials which should be excluded from the DST approach. The DST and rule set were benchmarked against a test set of chemicals with LLNA/human data. It is concluded that by combining the reactive DST with knowledge of chemistry a threshold can be established below which there is no appreciable risk of sensitisation for protein-reactive chemicals.     

Accuracy of transrectal ultrasound in predicting pathologic stage of rectal cancer before and after preoperative radiation therapy

Transrectal ultrasound (TRUS) and CT scan staging of rectal cancers before, and TRUS staging after, 45 Gy of irradiation were compared with the pathologic stage of the resected specimen in 19 patients. Accuracy of TRUS before and after irradiation, and of CT scan before irradiation, was 32 percent, 63 percent, and 53 percent, respectively. CT scan before and TRUS after irradiation predicted lymph node involvement in 79 percent and 68 percent of cases, respectively. Positive predictive value for lymph node involvement before irradiation was 60 percent for CT scan and 37.5 percent for TRUS; after irradiation, it was 50 percent for TRUS. Negative predictive value was 100 percent for CT scan and TRUS before radiation and 88 percent for TRUS after irradiation. Preoperative radiation therapy makes TRUS and CT scan less effective as staging techniques. The absence of lymph nodes on TRUS and CT scan before and after irradiation is reliable.Read in part at the Tripartitate Meeting, Birmingham, England, June 19 to 22, 1989.     

定量MRI诊断直肠癌淋巴结转移的研究进展

评估直肠癌淋巴结转移对治疗和预后至关重要。常规MRI诊断直肠癌淋巴结转移主要依据淋巴结的短径和形态学特征,诊断效能较低。定量MRI包括动态增强MRI（DCE-MRI）、动态磁敏感增强MRI（DSC-MRI）、单指数模型扩散加权成像（DWI）、扩散峰度成像（DKI）、体素内不相干运动扩散加权成像（IVIM-DWI）等,可以对直肠癌淋巴结及原发灶进行定量分析,从而有助于诊断淋巴结转移。就常规MRI及定量MRI诊断直肠癌淋巴结转移的研究进展予以综述。     

Colorectal Cancer Staging: Reappraisal of N/PN Classification

PURPOSE: Current American Joint Committee on Cancer and the Union Internationale Contre le Cancer TNM classification disregards location of positive nodes, discontinuing N3 category, which constitutes a major modification to 1987 version. This study was designed to assess the impact of the recategorization of former N3 cases and the reliability of the current N1-N2 subcategorization of Stage III patients. METHODS: Prospectively collected data from 1,391 patients (55.8 percent males; median age, 64 (range, 21–97) years), operated on with curative intent between 1980 and 1999, were analyzed. The median follow-up was 60 (interquartile range, 27–97) months with 129 cases lost to follow-up. RESULTS: Of positive node cases, 25.3 percent were former N3. Among them, 30.5 percent migrated to the N1 group and 69.5 percent to the N2 group. The proportions of former N3 cases in N1 and N2 groups were 12.5 percent and 46.1 percent, respectively (P < 0.001). Node-positive patients had an actuarial five-year survival rate of 56.7 percent (95 percent confidence interval, 53–59), with a significant difference between N1/N2 categories (63.6 vs. 44.1 percent, respectively; P < 0.001). Although apical node involvement and more than three positive nodes were associated with poorer outcomes in univariate analysis, only the number of positive nodes had independent association (hazard ratio, 1.6 (range, 1.2–2.2); P < 0.001). Integration of former N3 cases did not modify outcomes. CONCLUSIONS: The recategorization of former N3 involved a high proportion of positive node cases. Current N1/N2 categories clearly defined different outcomes and were not modified by the integration of former N3.     

Neuroblastic Differentiation of Metastases of Medulloblastoma to Extracranial Lymph Node: An Ultrastructural Study

Extracranial metastases of a poorly differentiated medulloblastoma in a 12-year-old girl were studied by thin section transmission electron microscopy and immunohistochemistry. The primary tumor did not show any differentiation as revealed by immunohistochemistry. On the contrary, the metastatic tumor cells and their processes disclosed features of neuroblastic differentiation when examined ultrastructurally: microtubules, dense core vesicles, and abortive synaptic ribbons. Several dystrophic neurites containing altered subcellular organelles were also found. Furthermore, few processes contained concentric arrays of paired membranes. This report is the first to clearly show the neuronal differentiation of extracranial metastases of poorly differentiated medulloblastoma. We speculate that metastases of medulloblastomas outside the neuraxis behave analogously to medulloblastoma explants cultured in vivo.     

Management of the clinically N0 neck in early-stage oral squamous cell carcinoma (OSCC). An EACMFS position paper

Metastasis of oral squamous cell carcinoma (OSCC) to the cervical lymph nodes has a significant impact on prognosis. Accurate staging of the neck is important in order to deliver appropriate treatment for locoregional control of the disease and for prognosis.The management of the neck in early, low volume disease (clinically T₁/T₂ oral cavity tumours) has long been debated. The risk of occult nodal involvement in cT₁/T₂ OSCC is estimated around 20–30%.We describe the natural evolutionary history of OSCC and its patterns of spread and metastasis to the local lymphatic basins. We discuss most published literature and studies on management of the clinically negative neck (cN₀). Particular focus is given to prospective randomized trials comparing the outcomes of upfront elective neck dissection against the observational stance, and we summarize the results of the sentinel node biopsy studies.The paper discusses the significance of the primary tumour histological characteristics and specifically the tumour's depth of invasion (DOI) and its impact on predicting nodal metastasis. The DOI has been incorporated in the TNM staging highlighting its significance in aiding the treatment decision making and this is reflected in world-wide oncological guidelines.The critical analysis of all available literature amalgamates the existing evidence in early OSCC and provides recommendations in the management of the clinically N₀ neck.     

Risk factors associated with lymphedema after lymph node dissection in melanoma patients

Background

Secondary lymphedema is a frequent complication after lymphadenectomy in melanoma patients, although few studies in melanoma adequately characterize risk factors for lymphedema, and of these, sample size is limited. This study aims to identify risk factors associated with the lymphedema after axillary lymph node dissection (ALND) and inguinal lymph node dissection (ILND) in a more robust cohort of melanoma patients.

Methods

We identified 269 ALND or ILND melanoma patients treated between 2008 and 2014. Demographic, clinical, and postoperative data were collected by review of the electronic medical record. Univariate and multivariate analysis were used to determine independent predictors of lymphedema.

Results

Fifty-six (20.8%) of the patients developed lymphedema after lymph node dissection with a median staging group of 3. ILND (odds ratio [OR] = 4.506, P < .001, 95% confidence interval [CI]: 2.289 to 8.869) and peripheral vascular disease (PVD; OR = 3.849, P = .020, 95% CI: 1.237 to 11.975) were significant predictors of lymphedema in multivariate analysis. Obese body mass index approached significance (OR = 1.802, P = .069, 95% CI: .955 to 3.399).

Conclusions

PVD and ILND were the 2 factors associated with the highest risk of lymphedema in melanoma surgery with PVD increasing risk 2-fold in ILND patients and 3-fold in ALND patients. These findings may improve surgeon-patient communication of care goals and surgical risk assessment.