Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016

Tumor budding is a well-established independent prognostic factor in colorectal cancer but a standardized method for its assessment has been lacking. The primary aim of the International Tumor Budding Consensus Conference (ITBCC) was to reach agreement on an international, evidence-based standardized scoring system for tumor budding in colorectal cancer. The ITBCC included nine sessions with presentations, a pre-meeting survey and an e-book covering the key publications on tumor budding in colorectal cancer. The 'Grading of Recommendation Assessment, Development and Evaluation' method was used to determine the strength of recommendations and quality of evidence. The following 10 statements achieved consensus: tumor budding is defined as a single tumor cell or a cell cluster consisting of four tumor cells or less (22/22, 100%). Tumor budding is an independent predictor of lymph node metastases in pT1 colorectal cancer (23/23, 100%). Tumor budding is an independent predictor of survival in stage II colorectal cancer (23/23, 100%). Tumor budding should be taken into account along with other clinicopathological features in a multidisciplinary setting (23/23, 100%). Tumor budding is counted on H&E (19/22, 86%). Intratumoral budding exists in colorectal cancer and has been shown to be related to lymph node metastasis (22/22, 100%). Tumor budding is assessed in one hotspot (in a field measuring 0.785 mm2) at the invasive front (22/22, 100%). A three-tier system should be used along with the budding count in order to facilitate risk stratification in colorectal cancer (23/23, 100%). Tumor budding and tumor grade are not the same (23/23, 100%). Tumor budding should be included in guidelines/protocols for colorectal cancer reporting (23/23, 100%). Members of the ITBCC were able to reach strong consensus on a single international, evidence-based method for tumor budding assessment and reporting. It is proposed that this method be incorporated into colorectal cancer guidelines/protocols and staging systems.

Dilated perivascular spaces in the Basal Ganglia are a biomarker of small-vessel disease in a very elderly population with dementia.

BACKGROUND AND PURPOSE: Dilated perivascular spaces have been shown to be a specific biomarker of cerebral small-vessel disease in young patients with dementia. Our aim was to examine the discriminative power of dilated cerebral perivascular spaces as biomarkers of small-vessel disease in a very elderly population of patients with dementia. MATERIALS AND METHODS: We studied healthy volunteers (n = 65; mean age, 78 ± 5.6 years) and subjects with vascular dementia (n = 39; mean age, 76.9 ± 7.7 years) and Alzheimer disease (n = 47; mean age, 74.1 ± 8.5 years). We compared white matter hyperintensity and 2 semiquantitative perivascular space scoring systems (perivascular space-1 and perivascular space-2). Intra- and interobserver agreement was assessed by using a weighted Cohen κ statistic. Multinomial regression modeling was used to assess the discriminative power of imaging features to distinguish clinical groups. RESULTS: White matter hyperintensity scores were higher in vascular dementia than in Alzheimer disease (P < .05) or healthy volunteers (P < .01). The perivascular space-1 score was higher in vascular dementia and Alzheimer disease than in healthy volunteers (P < .01). The perivascular space-2 score in the centrum semiovale showed no intergroup differences. However, perivascular space-2 in the basal ganglia was higher in vascular dementia than in Alzheimer disease (P < .05) or healthy volunteers (P < .001) and higher in Alzheimer disease than in healthy volunteers (P < .001). Modeling of dementia versus healthy volunteers, Alzheimer disease versus healthy volunteers, and vascular dementia against Alzheimer disease demonstrated perivascular space-2basal ganglia as the only imaging parameter with independent significant discriminative power (P < .01, P < .01, and P < .05) with areas under the receiver operating characteristic curve of 0.855, 0.774, and 0.71, respectively. Modeling of vascular dementia versus healthy volunteers showed that perivascular space-2basal ganglia (P < .01) and the modified Scheltens score (P < .05) contributed significant, independent discriminatory power, accounting for 34% and 13% of the variance in the model respectively. CONCLUSIONS: Dilated perivascular spaces remain a valuable biomarker of small-vessel disease in an elderly population.

Endoscopic ultrasound, endoscopic sonoelastography, and strain ratio evaluation of lymph nodes with histology as gold standard.

BACKGROUND AND STUDY AIMS: Accurate lymph node staging is essential for the selection of an optimal treatment in patients with upper gastrointestinal cancer. Endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) are considered to be the most accurate method for locoregional staging. Endoscopic sonoelastography (ESE) assesses the elasticity of lymph nodes and has been used to differentiate lymph nodes with promising results. The aim of this study was to evaluate the use of EUS, EUS - FNA, ESE, and ESE-strain ratio using histology as the gold standard. PATIENTS AND METHODS: Patients with upper gastrointestinal cancer who were referred for EUS examination were enrolled if surgical treatment was planned and the patient had a lymph node that was accessible for EUS - FNA and EUS-guided fine-needle marking (FNM). The lymph node was classified using EUS, ESE, and ESE-strain ratio. Finally, EUS - FNA and EUS - FNM were performed. The marked lymph node was isolated during surgery for histological examination. RESULTS: The marked lymph node was isolated for separate histological examination in 56 patients, of whom 22 (39 %) had malignant lymph nodes and 34 (61 %) had benign lymph nodes. There were no complications of EUS - FNM. The sensitivity of EUS for differentiation between malignant and benign lymph nodes was 86 % compared with 55 % - 59 % for the different ESE modalities. The specificity of EUS was 71 % compared with 82 % - 85 % using ESE modalities. CONCLUSION: The use of the EUS - FNM technique enabled the identification of a specific lymph node and thereby the use of histology as gold standard. ESE and ESE-strain ratio were no better than standard EUS in differentiating between malignant and benign lymph nodes in patients with resectable upper gastrointestinal cancer.

Photonic crystal fiber based evanescent-wave sensor for detection of biomolecules in aqueous solutions.

We demonstrate highly efficient evanescent-wave detection of fluorophore-labeled biomolecules in aqueous solutions positioned in the air holes of the microstructured part of a photonic crystal fiber. The air-suspended silica structures located between three neighboring air holes in the cladding crystal guide light with a large fraction of the optical field penetrating into the sample even at wavelengths in the visible range. An effective interaction length of several centimeters is obtained when a sample volume of less than 1 microL is used.

All-fiber format compression of frequency chirped pulses in air-guiding photonic crystal fibers.

Air-cored, photonic band-gap crystal fibers exhibiting low nonlinearity and anomalous chromatic dispersion in spectral ranges inaccessible to conventional fibers can be used in the realization of all-fiber-format pulse compressors with unprecedented peak powers and wavelength diversity. Linear compression of inherently chirped and prestretched pulses by factors ranging from 20 to 80 around 1.0 and 1.5 microm have allowed generation of pulses as short as 163 fs. The results show that totally integrated femtosecond fiber laser sources can be realized throughout the visible and near-infrared and point to the possibility of megawatt peak and tens of watt average in-fiber power levels.

Lipids in the proximal tubules of the kidney in diabetic coma.

Vacuolization of the renal tubular epithelial cells (the Armanni-Ebstein lesion) associated with diabetic hyperglycemia is usually regarded as an accumulation of glycogen. In a case of death of diabetic coma, the vacuoles were stained strongly for lipids. This observation may have both clinical and therapeutic consequences, and may increase our knowledge of the metabolism in diabetes.

The expression of p53, Ki-67 and urokinase plasminogen activator receptor in colorectal adenomas with true invasion and pseudoinvasion.

The recognition of pseudoinvasion is important in the differential diagnosis of adenocarcinoma in patients with adenomas. This distinction might occasionally be difficult, particularly when the dysplasia is pronounced. The present study was undertaken in order to investigate whether the immunohistochemical expression of p53, Ki-67 and the urokinase plasminogen activator receptor (uPAR) was different in adenomas with true invasion and pseudoinvasion. We studied 26 formalin-fixed, paraffin-embedded tumor samples, consisting of 10 cases of adenomas with pseudoinvasion and 16 cases of adenocarcinomas in adenomas. In this series of selected histologically typical cases a constant moderate or strong reaction for uPAR was present at the invasive front in all of the 16 adenomas with adenocarcinoma, but only focally in one of 10 adenomas with pseudoinvasion. The reactions for p53 and Ki-67 showed only minor differences. In conclusion, the immunohistochemical reaction for uPAR seems to be a useful supplement in cases without typical histology or with severe dysplasia.

A comparison of flow cytometry and immunohistochemistry in human colorectal cancers.

In human colorectal cancer it has been reported that some tumours lack the HLA-ABC antigens. This has been interpreted as reflecting tumour escape from the immune system. Earlier data have been obtained by immunohistochemistry. In this study, we compared the expression of HLA-ABC, HLA-DR, CD80 (B7-1) and CD54 (ICAM-1) in 20 tumours using both a conventional immunohistochemistry two-layer technique and multiparameter flow cytometry, gating on an epithelial cell marker. Colorectal cancer tissue used in flow cytometry was dissociated with collagenase, deoxyribonuclease and hyaluronidase. The intensity of expression of HLA-ABC, HLA-DR and CD80 was unaffected by the enzymes, but CD54 was decreased by 30%. The reproducibility of flow cytometry was good. Microscopy of sections revealed that about 5% of each tumour sample consisted of normal epithelium, but even after correction for this, flow cytometry was superior to immunohistochemistry in 33 out of 80 cases, and showed that tumours described as HLA-ABC negative by immunohistochemistry were in fact weakly positive for HLA-ABC. We conclude that flow cytometry and immunohistochemistry are complementary, and that flow cytometry is superior to immunohistochemistry for detecting antigens/epitopes present in low amounts.

Prognostic factors in papillary and follicular thyroid carcinomas: p53 expression is a significant indicator of prognosis.

To identify clinical and histologic prognostic factors and to investigate whether immunohistochemical detection of p53 expression might contain prognostic information, a retrospective study of patient and tumor characteristics was performed in 225 cases of papillary and follicular thyroid carcinomas. The analyses were based on cause-specific and crude survival. In univariate analysis, age at diagnosis, tumor size, presence of distant metastases, histology (papillary contra follicular type), extrathyroidal invasion, necrosis in primary tumor, and p53 expression were significant prognostic indicators. For 211 patients (96%) all information was available and Cox's proportional hazard model was applied. The authors found that age, distant metastases, necrosis in primary tumor, extrathyroidal invasion, and p53 expression were significant prognostic factors. Analyses of cause-specific and crude survival gave similar results. The authors conclude that age at diagnosis, presence of distant metastases, necrosis in primary tumor, and extrathyroidal invasion are important prognostic factors, and that immunohistochemical detection of p53 protein in the primary tumor is a significant and independent prognostic indicator, which might be of value in the treatment planning in patients with papillary or follicular thyroid carcinomas.

Sertoli-Leydig cell tumour of the ovary--a rare cause of virilization after menopause.

A case of Sertoli-Leydig cell tumour of the ovary causing virilization in a postmenopausal woman is presented. The patient had increasing facial hair growth, deepening of the voice, a dull pain in the lower part of the abdomen and enlargement of the clitoris. Laboratory investigations showed an elevated level of plasma testosterone. Considering an ovarian tumour the most likely cause of the above-mentioned findings, hysterectomy with bilateral salpingo-oophorectomy was performed. Both ovaries were macroscopically normal at operation, but pathological examination revealed a small well-differentiated Sertoli-Leydig cell tumour in the left ovary. Follow-up 3 months later showed decreasing signs of virilization and normalization of the hormone levels.

Riboflavin deficiency is associated with selective preservation of critical flavoenzyme-dependent metabolic pathways.

Riboflavin is a water soluble vitamin that serves as a precursor of flavin mononucleotide and flavin adenine dinucleotide. These two compounds are coenzymes in a variety of electron transfer reactions that occur in energy producing, biosynthetic, detoxifying and electron scavenging pathways. When an organism is confronted with inadequate dietary riboflavin, characteristic changes occur in the cellular distribution of the various flavin fractions as well as in the activities of flavin-dependent enzymes. These changes suggest a specific hierarchic response to riboflavin deficiency, e.g. the core electron transfer chain required for ATP synthesis is preserved while the enzymes required for the first step of fatty acid beta-oxidation are diminished. The mechanisms by which the specific changes in enzyme activity are mediated have not been completely identified, but appear to result from a combination of diminished access of normal or near normal levels of apoenzyme to coenzyme and diminished abundance of apoenzyme. The changes in apoenzyme content potentially result from alterations in either protein stability or gene expression. The response to riboflavin deficiency of several key enzyme systems and the pathways affected will be discussed and a hierarchic order by which specific enzyme activities are preserved while others are decreased will be proposed. The current understanding of the molecular mechanisms by which these changes are mediated will be discussed.