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Resistance to cancer chemotherapies leads to deadly consequences, yet current research focuses only on the roles of somatically acquired mutations in this resistance. The mutational status of the germline is also likely to play a role in the way cells respond to chemotherapy. The carrier status for the POLB rs3136797 germline mutation encoding P242R DNA polymerase beta (Pol β) is associated with poor prognosis for lung cancer, specifically in response to treatment with cisplatin. Here, it is revealed that the P242R mutation is sufficient to promote resistance to cisplatin in human cells and in mouse xenografts. Mechanistically, P242R Pol β acts as a translesion polymerase and prefers to insert the correct nucleotide opposite cisplatin intrastrand cross-links, leading to the activation of the nucleotide excision repair (NER) pathway, removal of crosslinks, and resistance to cisplatin. In contrast, wild-type (WT) Pol β preferentially inserts the incorrect nucleotide initiating mismatch repair and cell death. Importantly, in a mouse xenograft model, tumors derived from lung cancer cells expressing WT Pol β displayed a slower rate of growth when treated with cisplatin, whereas tumors expressing P242R Pol β had no response to cisplatin. Pol β is critical for mediating crosstalk in response to cisplatin. The current data strongly suggest that the status of Pol β influences cellular responses to crosslinking agents and that Pol β is a promising biomarker to predict responses to specific chemotherapies. Finally, these results highlight that the genetic status of the germline is a critical factor in the response to cancer treatment.Implications: Pol β has prognostic biomarker potential in the treatment of cancer with cisplatin and perhaps other intrastrand crosslinking agents. Mol Cancer Res; 15(3); 269–80. ©2017 AACR.

S1. Dose-response curve of MCF7 cells. S2. Western blotting analysis of Pol beta in cell lines. S3. Pol beta and XPA interact in vitro. S4. The effect of E295K Pol beta expression on survival following cisplatin treatment. Table S1. Difference in viability of crosslinking agents from high-throughput screen.

Precision-based molecular phenotyping of heart failure must overcome limited access to cardiac tissue. Although epigenetic alterations have been found to underlie pathological cardiac gene dysregulation, the clinical utility of myocardial epigenomics remains narrow owing to limited clinical access to tissue. Therefore, the current study determined whether patient plasma confers indirect phenotypic, transcriptional, and/or epigenetic alterations to ex vivo cardiomyocytes to mirror the failing human myocardium. Neonatal rat ventricular myocytes (NRVMs) and single-origin human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and were treated with blood plasma samples from patients with dilated cardiomyopathy (DCM) and donor subjects lacking history of cardiovascular disease. Following plasma treatments, NRVMs and hiPSC-CMs underwent significant hypertrophy relative to non-failing controls, as determined via automated high-content screening. Array-based DNA methylation analysis of plasma-treated hiPSC-CMs and cardiac biopsies uncovered robust, and conserved, alterations in cardiac DNA methylation, from which 100 sites were validated using an independent cohort. Among the CpG sites identified, hypo-methylation of the ATG promoter was identified as a diagnostic marker of HF, wherein cg03800765 methylation (AUC = 0.986, P

Item does not contain fulltext OBJECTIVE: Palliative pelvic exenteration (PPE) is a technically complex operation with high morbidity and mortality rates, considered in patients with limited life expectancy. There is little evidence to guide practice. We performed a systematic review to evaluate the impact of PPE on symptom relief and quality of life (QoL). METHODS: A systematic review was conducted according to the PRISMA guidelines using Ovid MEDLINE, EMBASe, and PubMed databases for studies reporting on outcomes of PPE for symptom relief or QoL. Descriptive statistics were used on pooled patient cohorts. RESULTS: Twenty-three historical cohorts and case series were included, comprising 509 patients. No comparative studies were found. Most malignancies were of colorectal, gynaecological and urological origin. Common indications for PPE were pain, symptomatic fistula, bleeding, malodour, obstruction and pelvic sepsis. The pooled median postoperative morbidity rate was 53.6% (13-100%), the median in-hospital mortality was 6.3% (0-66.7%), and median OS was 14 months (4-40 months). Some symptom relief was reported in a median of 79% (50-100%) of the patients, although the magnitude of effect was poorly measured. Data for QoL measures were inconclusive. Five studies discouraged performing PPE in any patient, while 18 studies concluded that the procedure can be considered in highly selected patients. CONCLUSION: Available evidence on PPE is of low-quality. Morbidity and mortality rates are high with a short median OS interval. While some symptom relief may be afforded by this procedure, evidence for improvement in QoL is limited. A highly selective individualised approach is required to optimise the risk:benefit equation.

We present a rarely described complication of unilateral rhinorrhea and sneezing in a patient who received intravenous sedation with propofol and supplemental oxygen via a nasal cannula during upper gastrointestinal endoscopy. The literature is reviewed and a mechanism is proposed. Mechanical irritation of the nasal mucosa is felt to be the trigger. Suggestions to avoid and to treat are offered.

Aldosterone-producing adenomas (APAs) are benign tumors of the adrenal gland that constitutively produce the salt-retaining steroid hormone aldosterone and cause millions of cases of severe hypertension worldwide. Either of 2 somatic mutations in the potassium channel KCNJ5 (G151R and L168R, hereafter referred to as KCNJ5MUT) in adrenocortical cells account for half of APAs worldwide. These mutations alter channel selectivity to allow abnormal Na+ conductance, resulting in membrane depolarization, calcium influx, aldosterone production, and cell proliferation. Because APA diagnosis requires a difficult invasive procedure, patients often remain undiagnosed and inadequately treated. Inhibitors of KCNJ5MUT could allow noninvasive diagnosis and therapy of APAs carrying KCNJ5 mutations. Here, we developed a high-throughput screen for rescue of KCNJ5MUT-induced lethality and identified a series of macrolide antibiotics, including roxithromycin, that potently inhibit KCNJ5MUT, but not KCNJ5WT. Electrophysiology demonstrated direct KCNJ5MUT inhibition. In human aldosterone-producing adrenocortical cancer cell lines, roxithromycin inhibited KCNJ5MUT-induced induction of CYP11B2 (encoding aldosterone synthase) expression and aldosterone production. Further exploration of macrolides showed that KCNJ5MUT was similarly selectively inhibited by idremcinal, a macrolide motilin receptor agonist, and by synthesized macrolide derivatives lacking antibiotic or motilide activity. Macrolide-derived selective KCNJ5MUT inhibitors thus have the potential to advance the diagnosis and treatment of APAs harboring KCNJ5MUT.

Insulin resistance drives the development of type 2 diabetes (T2D). In liver, diacylglycerol (DAG) is a key mediator of lipid-induced insulin resistance. DAG activates protein kinase C ε (PKCε), which phosphorylates and inhibits the insulin receptor. In rats, a 3-day high-fat diet produces hepatic insulin resistance through this mechanism, and knockdown of hepatic PKCε protects against high-fat diet-induced hepatic insulin resistance. Here, we employed a systems-level approach to uncover additional signaling pathways involved in high-fat diet-induced hepatic insulin resistance. We used quantitative phosphoproteomics to map global in vivo changes in hepatic protein phosphorylation in chow-fed, high-fat–fed, and high-fat–fed with PKCε knockdown rats to distinguish the impact of lipid- and PKCε-induced protein phosphorylation. This was followed by a functional siRNA-based screen to determine which dynamically regulated phosphoproteins may be involved in canonical insulin signaling. Direct PKCε substrates were identified by motif analysis of phosphoproteomics data and validated using a large-scale in vitro kinase assay. These substrates included the p70S6K substrates RPS6 and IRS1, which suggested cross talk between PKCε and p70S6K in high-fat diet-induced hepatic insulin resistance. These results identify an expanded set of proteins through which PKCε may drive high-fat diet-induced hepatic insulin resistance that may direct new therapeutic approaches for T2D.

We present a rarely described complication of unilateral rhinorrhea and sneezing in a patient who received intravenous sedation with propofol and supplemental oxygen via a nasal cannula during upper gastrointestinal endoscopy. The literature is reviewed and a mechanism is proposed. Mechanical irritation of the nasal mucosa is felt to be the trigger. Suggestions to avoid and to treat are offered.

Anorektale Tumoren sind nicht selten. Neben seltenen Entitaten finden sich in der klinischen Praxis in erster Linie das Analkarzinom und das Rektumkarzinom. In diesem Kapitel werden pathologische Grundlagen und Therapieoptionen vorgestellt. Wahrend bei den benignen Erkrankungen des Rektums in der Regel minimalinvasive endokopische oder transanale Verfahren zur Anwendung kommen, ist bei den Rektumkarzinomen und Analkarzinomen meist ein gemeinsames Vorgehen von Onkologen, Strahlentherapeuten und Koloproktologen indiziert.

A SELECT GROUP OF FIELD COLLECTORS, LED BY MANAGING PARTNER PAUL GEFFNER, REORGANIZED IN MARCH 2015 TO PURSUE SPECIMENS FROM AMERICA'S FINEST AMETHYST DEPOSIT, JACKSONS CROSSROADS IN WILKES COUNTY,...

Die zunehmende Inzidenz sowie eine Verbesserung im Gesamtuberleben fuhren weltweit zu einer steigenden Pravalenz von Patienten mit malignem Melanom. Laut Robert Koch-Institut zeigte sich eine 5-Jahres-Pravalenz von 37.000 Frauen und 36.100 Manner in Deutschland, basierend auf deutschen Krebsregisterdaten fur das Jahr 2012. Die fruhzeitige Exzision des primaren malignen Melanoms ist bis heute die Therapie der Wahl. In anatomisch schwierigen Lokalisationen wie Gesicht und Akren konnen die geforderten Sicherheitsabstande zwischen 0,5 und 2 cm in Abhangigkeit von der Tumordicke aufgrund der anatomischen Lokalisation jedoch nicht immer streng eingehalten werden. In diesem Fall ist oftmals eine mikrographisch kontrollierte Chirurgie mit anschliesender 3D-Histologie hilfreich. Diese Arbeit basiert auf einer selektiven Literaturrecherche sowie anhand der S3-Leitlinie „Diagnostik, Therapie und Nachsorge des Melanoms“ und aktueller Arbeiten. Die Metastasierung erfolgt beim malignen Melanom in uber 90 % primar lymphogen, wobei die Wahrscheinlichkeit einer Metastasierung mit steigender Tumordicke zunimmt. Die Indikation zur therapeutischen Lymphknotendissektion wird in den aktuellen S3-Leitlinien definiert. Die technische Durchfuhrung der Leisten-, Axilla- und Halsdissektion ist heute standardisiert. Vereinzelte Satelliten- oder Intransitmetastasen konnen mit dem Ziel einer R0-Resektion exzidiert werden. Bei multiplem Befall der unteren Extremitaten stellt die hypertherme isolierte Extremitatenperfusion eine weitere Behandlungsoption dar. Ist eine vollstandige chirurgische Entfernung der Fernmetastasen moglich, hat sich gezeigt, dass die Uberlebenszeit bei diesen Patienten durch eine vollstandige Metastasektomie signifikant verlangert werden kann. Im Vorfeld sollte bei Metastasierung die weitere Therapie in einer interdisziplinaren Tumorkonferenz individuell geplant werden.

Sepsis is a systemic inflammatory response to infection and a major cause of death worldwide. Because specific therapies to treat sepsis are limited, and underlying pathogenesis is unclear, current medical care remains purely supportive. Therefore targeted therapies to treat sepsis need to be developed. Although an important mediator of sepsis is thought to be mitochondrial dysfunction, the underlying molecular mechanism is unclear. Modulation of mitochondrial processes may be an effective therapeutic strategy in sepsis. Here, we investigated the role of the kinase MKK3 in regulation of mitochondrial function in sepsis. Using clinically relevant animal models, we examined mitochondrial function in primary mouse lung endothelial cells exposed to LPS. MKK3 deficiency reduces lethality of sepsis in mice and by lowering levels of lung and mitochondrial injury as well as reactive oxygen species. Furthermore, MKK3 deficiency appeared to simultaneously increase mitochondrial biogenesis and mitophagy through the actions of Sirt1, Pink1, and Parkin. This led to a more robust mitochondrial network, which we propose provides protection against sepsis. We also detected higher MKK3 activation in isolated peripheral blood mononuclear cells from septic patients compared with nonseptic controls. Our findings demonstrate a critical role for mitochondria in the pathogenesis of sepsis that involves a previously unrecognized function of MKK3 in mitochondrial quality control. This mitochondrial pathway may help reveal new diagnostic markers and therapeutic targets against sepsis.

JARID1B (also known as KDM5B or PLU1) is a member of the JARID1 family of histone lysine demethylases responsible for the demethylation of trimethylated lysine 27 in histone H3 (H3K4me3), a mark for actively transcribed genes. JARID1B is overexpressed in several cancers, including breast cancer, prostate cancer, and lung cancer. In addition, JARID1B is required for mammary tumor formation in syngeneic or xenograft mouse models. JARID1B-expressing melanoma cells are associated with increased self-renewal character. Therefore, JARID1B represents an attractive target for cancer therapy. Here we characterized JARID1B using a homogeneous luminescence-based demethylase assay. We then conducted a high throughput screen of over 15,000 small molecules to identify inhibitors of JARID1B. From this screen, we identified several known JmjC histone demethylase inhibitors, including 2,4-pyridinedicarboxylic acid and catechols. More importantly, we identified several novel inhibitors, including 2-4(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PBIT), which inhibits JARID1B with an IC50 of about 3 μm in vitro. Consistent with this, PBIT treatment inhibited removal of H3K4me3 by JARID1B in cells. Furthermore, this compound inhibited proliferation of cells expressing higher levels of JARID1B. These results suggest that this novel small molecule inhibitor is a lead compound that can be further optimized for cancer therapy.

Resistance to cancer chemotherapies leads to deadly consequences, yet current research focuses only on the roles of somatically acquired mutations in this resistance. The mutational status of the germline is also likely to play a role in the way cells respond to chemotherapy. The carrier status for the POLB rs3136797 germline mutation encoding P242R DNA polymerase beta (Pol β) is associated with poor prognosis for lung cancer, specifically in response to treatment with cisplatin. Here, it is revealed that the P242R mutation is sufficient to promote resistance to cisplatin in human cells and in mouse xenografts. Mechanistically, P242R Pol β acts as a translesion polymerase and prefers to insert the correct nucleotide opposite cisplatin intrastrand cross-links, leading to the activation of the nucleotide excision repair (NER) pathway, removal of crosslinks, and resistance to cisplatin. In contrast, wild-type (WT) Pol β preferentially inserts the incorrect nucleotide initiating mismatch repair and cell death. Importantly, in a mouse xenograft model, tumors derived from lung cancer cells expressing WT Pol β displayed a slower rate of growth when treated with cisplatin, whereas tumors expressing P242R Pol β had no response to cisplatin. Pol β is critical for mediating crosstalk in response to cisplatin. The current data strongly suggest that the status of Pol β influences cellular responses to crosslinking agents and that Pol β is a promising biomarker to predict responses to specific chemotherapies. Finally, these results highlight that the genetic status of the germline is a critical factor in the response to cancer treatment. Implications: Pol β has prognostic biomarker potential in the treatment of cancer with cisplatin and perhaps other intrastrand crosslinking agents. Mol Cancer Res; 15(3); 269–80. ©2017 AACR.

// Molly Gale 1 , Joyce Sayegh 1, 3 , Jian Cao 1 , Michael Norcia 2 , Peter Gareiss 2 , Denton Hoyer 2 , Jane S. Merkel 2 , Qin Yan 1 1 Department of Pathology, Yale School of Medicine, New Haven, CT, USA 2 Yale Center for Molecular Discovery, Yale University, West Haven, CT, USA 3 Current address: Department of Biology and Chemistry, Azusa Pacific University, Azusa, CA, USA Correspondence to: Qin Yan, email: qin.yan@yale.edu Keywords: histone demethylase inhibitor, KDM5A, anti-cancer drug, drug resistance, epigenetics Received: February 23, 2016 Accepted: May 05, 2016 Published: May 21, 2016 ABSTRACT Lysine demethylase 5A (KDM5A/RBP2/JARID1A) is a histone lysine demethylase that is overexpressed in several human cancers including lung, gastric, breast and liver cancers. It plays key roles in important cancer processes including tumorigenesis, metastasis, and drug tolerance, making it a potential cancer therapeutic target. Chemical tools to analyze KDM5A demethylase activity are extremely limited as available inhibitors are not specific for KDM5A. Here, we characterized KDM5A using a homogeneous luminescence-based assay and conducted a screen of about 9,000 small molecules for inhibitors. From this screen, we identified several 3-thio-1,2,4-triazole compounds that inhibited KDM5A with low μM in vitro IC 50 values. Importantly, these compounds showed great specificity and did not inhibit its close homologue KDM5B (PLU1/JARID1B) or the related H3K27 demethylases KDM6A (UTX) and KDM6B (JMJD3). One compound, named YUKA1, was able to increase H3K4me3 levels in human cells and selectively inhibit the proliferation of cancer cells whose growth depends on KDM5A. As KDM5A was shown to mediate drug tolerance, we investigated the ability of YUKA1 to prevent drug tolerance in EGFR-mutant lung cancer cells treated with gefitinib and HER2+ breast cancer cells treated with trastuzumab. Remarkably, this compound hindered the emergence of drug-tolerant cells, highlighting the critical role of KDM5A demethylase activity in drug resistance. The small molecules presented here are excellent tool compounds for further study of KDM5A’s demethylase activity and its contributions to cancer.

Das maligne Melanom mit unbekanntem Primartumor ist immer eine metastasierte Tumorerkrankung. Das klinische Bild zeigt haufig regionare Tumormanifestationen in Form von kutanen und subkutanen Absiedelungen sowie Lymphknotenfiliae, nicht selten aber auch Organmetastasen in Lunge, Leber, Gehirn, Knochen, Milz und gastrointestinal. Diagnostik und Therapie sind nicht immer unmittelbar zu trennen. Da gehauft Mehrfachlokalisationen vorkommen, sollte nach Durchfuhrung eines Ganzkorperstagings die individuelle Therapieplanung in einem interdisziplinaren Tumorboard erfolgen. Gesicherte regionare Metastasen in Haut und Weichteilen oder Lymphknotenfiliae in einem Bassin werden als Stadium III klassifiziert und entsprechend behandelt. Ihre Prognose ist vergleichbar oder besser als die bei bekanntem Primarius. Auch nach kurativer Resektion sind erneute Rezidive haufig, welche aber auch oft erneut kurativ reseziert werden konnen. An palliativen Masnahmen stehen in Abhangigkeit von Umfang und Lokalisation der Metastasen interventionelle Verfahren, Strahlentherapie, Chemotherapie, neue Kinaseinhibitoren und neue Immuntherapeutika zur Verfugung.

Summary The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new pharmacophores. Hookworms are blood-feeding, intestinal nematode parasites that infect up to 600 million people worldwide. Vaccination with recombinant Ancylostoma ceylanicum macrophage migration inhibitory factor (rAceMIF) provided partial protection from disease, thus establishing a "proof-of-concept" for targeting AceMIF to prevent or treat infection. A high-throughput screen (HTS) against rAceMIF identified six AceMIF-specific inhibitors. A nonsteroidal anti-inflammatory drug (NSAID), sodium meclofenamate, could be tested in an animal model to assess the therapeutic efficacy in treating hookworm disease. Furosemide, an FDA-approved diuretic, exhibited submicromolar inhibition of rAceMIF tautomerase activity. Structure-activity relationships of a pharmacophore based on furosemide included one analog that binds similarly to the active site, yet does not inhibit the Na-K-Cl symporter (NKCC1) responsible for diuretic activity.

Due to the broad variation of clinical presentation in metastasised malignant melanoma, a careful staging and individual treatment of these patients is required. Especially, the occurrence of locoregional or / and distant metastasis presents an important problem. Not only treatment with a curative intent but also sophisticated surgical procedures with a palliative intent are necessary in patients with tumour complications. These procedures do not improve the oncological prognosis. However, they may rescue patients from life-threatening situations. Therefore, palliative surgery of metastases plays an important role and requires assessment by an experienced oncological team.

Das maligne Melanom zahlt zu den Malignomen mit der hochsten Zuwachsrate. Histologisch unterscheidet man das superfiziell spreitende Melanom, das nodulare Melanom, das akrolentiginose Melanom und das Lentigo-maligna-Melanom. Die TNM-Klassifikation berucksichtigt die Infiltrationstiefe nach Clark, den grosten vertikalen Tumordurchmesser nach Breslow, Ulzeration des Primartumors, Satelliten- und Intransitmetastasen, regionare Lymphknoten- und Fernmetastasen. Bei der Exzision ist ein adaquater Sicherheitsabstand wichtig. Die Sentinel-node-Biopsie ist bei allen Primartumoren mit einem Breslow-Durchmesser >1 mm und klinisch nicht verdachtigen Lymphknoten von Bedeutung. Bei klinisch auffalligen Lymphknoten ist die therapeutische Dissektion indiziert, bei Intransitmetastasen der Extremitaten die isolierte regionare hypertherme Zytostatikaperfusion zu diskutieren. Fernmetastasen werden in der Regel nur bei Einorganbefall oder bei voraussichtlichem Erreichen einer R0-Situation reseziert. Adjuvante, neoadjuvante und palliative Masnahmen in Form von Strahlen-, Chemo- und Immuntherapie erganzen die Therapieoptionen.

Twenty three epimeric pairs of protected tripeptides of the type Z-Ala-Xaa-Val-OMe have been synthesized by conventional coupling procedures in solution. Optimal conditions for baseline separation of LLL/LDL epimers were found by high-performance liquid chromatography on a RP-18 column with aqueous methanol as mobile phase. The hydrophobic parameters (log kw) were determined for all tripeptides.

The acquisition of DNA and the loss of genetic information are two important mechanisms that contribute to strain-specific differences in genome content. In this study, comparative genomics has allowed us to infer the roles of genomic rearrangement and changes in both distribution and copy number of the insertion element, IS1096, in the evolution of Mycobacterium smegmatis mc2155 from its progenitor, M. smegmatis ATCC 607. Comparative analysis revealed that the ATCC 607 genome contains only 11 IS1096 elements against the 24 reported in mc2155. As mc2155 evolved, there was a considerable expansion in the copy number of IS1096 (+13) as well as duplication of a 56-kb fragment flanked on both sides by IS1096; concurrently, a single IS1096 element and its flank were deleted. This study demonstrates that insertion sequence (IS) expansion and IS-induced rearrangements such as duplication, deletion and shuffling are major forces driving genomic diversity and evolution.

In this review, standards of diagnosis and treatment of colorectal liver metastases are described on the basis of a workshop discussion. Algorithms of care for patients with synchronous / metachronous colorectal liver metastases or locoregional recurrent tumour are presented. Surgical resection is the procedure of choice in the curative treatment of liver metastases. The decision about the resection of liver metastases should consider the following parameters: 1. General operability of the patient (comorbidity); 2. Achievability of an R 0 situation: i. if necessary, in combination with ablative methods, ii. if necessary, neoadjuvant chemotherapy, iii. the ability to eradicate extrahepatic tumour manifestations; 3. Sufficient volume of the liver remaining after resection ("future liver remnant = FLR): i. if necessary, in combination with portal vein embolisation or two-stage hepatectomy; 4. The feasibility to preserve two contiguous hepatic segments with adequate vascular inflow and outflow as well as biliary drainage; 5. Tumour biological aspects ("prognostic variables"); 6. Experience of the surgeon and centre! Extrahepatic disease does not contraindicate hepatectomy for colorectal liver metastases provided a complete resection of both intra- and extrahepatic disease is feasible. Even in bilobar colorectal metastases and 5 or more tumours in the liver, a complete tumour resection has been described. The type of resection (hepatic wedge resection or anatomic resection) does not influence the recurrence rate. Preoperative volumetry is indicated when major hepatic resection is planned. The FLR should be 25 % in patients with normal liver, 40 % in patients who have received intensive chemotherapy or in cases of fatty liver, liver fibrosis or diabetes, and 50-60 % in patients with cirrhosis. In patients with initially unresectable colorectal liver metastases, preoperative chemotherapy enables complete resection in 15-30 % of the cases, whereas the value of neoadjuvant chemotherapy in patients with resectable liver metastases has not been sufficiently supported. In situ ablative procedures (radiofrequency ablation = RFA and laser-induced interstitial thermotherapy = LITT) are local therapy options in selected patients who are not candidates for resection (central recurrent liver metastases, bilobar multiple metastases and high-risk resection or restricted patient operability). Patients with tumours larger than 3 cm have a high local recurrence rate after percutaneous RFA and are not optimal candidates for this procedure. The physician's experience influences the results significantly, both after hepatectomy and after in situ ablation. Therefore, patients with colorectal liver metastases should be treated in centres with experience in liver surgery.

Beim Analkarzinom ist entsprechend der Topographie zwischen Analkanal- und Analrandkarzinom zu unterscheiden. Fur Therapiewahl, Prognoseschatzung und Beurteilung der Therapieergebnisse ist eine sorgfaltige Tumorklassifikation nach internationalen Regeln erforderlich. Dabei sind stets histologischer Typ, anatomische Ausbreitung vor und nach Therapie (TNM- und R-Klassifikation) und klinische Responsebeurteilung zu erfassen. Die Tumorklassifikation erfordert eine enge Zusammenarbeit von Klinik und Pathologie.

Die totale mesorektale Exzision (TME) hat sich als standardisiertes radikales Operationsverfahren bei malignen Tumoren im mittleren und unteren Rektumdrittel etabliert. Die partielle mesorektale Exzision (PME) wird bei Karzinomen des oberen Rektumdrittels durchgefuhrt. Ziele der TME sind gute funktionelle Ergebnisse und niedrige Raten lokoregionarer Rezidive. Die Ergebnisse der laparoskopischen TME zeigen bisher keine Vorteile gegenuber der konventionellen TME. Die Qualitat der TME sollte vom Pathologen nach definierten Kriterien bewertet werden. Auch in multimodalen Behandlungskonzepten hat die TME einen zentralen Stellenwert.

Sodium-rich glasses of the system Na2O-SiO2 are well known to be easily soluble in water. This is not true for silica-rich compositions. We have manufactured quenched glasses with silica contents between 65 and 80 wt.% SiO2 and followed the water interaction at 100°C by measuring mass and sample dimensions in intervals. Comparing the path of edge length, mass and volume to a general shrinking core model for cuboids we conclude that only compositions between 65 and 70 wt% SiO2 can be described well by a simple dissolution process. The logarithm of the dissolution rate constant varies linearly with the SiO2 content. At higher silica contents the mechanism changes towards leaching of sodium. We propose changing glass structures to be responsible for the change in mechanism.

INTRODUCTION About 10% of all operations in colon carcinoma are performed in emergency situations because of severe preoperative complications. PATIENTS AND METHOD The prospectively collected data of 1496 patients with colon carcinoma treated from 1987 to 2002 at the Department of Surgery of the University of Erlangen were analysed with special interest on postoperative morbidity and long-term prognosis after elective and urgent surgery. RESULTS The rate of urgent surgery was 11%. The most frequent complication was bowel obstruction (73%) followed by perforation (20%). Emergency patients were significantly older (p

In a prospective multicenter observational study (OCUM) neoadjuvant chemoradiotherapy (nRCT) was selectively administered depending on the risk of local recurrence and based on the distance between tumor and mesorectal fascia in pretherapeutic high-resolution magnetic resonance imaging (MRI).Frequency and quality of abdominoperineal excision (APE) and sphincter preserving operations.Of 642 patients treated in 13 hospitals 389 received surgery alone and 253 nRCT followed by surgery. By univariate and multivariate analysis risk factors for APE were determined. Quality parameters were the quality grade of mesorectal excision, the pathohistological involvement of the circumferential resection margin and intraoperative local dissemination of tumor cells.In 12.8 % of the patients APE was performed. Independent risk factors for APE were tumor location in the lower third of the rectum and the individual hospitals, where APE varied between 0 and 32 %. This variation was chiefly caused by the different case mix. Hospitals with a high APE rate ( 30 %) treated significantly more patients with very low lying carcinomas ( 3 cm above the anal verge) and more advanced tumors. The median height of the tumor in cases of APE was nearly equal in all participating hospitals. Independent on the number of cases the quality of rectal surgery was high. Within the patient groups of primary surgery and nRCT the oncological quality parameter did not significantly differ between sphincter preservation and APE. As far as sphincter preservation is concerned the results justify a selective application of nRCT in patients with rectal carcinoma. The long-term results still have to be awaited.

The OCUM trial (NCT01325649) aims to clarify whether low rates of local recurrence are also achieved when the indications for neoadjuvant radiochemotherapy are not based on the clinical TNM staging but on preoperative magnetic resonance imaging with measurement of the tumor distance to the circumferential resection margin. In this interim analysis the lymph node status in OCUM patients was investigated as a surrogate parameter for quality of surgery and histopathological work-up.Until now a total of 560 patients have been included in this study. Total mesorectal excision (TME) without pretreatment was undertaken in 338 patients (60.4 %) and neoadjuvant radiochemotherapy was administered in 222 (39.6 %) patients. The histological work-up was performed according to the guidelines of the German Association of Pathologists. Data are given as median values and ranges in brackets.The lymph node yield was 24 (7-79) in 338 patients undergoing primary TME surgery without pretreatment, while 20 (3-56) lymph nodes were identified in patients after neoadjuvant radiochemotherapy (p = 0.001). A minimum of 12 lymph nodes were analyzed in 335 out of 338 patients (99.1 %) and in 209 out of 222 patients (94.1 %) following neoadjuvant radiochemotherapy (p = 0.001). Lymph node metastasis was identified (p = 0.362) in 116 out of 338 patients without pretreatment (34.3 %) and in 71 out of 222 patients after neoadjuvant radiochemotherapy (32.0 %). Patient age did not influence the number of identified lymph nodes or rate of lymph node metastasis.In this trial the number of identified lymph nodes suggests that the quality of surgery and histopathological work-up were adequate compared to the standards defined by national guidelines. Neoadjuvant radiochemotherapy led to a reduced lymph node yield compared to surgery without pretreatment; however, this did not influence the rate of lymph node metastasis.

The implementation and diffusion of telecare and telehealth products and services falls behind the expectations of policymakers and developers. While several European and national programmes promote the research and development of innovative solutions, products and services have not yet scaled up. This paper tries to identify and categorize existing barriers. We conducted a literature review between July and August 2014 covering multiple literature databases and search engines. The data was analysed qualitatively; analysis was guided by a categorization scheme. We categorized five domains affecting the adoption, implementation and diffusion of telehealth and telecare: technology, acceptance, financial, organizational and the outer context, each covering multiple barriers.

Antibody drug conjugates (ADCs) have recently been proven to be highly potent anti-tumor drugs, typically exceeding the efficacy of conventional monoclonal antibodies (mAbs). ADCs are currently produced by chemical conjugation of a small-molecule toxin to the mAb through lysine or cysteine side chains. This leads to heterogeneous mixtures of ADCs in which variable numbers of drugs are conjugated to individual antibodies and in which the site of conjugation cannot be defined. Consequently, there is currently significant interest in further development of drug conjugation technologies, with a particular focus on site-specific payload conjugation. Here, we present an enzymatic conjugation platform based on the S. aureus sortase A-mediated transpeptidation reaction, allowing the efficient generation of ADCs with toxins conjugated to pre-defined sites at pre-defined drug-to-antibody ratios. For this, two modifications were introduced: first, immunoglobulin heavy (IgH) and light (IgL) chains were modified at their C-termini by addition of the sortase A recognition motif LPETG, and second, the small molecule tubulin polymerization inhibitors monomethylauristatin E (MMAE) and maytansine were modified by addition of a pentaglycine peptide, thus making them suitable substrates for sortase A-mediated transpeptidation. We demonstrate efficient generation and characterization of the anti-CD30 ADC Ac10-vcPAB-MMAE, an enzymatically conjugated counterpart of brentuximab vedotin (Adcetris), as well as several anti-HER-2 ADCs including trastuzumab-maytansine, the counterpart of trastuzumab emtansine (Kadcyla). ADCs generated in this manner were found to display in vitro cell killing activities indistinguishable from the classic conjugates. Further, when tested in vivo in a HER-2-overexpressing ovarian cancer xenograft mouse model, enzymatically generated trastuzumab-maytansine was found to lead to complete regression of established tumors, similar to Kadcyla.

Arrays of immobilized proteins have been developed for the discovery and characterization of protein functions ranging from molecular recognition to enzymatic activity. The success of these applications is highly dependent upon the maintenance of protein structure and function while in an immobilized state - a largely untested hypothesis. However, the immobilization of functional proteins is not without precedent. Active enzymes have been successfully immobilized for industrial applications for several decades. Furthermore, a survey of recent protein microarray literature reveals that an even wider range of proteins can maintain 'proper' function while immobilized. These reports help to validate the functionality of so-called functional protein microarrays.