TY  - JOUR
A1  - Drube, Sebastian
A1  - Weber, Franziska
A1  - Loschinski, Romy
A1  - Beyer, Mandy
A1  - Rothe, Mandy
A1  - Rabenhorst, Anja
A1  - Göpfert, Christiane
A1  - Meininger, Isabel
A1  - Diamanti, Michaela A.
A1  - Stegner, David
A1  - Häfner, Norman
A1  - Böttcher, Martin
A1  - Reinecke, Kirstin
A1  - Herdegen, Thomas
A1  - Greten, Florian R.
A1  - Nieswandt, Bernhard
A1  - Hartmann, Karin
A1  - Krämer, Oliver H.
A1  - Kamradt, Thomas
T1  - Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells
JF  - Oncotarget
N2  - Mast cell differentiation and proliferation depends on IL-3. IL-3 induces the activation of MAP-kinases and STATs and consequently induces proliferation and survival. Dysregulation of IL-3 signaling pathways also contribute to inflammation and tumorigenesis. We show here that IL-3 induces a SFK- and Ca2\(^{+}\)-dependent activation of the inhibitor of κB kinases 2 (IKK2) which results in mast cell proliferation and survival but does not induce IκBα-degradation and NFκB activation. Therefore we propose the term "subthreshold IKK activation". This subthreshold IKK activation also primes mast cells for enhanced responsiveness to IL-33R signaling. Consequently, co-stimulation with IL-3 and IL-33 increases IKK activation and massively enhances cytokine production induced by IL-33. We further reveal that in neoplastic mast cells expressing constitutively active Ras, subthreshold IKK activation is associated with uncontrolled proliferation. Consequently, pharmacological IKK inhibition reduces tumor growth selectively by inducing apoptosis in vivo. Together, subthreshold IKK activation is crucial to mediate the full IL-33-induced effector functions in primary mast cells and to mediate uncontrolled proliferation of neoplastic mast cells. Thus, IKK2 is a new molecularly defined target structure.
KW  - mast cells
KW  - subthreshold IKK activation
KW  - mitogenic signaling
KW  - NFκB-activation
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143681
VL  - 6
IS  - 7
ER  - 
TY  - THES
A1  - Krämer, Karin
T1  - Adjuvante Radiochemotherapie des Rektumkarzinoms - multizentrische retrospektive Analyse von 534 Patienten in Franken - Prognosefaktoren und adjuvante Therapieregime (B) - eine retrospektive Analyse des Krankenguts 6 fränkischer Strahlenkliniken im Zeitraum 4/93 bis 3/98
T1  - Adjuvant radiochemotherapy of rectal cancer - a multi-institutional retrospective quality control analysis of 534 patients - prognostic factors and adjuvant therapy regimes (B) -
N2  - Die adjuvante Radiochemotherapie des Rektumkarzinoms im UICC-Stadium II/III wird seit 1991 von National Cancer Institute (NCI) und in Deutschland seit 1994 als Standard empfohlen. Die Qualität und Ergebnisse der postoperativen Therapie in der täglichen klinischen Praxis wurden flächendeckend retrospektiv untersucht. Insgesamt wurden 534 Patienten aus 6 Institutionen ausgewertet, die zwischen 1993 und 1998 behandelt wurden. Die beteiligten Kliniken versorgten strahlentherapeutisch flächendeckend große Teile des nordbayerischen Raumes. Die Stadienverteilung der Patienten war: UICC I 1%, II 28%, III 69% und IV 2%. 92% erhielten eine RChT, 8% eine alleinige RT. Die mediane Nachbeobachtungszeit der Patienten betrug 40 Monate. Ergebnisse (Teil B): Die Qualität der adjuvanten Therapie entsprach den gültigen Standards. Die lokale Kontrolle wurde in der multivariaten Analyse signifikant durch die pT- und pN-Kategorie, das Tumorgrading und eine RChT anstelle einer alleinigen RT beeinflusst. Bei 6% aller Patienten war nicht in sano, d.h. R1/R2 reseziert worden; bei 33% der pN0 kategorisierten Tumoren wurden weniger als die geforderten 12 Lymphknoten untersucht; beides führte zu einer signifikant reduzierten lokalen Kontrolle. Weitere Ergebnisse siehe Teil A. Schlussfolgerung: Der niedrige Anteil an der adjuvanten Therapie zugewiesenen Patienten sowie die im Vergleich zu randomisierten Studien ungünstigeren Ergebnisse weisen auf die Auswahl eines Risikokollektivs hin. Anstelle einer stadienbezogenen Zuweisung scheint eine Auswahl mit individueller Risikoabschätzung durch den Chirurgen bevorzugt zu werden. Neben Therapieverbesserungen durch randomisierte Studien sollten ebenso Anstrengungen zur Übertragung dieser Ergebnisse in die flächendeckende Praxis unternommen werden.
N2  - Radiochemotherapy as adjuvant treatment for rectal cancer UICC stage II/III has been recommended by the National Cancer Institute (NCI) since 1991 and in Germany since 1994. Quality and results of postoperative treatment in day-to-day clinical practice in a complete region are evaluated retrospectively in a multi-institutional approach. 534 patients from six institutions treated between 1993 and 1998 were evaluated. The institutions covered a complete region with radiotherapeutic care. Patients were staged as follows: UICC I 1%, II 28%, III 69%, and IV 2%. 92% received RChT, 8% RT alone. Median follow-up of patients was 40 months. Results (part B): Quality of adjuvant treatment was well within a "corridor of adequate treatment". In multivariate analysis, local control was significantly influenced by T- and N-category, tumor grading, and RChT instead of RT alone. 6% of patients showed involved resection margins, in 33% of patients categorized pN0 less than the required 12 lymph nodes were examined, both leading to a significant decrease of local control. For further results see part A. Conclusion: While the quality of adjuvant treatment followed consensus guidelines, the number of referred patients which was lower than expected and the inferior treatment results as compared to randomized studies indicate that the consensus recommendations for adjuvant treatment have not been fully accepted. Instead of patient referral according to UICC stage, patient selection by the surgeons has been performed according to individual risk factors. Efforts have to be made not only to improve treatment results in randomized studies but also to transfer and control these standards in daily practice.
KW  - Rektumkarzinom
KW  - Adjuvante Therapie
KW  - Radiochemotherapie
KW  - Qualitätskontrolle
KW  - rectal cancer
KW  - adjuvant treatment
KW  - radiochemotherapy
KW  - patterns of care
Y1  - 2003
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-7690
ER  - 
TY  - JOUR
A1  - Silvestri, Valentina
A1  - Barrowdale, Daniel
A1  - Mulligan, Anna Marie
A1  - Neuhausen, Susan L.
A1  - Fox, Stephen
A1  - Karlan, Beth Y.
A1  - Mitchell, Gillian
A1  - James, Paul
A1  - Thull, Darcy L.
A1  - Zorn, Kristin K.
A1  - Carter, Natalie J.
A1  - Nathanson, Katherine L.
A1  - Domchek, Susan M.
A1  - Rebbeck, Timothy R.
A1  - Ramus, Susan J.
A1  - Nussbaum, Robert L.
A1  - Olopade, Olufunmilayo I.
A1  - Rantala, Johanna
A1  - Yoon, Sook-Yee
A1  - Caligo, Maria A.
A1  - Spugnesi, Laura
A1  - Bojesen, Anders
A1  - Pedersen, Inge Sokilde
A1  - Thomassen, Mads
A1  - Jensen, Uffe Birk
A1  - Toland, Amanda Ewart
A1  - Senter, Leigha
A1  - Andrulis, Irene L.
A1  - Glendon, Gord
A1  - Hulick, Peter J.
A1  - Imyanitov, Evgeny N.
A1  - Greene, Mark H.
A1  - Mai, Phuong L.
A1  - Singer, Christian F.
A1  - Rappaport-Fuerhauser, Christine
A1  - Kramer, Gero
A1  - Vijai, Joseph
A1  - Offit, Kenneth
A1  - Robson, Mark
A1  - Lincoln, Anne
A1  - Jacobs, Lauren
A1  - Machackova, Eva
A1  - Foretova, Lenka
A1  - Navratilova, Marie
A1  - Vasickova, Petra
A1  - Couch, Fergus J.
A1  - Hallberg, Emily
A1  - Ruddy, Kathryn J.
A1  - Sharma, Priyanka
A1  - Kim, Sung-Won
A1  - Teixeira, Manuel R.
A1  - Pinto, Pedro
A1  - Montagna, Marco
A1  - Matricardi, Laura
A1  - Arason, Adalgeir
A1  - Johannsson, Oskar Th
A1  - Barkardottir, Rosa B.
A1  - Jakubowska, Anna
A1  - Lubinski, Jan
A1  - Izquierdo, Angel
A1  - Pujana, Miguel Angel
A1  - Balmaña, Judith
A1  - Diez, Orland
A1  - Ivady, Gabriella
A1  - Papp, Janos
A1  - Olah, Edith
A1  - Kwong, Ava
A1  - Nevanlinna, Heli
A1  - Aittomäki, Kristiina
A1  - Segura, Pedro Perez
A1  - Caldes, Trinidad
A1  - Van Maerken, Tom
A1  - Poppe, Bruce
A1  - Claes, Kathleen B. M.
A1  - Isaacs, Claudine
A1  - Elan, Camille
A1  - Lasset, Christine
A1  - Stoppa-Lyonnet, Dominique
A1  - Barjhoux, Laure
A1  - Belotti, Muriel
A1  - Meindl, Alfons
A1  - Gehrig, Andrea
A1  - Sutter, Christian
A1  - Engel, Christoph
A1  - Niederacher, Dieter
A1  - Steinemann, Doris
A1  - Hahnen, Eric
A1  - Kast, Karin
A1  - Arnold, Norbert
A1  - Varon-Mateeva, Raymonda
A1  - Wand, Dorothea
A1  - Godwin, Andrew K.
A1  - Evans, D. Gareth
A1  - Frost, Debra
A1  - Perkins, Jo
A1  - Adlard, Julian
A1  - Izatt, Louise
A1  - Platte, Radka
A1  - Eeles, Ros
A1  - Ellis, Steve
A1  - Hamann, Ute
A1  - Garber, Judy
A1  - Fostira, Florentia
A1  - Fountzilas, George
A1  - Pasini, Barbara
A1  - Giannini, Giuseppe
A1  - Rizzolo, Piera
A1  - Russo, Antonio
A1  - Cortesi, Laura
A1  - Papi, Laura
A1  - Varesco, Liliana
A1  - Palli, Domenico
A1  - Zanna, Ines
A1  - Savarese, Antonella
A1  - Radice, Paolo
A1  - Manoukian, Siranoush
A1  - Peissel, Bernard
A1  - Barile, Monica
A1  - Bonanni, Bernardo
A1  - Viel, Alessandra
A1  - Pensotti, Valeria
A1  - Tommasi, Stefania
A1  - Peterlongo, Paolo
A1  - Weitzel, Jeffrey N.
A1  - Osorio, Ana
A1  - Benitez, Javier
A1  - McGuffog, Lesley
A1  - Healey, Sue
A1  - Gerdes, Anne-Marie
A1  - Ejlertsen, Bent
A1  - Hansen, Thomas V. O.
A1  - Steele, Linda
A1  - Ding, Yuan Chun
A1  - Tung, Nadine
A1  - Janavicius, Ramunas
A1  - Goldgar, David E.
A1  - Buys, Saundra S.
A1  - Daly, Mary B.
A1  - Bane, Anita
A1  - Terry, Mary Beth
A1  - John, Esther M.
A1  - Southey, Melissa
A1  - Easton, Douglas F.
A1  - Chenevix-Trench, Georgia
A1  - Antoniou, Antonis C.
A1  - Ottini, Laura
T1  - Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2
JF  - Breast Cancer Research
N2  - Background

BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs).

Methods

We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database.

Results

Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10−5) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor–positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15–21.80] and progesterone receptor–positive (OR 5.04; 95 % CI 3.17–8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10−12).

Conclusions

On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.
KW  - Male breast cancer
KW  - BRCA1/2
KW  - Pathology
KW  - Histologic grade
KW  - Genotype–phenotype correlations
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164769
VL  - 18
IS  - 15
ER  -