Expression of the costimulatory molecule B7-H3 is associated with prolonged survival in human pancreatic cancer

<p>Abstract</p> <p>Background</p> <p>Costimulatory signaling has been implicated as a potential regulator of antitumor immunity in various human cancers. In contrast to the negative prognostic value of aberrant B7-H1 expression by pancreatic cancer cells, the role of B7-H3 is still unknown. Therefore, we investigated the expression pattern and clinical significance of B7-H3 expression in human pancreatic cancer.</p> <p>Methods</p> <p>B7-H3 expression was evaluated by immunohistochemistry in 68 patients with pancreatic cancer who underwent surgical tumor resection. Expression data was correlated with clinicopathologic features and with the number of tumor-infiltrating T cells.</p> <p>Results</p> <p>B7-H3 expression was significantly upregulated in pancreatic cancer compared to normal pancreas (p < 0.05). In 60 of 68 examined tumors B7-H3 protein was detectable in pancreatic cancer cells. Patients with high tumor B7-H3 levels had a significantly better postoperative prognosis than patients with low tumor B7-H3 levels (p = 0.0067). Furthermore, tumor B7-H3 expression significantly correlated with the number of tumor-infiltrating CD8+ T cells (p = 0.018).</p> <p>Conclusion</p> <p>We demonstrate for the first time that B7-H3 is abundantly expressed in pancreatic cancer and that tumor-associated B7-H3 expression significantly correlates with prolonged postoperative survival. Our findings suggest that B7-H3 might play an important role as a potential stimulator of antitumor immune response in pancreatic cancer.</p

Glucosylceramide synthase inhibitors induce ceramide accumulation and sensitize H3K27 mutant diffuse midline glioma to irradiation

H3K27M mutant (mut) diffuse midline glioma (DMG) is a lethal cancer with no effective cure. The glycosphingolipids (GSL) metabolism is altered in these tumors and could be exploited to develop new therapies. We tested the effect of the glucosylceramide synthase inhibitors (GSI) miglustat and eliglustat on cell proliferation, alone or in combination with temozolomide or ionizing radiation. Miglustat was included in the therapy protocol of two pediatric patients. The effect of H3.3K27 trimethylation on GSL composition was analyzed in ependymoma. GSI reduced the expression of the ganglioside GD2 in a concentration and time-dependent manner and increased the expression of ceramide, ceramide 1-phosphate, sphingosine, and sphingomyelin but not of sphingosine 1-phosphate. Miglustat significantly increased the efficacy of irradiation. Treatment with miglustat according to dose recommendations for patients with Niemann–Pick disease was well tolerated with manageable toxicities. One patient showed a mixed response. In ependymoma, a high concentration of GD2 was found only in the presence of the loss of H3.3K27 trimethylation. In conclusion, treatment with miglustat and, in general, targeting GSL metabolism may offer a new therapeutic opportunity and can be administered in close proximity to radiation therapy. Alterations in H3K27 could be useful to identify patients with a deregulated GSL metabolism

ICAR: endoscopic skull‐base surgery

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Klinische Erfahrungen mit dem Sourire Cage bei 113 Patienten mit ventraler Spondylodese der Halswirbelsäule

Die ventrale Spondylodese ist ein Standardeingriff zur operativen Behandlung von degenerativen Erkrankungen der Halswirbelsäule. Um die operative Fusion zweier Wirbelkörper zu erreichen, werden auf dem Markt verschiedene intervertebrodiskale Spacer zur Implantation angeboten. Das Ziel dieser Studie ist es, den klinischen und implantatspezifischen Krankheitsverlauf bei Patienten zu ermitteln, denen ein Sourire Cage implantiert wurde. Im Zeitraum vom 01. 01. 2008 bis zum 26. 08. 2012 operierten wir 113 Patienten aufgrund einer degenerativen Erkrankung der Halswirbelsäule mittels ventraler Spondylodese und Sourire-Cage-Implantation in der Neurochirurgischen Klinik im Unfallkrankenhaus Berlin. Bei allen Patienten fanden Nachuntersuchungen im Rahmen der Qualitätskontrolle nach SGB V nach 6 Wochen, 6 Monaten und 1 Jahr statt. Zur Bewertung der klinischen Symptomatik fand der von der Japanese Orthopedic Association eingeführte JOA-Score Anwendung. Des Weiteren erfolgten Röntgenuntersuchungen. Im Rahmen einer retrospektiven Studie untersuchten wir das Operationsergebnis sowie die Sinterungs- und Dislokationsrate. Die Symptomatik der Patienten verbesserte sich postoperativ zu 89 %. Die Verbesserung zeigte sich in den Nachuntersuchungen konstant. Sinterung des Implantats zeigte sich bei 10 % der Patienten. Eine Dislokation des Spacers ist bei keinem Patienten aufgetreten. Die Studie zeigt, dass die ventrale Fusion mittels Sourire-Cage-Implantation zu exzellenten und guten klinischen Ergebnissen bei niedrigen Komplikationsraten führt.</jats:p