Perioperative platin-based chemotherapy for locally advanced esophagogastric adenocarcinoma: Postoperative chemotherapy has a substantial impact on outcome.

BACKGROUND: A combination of platin-based perioperative chemotherapy (PBPC) plus surgical resection has become the standard of care in Europe for locally advanced esophagogastric adenocarcinoma (EGAC). In contrast to preoperative chemotherapy, the postoperative administration of chemotherapy is omitted in a high percentage of patients. We conducted this database study to analyse the impact of postoperative completion of perioperative chemotherapy on patient outcome. METHODS: Patients with EGAC (cT3-4 and/or cN+) were treated with preoperative PBPC plus curative surgical resection. Patient demographics, postoperative tumour stages, histopathological regression (HPR) and administration of postoperative chemotherapy were correlated with overall survival. RESULTS: Of one-hundred-thirty-four patients, 76 received preoperative docetaxel, folinic acid, fluorouracil, oxaliplatin (FLOT), 53 patients epirubicin, cisplatin, folinic acid (ECF) and 5 epirubicin, oxaliplatin, capecitabine (EOX) chemotherapy. The 5-year-survival for the whole collective was 58%. Designated postoperative chemotherapy was omitted in 36% of the patients. 5-year-survival was 75.8% in patients who received pre- and post-operative chemotherapy and 40.3% in patients with only preoperative chemotherapy (p < 0.001). Histopathological regression, postoperative nodal status and administration of postoperative chemotherapy were identified as independent prognostic factors. Analysis of subgroups revealed a pronounced survival benefit after administration of postoperative chemotherapy in patients with ypN+ stages (5-year-survival 64.5% vs 9.7%, p = 0.002) and poor HPR (5-year-survival 55.5% vs 19.3%, p = 0.015). CONCLUSION: Our study provides further evidence that administration of postoperative chemotherapy may contribute to the achieved survival benefit of PBPC in patients with EGAC and implies a beneficial effect especially in presence of lymphonodular tumour involvement and limited HPR.

F604S exchange in FIP1L1-PDGFRA enhances FIP1L1-PDGFRA protein stability via SHP-2 and SRC: a novel mode of kinase inhibitor resistance.

FIP1L1-PDGFRA is a constitutively activated kinase described in chronic eosinophilic leukemia (CEL) and hypereosinophilic syndrome (HES). Imatinib is clinically active in FIP1L1-PDGFRA-positive diseases. Using in vitro screening to identify imatinib-resistant mutations, we frequently detected a Phe to Ser exchange at position 604 (F604S) of FIP1L1-PDGFRA alone or in combination with other exchanges. Surprisingly, FIP1L1-PDGFRA/F604S did not increase the biochemical or cellular IC50 value of imatinib when compared with unmutated FIP1L1-PDGFRA. However, FIP1L1-PDGFRA/F604S more efficiently induced growth factor independence in cell lines and primary mouse bone marrow cells. Pulse chase analysis revealed that the F604S exchange strongly stabilized FIP1L1-PDGFRA/F604S. The F604S mutation creates a binding site for the phosphatase domain of SHP-2, leading to lower autophosphorylation of FIP1L1-PDGFRA/F604S. This is associated with a reduced activation of SRC and CBL by FIP1L1-PDGFRA/F604S compared with the unmutated oncogene. As SRC inhibition and knockdown resulted in FIP1L1-PDGFRA stabilization, this explains the extended half-life of FIP1L1-PDGFRA/F604S. Interestingly, FIP1L1-PDGFRA/L629P, a recently identified mutation in an imatinib-resistant CEL patient, also showed protein stabilization similar to that observed with FIP1L1-PDGFRA/F604S. Therefore, resistance mutations in FIP1L1-PDGFRA that do not interfere with drug binding but rather increase target protein stability seem to be one of the drug-resistance mechanisms in FIP1L1-PDGFRA-positive disease.

[Surgical treatment of esophageal cancer : Evolution of management and prognosis over the last 3 decades]. / Chirurgische Therapie des Ösophaguskarzinoms : Entwicklung von Management und Prognose über die letzten drei Jahrzehnte.

BACKGROUND: An increasing incidence of adenocarcinoma, a modified surgical strategy and the increasing use of multimodal therapeutic protocols have had a major impact on the surgical treatment of esophageal cancer during the last 3 decades. OBJECTIVES: This study analyzed the development of these factors and their impact on the short and long-term prognosis of esophageal cancer over the last 25 years. PATIENTS AND METHODS: The study included 366 patients with esophageal cancer treated by esophagectomy at the University Hospital in Freiburg from 1988 to 2012. The study period was split into four time periods for further comparisons, i.e. 1988-1994, 1995-2001, 2001-2006 and 2007-2012. RESULTS: Within the time periods analyzed a marked increase in adenocarcinoma was found (time periods1988-1994, 1995-2001, 2001-2006 and 2007-2012: 21%, 37%, 61% and 64%, respectively, p<0.001). The initially commonly used transhiatal approach and reconstruction with cervical anastomosis was gradually replaced by the thoracoabdominal procedure with intrathoracic reconstruction (i.e. Ivor Lewis esophagectomy, 2007-2012: 98 %). During the study period increasingly more patients received multimodal therapy (13%, 85%, 72% and 84%, p<0.001), the overall rate of perioperative complications (70%, 88%, 73% and 56%, p<0.001) and perioperative mortality (16%, 18%, 8% and 2.5%, p<0.001) were significantly reduced, while the overall 5-year survival (12%, 34%, 41% and 62%, p<0.001) improved. An early tumor stage (p=0.002), N0 status (p<0.001) and histological type of adenocarcinoma (p=0.011) were identified as independent predictors of improved survival. CONCLUSION: During the period from 1988 to 2012 a significant improvement of long-term survival as well as a marked reduction of perioperative mortality after esophagectomy were observed. The improved outcome was associated with an increased use of multimodal therapeutic protocols, the preferred use of thoracoabdominal esophagectomy and epidemiological changes in histology over the study period.

Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels.

Acute graft-versus-host disease (GvHD) limits the applicability of allogeneic hematopoietic cell transplantation for the treatment of leukemia. GvHD occurs as a consequence of multiple activating events in antigen-presenting cells (APCs) and T cells (Tcs). Spleen tyrosine kinase (Syk) is an intracellular non-receptor tyrosine kinase involved in multiple signaling events of immune cells. Therefore, we hypothesized that Syk may be a promising target to inhibit GvHD, which involves activation of different immune cell populations. In vivo expansion of luciferase(+) donor Tcs in mice developing GvHD was reduced by treatment with the Syk inhibitor Fostamatinib, which led to increased survival and reduced histologically confirmed GvHD severity. Importantly, in vivo and in vitro cytotoxicity against leukemia target cells and anti-murine cytomegalovirus immune responses were not impacted by Fostamatinib. In APCs Syk inhibition reduced the expression of costimulatory molecules and disrupted cytoskeletal organization with consecutive APC migratory defects in vitro and in vivo while phagocytic activity remained intact. On the basis of these immunomodulatory effects on different cell populations, we conclude that Syk targeting in alloantigen-activated Tcs and APCs with pharmacologic inhibitors, already applied successfully in anti-lymphoma therapy, has clinical potential to reduce GvHD, especially as anti-leukemia and anti-viral immunity were preserved.