Cholecystokinin (CCK) and other pancreatic secretagogues have recently been shown to activate signaling kinase cascades in pancreatic acinar cells, leading to the activation of extracellular signal-regulated kinases and Jun N-terminal kinases. We now show the presence of a third kinase cascade activating p38 mitogen-activated protein (MAP) kinase in isolated rat pancreatic acini. CCK and osmotic stress induced by sorbitol activated p38 MAP kinase within minutes; their effects were dosedependent, with maximal activation of 2.8-and 4.4-fold, respectively. The effects of carbachol and bombesin on p38 MAP kinase activity were similar to those of CCK, whereas phorbol ester, epidermal growth factor, and vasoactive intestinal polypeptide stimulated p38 MAP kinase by 2-fold or less. Both CCK and sorbitol also increased the tyrosyl phosphorylation of p38 MAP kinase. Using the specific inhibitor of p38 MAP kinase, SB 203580, we found that p38 MAP kinase activity was required for MAP kinase-activated protein kinase-2 activation in pancreatic acini. SB 203580 reduced the level of basal phosphorylation and blocked the increased phosphorylation of Hsp 27 after stimulation with either CCK or sorbitol. CCK treatment induced an initial rapid decrease in total F-actin content of acini, followed by an increase after 40 min. Preincubation with SB 203580 significantly inhibited these changes in F-actin content. Staining of the actin cytoskeleton with rhodamine-conjugated phalloidin and analysis by confocal fluorescence microscopy showed disruption of the actin cytoskeleton after 10 and 40 min of CCK stimulation. Pretreatment with SB 203580 reduced these changes. These findings demonstrate that the activation of p38 MAP kinase is involved not only in response to stress, but also in physiological signaling by gastrointestinal hormones such as CCK, where activation of G q -coupled receptors stimulates a cascade in which p38 MAP kinase activates MAP kinase-activated protein kinase-2, resulting in Hsp 27 phosphorylation. Activation of p38 MAP kinase, most likely through phosphorylation of Hsp 27, plays a role in the organization of the actin cytoskeleton in pancreatic acini.

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Perioperative treatment is a standard of care in locally advanced gastroesophageal cancer (GEC) (gastric adenocarcinoma and gastroesophageal junction (GEJ) adenocarcinoma). While preoperative treatment can be applied to the majority of patients, postoperative chemotherapy can be given only to a fraction. The NeoFLOT-study therefore investigates the application of prolonged neoadjuvant chemotherapy (NACT). Patients with T3, T4, and/or node-positive adenocarcinoma (GEC) were eligible for this multicenter phase II trial. NACT consisted of 6 cycles of oxaliplatin 85 mg/m 2 , leucovorin 200 mg/m 2 , 5-fluorouracil 2600 mg/m 2 and docetaxel 50 mg/m 2 (FLOT) applied q 2 wks. Application of adjuvant chemotherapy was explicitly not part of the protocol. R0-resection rate was evaluated as a primary endpoint. Of 59 enrolled patients, 50 patients underwent surgery and were assessable for the primary endpoint. R0-resection rate was 86.0% (43/50). Pathologic complete response (pCR) was 20.0% (10/50) and a further 20% (10/50) of patients achieved near complete histological remission (<10% residual tumor). Among these very good responders, 85% (17/20) had intestinal type tumors, 10% (2/20) had diffuse and 5% (1/20) had mixed type tumors. After 3 cycles of NACT, 6.9% (4/58) of patients developed progressive disease. Median disease-free survival was 32.9 months. The 1-year survival-rate was 79.3%. Grade 3-4 toxicities included neutropenia 29.3%, febrile neutropenia 1.7%, diarrhea 12.1% and mucositis 6.9%. This study indicates that intensified NACT with 6 cycles of FLOT is highly effective and tolerable in resectable GEC. Very good response (pCR and <10% residual tumor) was predominantly observed in patients with intestinal type tumors.