Toxicity Assessment of a Phase III Study Evaluating FEC-Doc and FEC-Doc Combined with Gemcitabine as an Adjuvant Treatment for High-Risk Early Breast Cancer: the SUCCESS-A Trial.

Introduction: This paper aims to evaluate the toxicity profile of additive gemcitabine to adjuvant taxane-based chemotherapy in breast cancer patients. Methods: Patients enrolled in this open-label randomized controlled Phase III study were treated with 3 cycles of epirubicin-fluorouracil-cyclophosphamide (FEC) chemotherapy followed by 3 cycles of docetaxel with those receiving 3 cycles of FEC followed by 3 cycles of gemcitabine-docetaxel (FEC-DG). 3690 patients were evaluated according to National Cancer Institute (NCI) toxicity criteria (CTCAE). The study medications were assessed by the occurrence of grade 3-4 adverse events, dose reductions, postponements of treatment cycles and granulocyte colony-stimulating factor (G-CSF) support. Results: No differences in neutropenia or febrile neutropenia were demonstrated. However, thrombocytopenia was significantly increased with FEC-DG treatment (2.0 vs. 0.5 %, p < 0.001), as was leukopenia (64.1 vs. 58.5 %, p < 0.001). With FEC-DG significantly more G-CSF support in cycles 4 to 6 (FEC-DG: 57.8 %, FEC-D: 36.3 %, p < 0.001) was provided. Transaminase elevation was significantly more common with FEC-DG (SGPT: 6.3 %, SGOT: 2 %), whereas neuropathy (1.2 %), arthralgia (1.6 %) and bone pain (2.6 %) were more common using FEC-D. Dose reductions > 20 % (4 vs. 2.4 %) and postponement of treatment cycles (0.9 vs. 0.4 %) were significantly more frequent in the FEC-DG arm. Eight deaths occurred during treatment in the FEC-DG arm and four in the FEC-D arm. Conclusion: The addition of gemcitabine increased hematological toxicity and was associated with more dose reductions and postponements of treatment cycles.

Right-sided diaphragmatic rupture after repair of a large Morgagni hernia.

We present a case of a combination of primary and secondary diaphragmatic hernia in a 63-year male patient. For progressive dyspnea and palpitations caused by a large and symptomatic Morgagni hernia resulting in a right-sided enterothorax, an open tension-free mesh repair was performed. The postoperative course was complicated by a secondary hepatothorax through a spontaneous rupture of the right diaphragm. Primary mesh repair of the Morgagni hernia, however, proved to be sufficient. This recurrent herniation might be a consequence of (1) preexisting atrophy of the right diaphragm caused by disposition and/or long-term diaphragmatic dysfunction due to the large hernia, combined with (2) further thinning out of the diaphragm by intraoperative hernia sac resection, and (3) postoperative increase of intra-abdominal pressure.

Right-sided diaphragmatic rupture after repair of a large Morgagni hernia.

We present a case of a combination of primary and secondary diaphragmatic hernia in a 63-year male patient. For progressive dyspnea and palpitations caused by a large and symptomatic Morgagni hernia resulting in a right-sided enterothorax, an open tension-free mesh repair was performed. The postoperative course was complicated by a secondary hepatothorax through a spontaneous rupture of the right diaphragm. Primary mesh repair of the Morgagni hernia, however, proved to be sufficient. This recurrent herniation might be a consequence of (1) preexisting atrophy of the right diaphragm caused by disposition and/or long-term diaphragmatic dysfunction due to the large hernia, combined with (2) further thinning out of the diaphragm by intraoperative hernia sac resection, and (3) postoperative increase of intra-abdominal pressure.

Mtbp haploinsufficiency in mice increases tumor metastasis.

Mdm2 inhibits the function of the p53 tumor suppressor. Mdm2 is overexpressed in many tumors with wild-type p53 suggesting an alternate mechanism of loss of p53 activity in tumors. An Mdm2-binding protein (MTBP) was identified using a yeast two-hybrid screen. In tissue culture, MTBP inhibits Mdm2 self-ubiquitination, leading to stabilization of Mdm2 and increased degradation of p53. To address the role of MTBP in the regulation of the p53 pathway in vivo, we deleted the Mtbp gene in mice. Homozygous disruption of Mtbp resulted in early embryonic lethality, which was not rescued by loss of p53. Mtbp+/- mice were not tumor prone. When mice were sensitized for tumor development by p53 heterozygosity, we found that the Mtbp+/-p53+/- mice developed significantly more metastatic tumors (18.2%) as compared to p53+/- mice (2.6%). Results of in vitro migration and invasion assays support the in vivo findings. Downmodulation of Mtbp in osteosarcoma cells derived from p53+/- mice resulted in increased invasiveness, and overexpression of Mtbp in Mtbp+/-p53+/- osteosarcoma cells inhibited invasiveness. These results suggest that MTBP is a metastasis suppressor. These results advance our understanding of the cellular roles of MTBP and raise the possibility that MTBP is a novel therapeutic target for metastasis.