A regimen combining the Wee1 inhibitor AZD1775 with HDAC inhibitors targets human acute myeloid leukemia cells harboring various genetic mutations.

AZD1775 targets the cell cycle checkpoint kinase Wee1 and potentiates genotoxic agent cytotoxicity through p53-dependent or -independent mechanisms. Here, we report that AZD1775 interacted synergistically with histone deacetylase inhibitors (HDACIs, for example, Vorinostat), which interrupt the DNA damage response, to kill p53-wild type (wt) or -deficient as well as FLT3-ITD leukemia cells in association with pronounced Wee1 inhibition and diminished cdc2/Cdk1 Y15 phosphorylation. Similarly, Wee1 shRNA knockdown significantly sensitized cells to HDACIs. Although AZD1775 induced Chk1 activation, reflected by markedly increased Chk1 S296/S317/S345 phosphorylation leading to inhibitory T14 phosphorylation of cdc2/Cdk1, these compensatory responses were sharply abrogated by HDACIs. This was accompanied by premature mitotic entry, multiple mitotic abnormalities and accumulation of early S-phase cells displaying increased newly replicated DNA, culminating in robust DNA damage and apoptosis. The regimen was active against patient-derived acute myelogenous leukemia (AML) cells harboring either wt or mutant p53 and various next-generation sequencing-defined mutations. Primitive CD34(+)/CD123(+)/CD38(-) populations enriched for leukemia-initiating progenitors, but not normal CD34(+) hematopoietic cells, were highly susceptible to this regimen. Finally, combining AZD1775 with Vorinostat in AML murine xenografts significantly reduced tumor burden and prolonged animal survival. A strategy combining Wee1 with HDACI inhibition warrants further investigation in AML with poor prognostic genetic aberrations.

Correlation of BAG-3 and heat shock protein 70 with CD30 expression in T-cell lymphomas.

T-cell lymphomas are aggressive lymphomas with decreased prognosis and resistance to therapy. BAG-3 and heat shock protein 70 (HSP70) function in chemotherapeutic resistance and cellular survival. Expression of BAG-3 has not been investigated in T cell lymphomas. We investigated fifty cases including benign, systemic and cutaneous T cell lymphomas. Benign T cells were negative for BAG-3 and HSP70 immunohistochemical staining. BAG-3 expression correlated with increased HSP70 expression in a subset of systemic T cell lymphoma cases co-expressing the CD30 antigen. Correlation between BAG-3, HSP70 and CD30 expression was not seen in cutaneous T cell lymphoma cases. However, these cases showed a significant increase in BAG-3 staining when compared to CD30 negative systemic T cell lymphoma cases. The differential protein expression profile of BAG-3 and HSP70 may indicate a specific role for these proteins and the ubiquitin-proteasome system/autophagy in T cell lymphomas which may help guide future targeted therapy.

Delayed pharyngoesophageal perforation: a complication of anterior spine surgery.

Stabilization of the cervical spine is often accomplished via an anterior cervical approach. Bone grafts and/or plates and screws are used to achieve stabilization. Injuries to the pharynx and esophagus are known complications in anterior exposure of the cervical spine. These injuries are manifest in the early postoperative period. Reports of late perforations are very rare. We present four cases of delayed injury to the pharynx and esophagus that resulted in abscess or fistula. We postulate that graft displacement with resulting erosion was responsible for these serious complications. Postoperative odynophagia in patients who undergo anterior cervical fusion warrants evaluation of the bone graft location. Early surgical intervention and repair may decrease prolonged morbidity in these patients.

Approach for oxygenation of the newborn with airway obstruction due to a cervical mass.

Large congenital cervical neck masses present major difficulties in management of the neonatal airway at delivery and in the perinatal period. With ultrasound, these lesions can be predicted prenatally. An airway treatment plan can then be formulated and modified in relation to the airway presentation at birth. We describe a case of a massive cervical-mediastinal teratoma and our management plan. Preparation involved a multidisciplinary approach including endoscopy to secure the airway while the neonate remained on fetal circulation and an extracorporeal membrane oxygenation system was available. Once the infant's condition was stable, a cervical approach with resection of the massive teratoma with mediastinal dissection without sternotomy was successful. A differential diagnosis of cervical neck masses and review of cervical teratomas is presented.

Diagnosis and treatment of congenital choanal atresia.

Choanal atresia is the developmental failure of the posterior nasal cavity to communicate with the nasopharynx. Because of its rare incidence, otolaryngologists have limited experience in treating this unusual congenital anomaly. We report the case of a seventeen year old female with bilateral membrano-osseous choanal atresia who miraculously survived her anomaly and was not definitively diagnosed and surgically treated until she was seventeen. Definitive surgical correction of choanal atresia is challenging. The various methods advocated include the transnasal, transpalatal, trans-septal and sublabial approaches. We will discuss the various treatment options and relate our own personal experience in the management of choanal atresia. A review of the literature on the various modalities available for surgery, stenting and rehabilitation will be discussed also.