Diagnostic and Therapeutic Challenges of Concurrent Intracranial Hemorrhage and Cerebral Venous Thrombosis in a Patient With Acute Lymphoblastic Leukemia: A Case Report and Literature Review.

Cerebral venous sinus thrombosis (CVST) is a cerebrovascular condition due to the thrombosis of cerebral venous sinuses, leading to intracranial hemorrhage, increased intracranial pressure, focal deficit, seizure, toxic edema, encephalopathy, and death. The diagnosis and therapeutic approach of CVST remain challenging because of its highly nonspecific clinical presentation including headaches, seizures, focal neurologic deficits, and altered mental status, etc. Anticoagulation is the mainstay of CVST treatment and should be started as soon as the diagnosis is confirmed. Here, we present the case of a 34-year-old male construction worker who presented to the emergency department with a complaint of right chest wall pain and swelling. He was admitted to the hospital following a diagnosis of anterior chest wall abscess and mediastinitis. During hospitalization, his complete blood count revealed pancytopenia with blast cells, and bone marrow biopsy revealed 78.5% lymphoid blasts by aspirate differential count and hypercellular marrow (100%) with decreased hematopoiesis. He developed concurrent CVST and intracranial hemorrhage while receiving CALGB10403 (vincristine, daunorubicin, pegaspargase, prednisone) with intrathecal cytarabine induction chemotherapy for acute lymphoblastic leukemia (ALL). The patient failed two standard chemotherapy for ALL and achieved remission while on third-line chemotherapy with an anti-CD19 monoclonal antibody, blinatumomab. Although this patient had an MRI scan of the brain with multiple follow-up non-contrast CT scans, it was CT angiography that revealed CVST. This showed the diagnostic challenge in CVST, with CT and MRI venography having excellent sensitivity in diagnosing CVST. Risk factors for CVST in our patient were ALL and its intensive induction chemotherapy with pegaspargase.

A Rare Case of Metastatic Gastric Signet Ring Cell Adenocarcinoma in a 23-Year-Old Female Presenting as Malignant Pleural Effusion.

Signet ring cell carcinoma (SRCC) is a poorly differentiated mucin-producing adenocarcinoma with greater than 50% signet ring cells. It commonly arises from the gastrointestinal (GI) tract and rarely from extraintestinal organs. This is a rare case of a young African American female who presented with metastatic spread of signet ring cell gastric cancer (pleural and lymph nodal involvement) as the initial presentation of SRCC. Knowledge of the various clinical manifestations of SRCC can help with its early diagnosis, and there is a high need for detailed physical examination, early referral, and prompt treatment in patients with SRCC.

t(3;9;22) 3-way chromosome translocation in chronic myeloid leukemia is associated with poor prognosis.

Chronic myelogenous leukemia (CML) is genetically characterized by the reciprocal translocation of chromosome 9 and 22. Around 5-8% of CML develop complex variant Ph translocations involving one or more chromosomal regions besides 9 and 22. Chromosome 3 is not frequently involved in complex translocations in CML. We report in this study a case of CML displaying a t(3;9;22) 3-way translocation. A review of the literature appears to indicate that CML patients with this translocation tend to have an aggressive course and poor outcome. Additional 3-way chromosome translocations associated with CML are also reviewed.

STI571 (Gleevec) improves tumor growth delay and survival in irradiated mouse models of glioblastoma.

PURPOSE: Glioblastoma multiforme (GBM) is a devastating brain neoplasm that is essentially incurable. Although radiation therapy prolongs survival, GBMs progress within areas of irradiation. Recent studies in invertebrates have shown that STI571 (Gleevec; Novartis, East Hanover, NJ) enhances the cytotoxicity of ionizing radiation. In the present study, the effectiveness of STI571 in combination with radiation was studied in mouse models of GBM. METHODS AND MATERIALS: Murine GL261 and human D54 GBM cell lines formed tumors in brains and hind limbs of C57BL6 and nude mice, respectively. GL261 and D54 cells were treated with 5 micromol/L of STI571 for 1 h and/or irradiated with 3 Gy. Protein was analyzed by Western immunoblots probed with antibodies to caspase 3, cleaved caspase 3, phospho-Akt, Akt, and platelet-derived growth factor receptor (PDGFR) alpha and beta. Tumor volumes were assessed in mice bearing GL261 or D54 tumors treated with 21 Gy administered in seven fractionated doses. Histologic sections from STI571-treated mice were stained with phospho-Akt and phospho-PDGFR beta antibodies. Kaplan-Meier survival curves were used to study the response of mice bearing intracranial implants of GL261. RESULTS: STI571 penetrated the blood-brain barrier, which resulted in a reduction in phospho-PDGFR in GBM. STI571-induced apoptosis in GBM was significantly enhanced by irradiation. STI571 combined with irradiation induced caspase 3 cleavage in GBM cells. Glioblastoma multiforme response to therapy correlated with an increase in tumor growth delay and survival when STI571 was administered in conjunction with daily irradiation. CONCLUSION: These findings suggest that STI571 has the potential to augment radiotherapy and thereby improve median survival.

SRC family kinase inhibitor SU6656 enhances antiangiogenic effect of irradiation.

PURPOSE: Src family kinases (SFK) have been identified as molecular targets. SU6656 is a small-molecle indolinone that specifically inhibits this family of kinases. METHODS AND MATERIALS: Human umbilical vein endothelial cells were used to study the effects of SFK inhibition. Western blot analysis was performed to determine the effect of SFK inhibition on the PI3K/Akt pathway and caspase cleavage. Apoptosis was studied by propidium iodide staining of nuclei. Angiogenesis was examined using capillary tubule formation in Matrigel. Tumor response was further studied in vivo using Lewis lung carcinoma cells implanted into the dorsal skin fold of mice in the window model and in the hind limb in the tumor volume model. RESULTS: Clonogenic survival of endothelial cells was decreased after the combined therapy of SU6656 and radiation compared with radiotherapy alone. Furthermore, SFK inhibition by SU6656 attenuated radiation-induced Akt phosphorylation and increased radiation-induced apoptosis and vascular endothelium destruction. In vivo, SU6656 administered before irradiation significantly enhanced radiation-induced destruction of blood vessels within the tumor windows and enhanced tumor growth delay when administered during fractionated irradiation. CONCLUSIONS: This study demonstrates the potential use of SFK inhibition to enhance the effects of ionizing radiation during radiotherapy.

Growth factor-independent activation of protein kinase B contributes to the inherent resistance of vascular endothelium to radiation-induced apoptotic response.

The phosphatidylinositol 3'-kinase (PI3K)/protein kinase B (Akt) signal transduction pathway plays a critical role in mediating endothelial cell survival during oxidative stress. The role of the PI3K/Akt pathway in promoting cell viability was studied in vascular endothelial cells treated with ionizing radiation. Western blot analysis showed that Akt was phosphorylated rapidly in response to radiation in primary culture human umbilical vein endothelial cells in the absence of serum or growth factors. Akt phosphorylation occurred after doses as low as 1 Gy. PI3K consists of p85 and p110 subunits, which play a central role in Akt activation in response to exogenous stimuli. A mutation within the Src homology region 2 domain of mutant p85 (Deltap85) prevented radiation-induced Akt phosphorylation, when overexpressed in endothelial cells. Vascular endothelial cells transduced with control vector were resistant to radiation-induced apoptosis, whereas endothelial cell transduction with adenovirus encoding the mutated p85 (Ad.Deltap85) reversed this resistance to apoptosis after treatment with intermediate radiation doses (2-6 Gy). Deltap85 overexpression alone had no effect on the viability or apoptosis of endothelial cells. However, irradiated endothelial cells overexpressing Deltap85 released cytochrome c into the cytosol fraction and activated proteolytic cleavage of caspases 3 and 9, thereby inducing the apoptotic response. Inhibition of caspase 3 blocked endothelial apoptosis induced by overexpression of Deltap85 and radiation. These findings suggest that growth factor-independent activation of Akt contributes, in part, to the inherent resistance of irradiated vascular endothelium to the activation of apoptotic response.

A specific antagonist of the p110delta catalytic component of phosphatidylinositol 3'-kinase, IC486068, enhances radiation-induced tumor vascular destruction.

The phosphatidylinositol 3'-kinase (PI3k)/protein kinase B (PKB/Akt) signal transduction pathway plays a critical role in mediating endothelial cell survival and function during oxidative stress. The role of the PI3k/Akt signaling pathway in promoting cell viability was studied in vascular endothelial cells treated with ionizing radiation. Western blot analysis showed that Akt was rapidly phosphorylated in response to radiation in primary culture endothelial cells (human umbilical vascular endothelial cells) in the absence of serum or growth factors. PI3k consists of p85 and p110 subunits, which play a central upstream role in Akt activation in response to exogenous stimuli. The delta isoform of the p110 subunit is expressed in endothelial cells. We studied the effects of the p110delta specific inhibitor IC486068, which abrogated radiation-induced phosphorylation of Akt. IC486068 enhanced radiation-induced apoptosis in endothelial cells and reduced cell migration and tubule formation of endothelial cells in Matrigel following irradiation. In vivo tumor growth delay was studied in mice with Lewis lung carcinoma and GL261 hind limb tumors. Mice were treated with daily i.p. injections (25 mg/kg) of IC486068 during 6 days of radiation treatment (18 Gy). Combined treatment with IC486068 and radiation significantly reduced tumor volume as compared with either treatment alone. Reduction in vasculature was confirmed using the dorsal skinfold vascular window model. The vascular length density was measured by use of the tumor vascular window model and showed IC486068 significantly enhanced radiation-induced destruction of tumor vasculature as compared with either treatment alone. IC486068 enhances radiation-induced endothelial cytotoxicity, resulting in tumor vascular destruction and tumor control when combined with fractionated radiotherapy in murine tumor models. These findings suggest that p110delta is a therapeutic target to enhance radiation-induced tumor control.

The use of tyrosine kinase inhibitors in modifying the response of tumor microvasculature to radiotherapy.

The response of the tumor microvasculature to ionizing radiation can be modified to improve tumor control in preclinical mouse models of cancer. Recent studies have shown that a variety of cancer drugs can improve the response of cancers to radiotherapy. Protein tyrosine kinase inhibitors (TKIs) have been shown to enhance radiation-induced destruction of tumor blood vessels. Among these compounds are inhibitors of a broad spectrum of receptor tyrosine kinases (RTKs). Inhibition of RTKs attenuates downstream signaling from various angiogenic growth factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF). RTK inhibitors with various specificities against the receptors for VEGF, PDGF, and FGF manifest significant antiangiogenic activities as well. We have shown using tumor vascular window model and tumor growth delay assays that these compounds can enhance tumor radiation response by attacking tumor microvasculature. Furthermore, we have shown that radiation and RTK inhibitors exert their antiangiogenic effect through inhibition of the PI3K/Akt signaling pathway, which results in induction of apoptosis. Our studies have provided a basis for future clinical investigations of combining radiotherapy and RTK inhibitors.

Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents.

Histone deacetylases (HDACs) can regulate expression of tumor suppressor genes and activities of transcriptional factors involved in both cancer initiation and progression through alteration of either DNA or the structural components of chromatin. Recently, the role of gene repression through modulation such as acetylation in cancer patients has been clinically validated with several inhibitors of HDACs. One of the HDAC inhibitors, vorinostat, has been approved by FDA for treating cutaneous T-cell lymphoma (CTCL) for patients with progressive, persistent, or recurrent disease on or following two systemic therapies. Other inhibitors, for example, FK228, PXD101, PCI-24781, ITF2357, MGCD0103, MS-275, valproic acid and LBH589 have also demonstrated therapeutic potential as monotherapy or combination with other anti-tumor drugs in CTCL and other malignancies. At least 80 clinical trials are underway, testing more than eleven different HDAC inhibitory agents including both hematological and solid malignancies. This review focuses on recent development in clinical trials testing HDAC inhibitors as anti-tumor agents.