Pharmacological Inhibition of Epidermal Growth Factor Receptor Prevents Intracranial Aneurysm Rupture by Reducing Endoplasmic Reticulum Stress.

BACKGROUND: Multiple pathways and factors are involved in the rupture of intracranial aneurysms. The EGFR (epidermal growth factor receptor) has been shown to mediate inflammatory vascular diseases, including atherosclerosis and aortic aneurysm. However, the role of EGFR in mediating intracranial aneurysm rupture and its underlying mechanisms have yet to be determined. Emerging evidence indicates that endoplasmic reticulum (ER) stress might be the link between EGFR activation and the resultant inflammation. ER stress is strongly implicated in inflammation and apoptosis of vascular smooth muscle cells, both of which are key components of the pathophysiology of aneurysm rupture. Therefore, we hypothesized that EGFR activation promotes aneurysmal rupture by inducing ER stress. METHODS: Using a preclinical mouse model of intracranial aneurysm, we examined the potential roles of EGFR and ER stress in developing aneurysmal rupture. RESULTS: Pharmacological inhibition of EGFR markedly decreased the rupture rate of intracranial aneurysms without altering the formation rate. EGFR inhibition also significantly reduced the mRNA (messenger RNA) expression levels of ER-stress markers and inflammatory cytokines in cerebral arteries. Similarly, ER-stress inhibition also significantly decreased the rupture rate. In contrast, ER-stress induction nullified the protective effect of EGFR inhibition on aneurysm rupture. CONCLUSIONS: Our data suggest that EGFR activation is an upstream event that contributes to aneurysm rupture via the induction of ER stress. Pharmacological inhibition of EGFR or downstream ER stress may be a promising therapeutic strategy for preventing aneurysm rupture and subarachnoid hemorrhage.

Therapy of childhood acute lymphoblastic leukemia in resource-poor geospaces.

The therapy of children with acute lymphoblastic leukemia (ALL) in limited resource geospaces is challenging and must balance safety, efficacy, availability, and affordability. We modified the control arm of the St. Jude Total XI protocol for outpatient delivery including once-weekly daunorubicin and vincristine in initial therapy, postponing intrathecal chemotherapy until day 22, prophylactic oral antibiotics/antimycotics, use of generic drugs, and no central nervous system (CNS) radiation. Data were interrogated from 104 consecutive children ≤12 years (median, 6 years [interquartile range (IQR), 3, 9 years]. All therapies were given in an outpatient setting in 72 children. Median follow-up is 56 months (IQR 20, 126 months). A total of 88 children achieved a hematological complete remission. Median event-free survival (EFS) is 87 months [95% confidence interval (CI), 39, 60], 7.6 years in low-risk children (3.4, 8 years) whereas 2.5 years (1, 10 years) in high-risk children. The 5-year cumulative incidence of relapse (CIR) is 28% (18, 35%), 26% (14, 37%) in low-risk children and 35% (14, 52%) in high-risk children. Median survival for all subjects is not reached but must exceed 5 years. A total of 36 children relapsed at a median of 12 months (5, 23 months). Outcomes were comparable to those reported in the control arm of the Total Therapy XI study, but inferior to current treatment protocols in high-income countries. The average cost of the first 2 years of therapy was $28,500 USD compared with an average cost of approximately $150,000 USD in the US, an 80% saving. In conclusion, using an outpatient-based modification of the St. Jude Total XI protocol, we obtained good results with relatively few hospitalizations or adverse events and at a substantial saving. This model can be applied in other resource-poor geospaces.

Long-term results of the treatment of adolescents and adults with acute lymphoblastic leukemia with a pediatric-inspired regimen delivered on an outpatient basis: A single institution experience.

The results of treatment of adolescents and adults with acute lymphoblastic leukemia (ALL) remain unsatisfactory. Pediatric-inspired treatments seem to be related with better outcomes. 126 adolescent and adult patients with ALL were treated in a 37-year period with a pediatric inspired combined chemotherapy (PICC) schedule, delivered on an outpatient basis and based on the St. Jude´s TOTAL XI pediatric protocol employing vincristine, prednisone, asparaginase, daunorubicin, etoposide, cytarabine, methotrexate, mercaptopurine and triple intrathecal therapy. 80 % of patients were able to receive the initial seven-week period of induction / consolidation fully as outpatients and 77 % achieved a complete remission. In adolescents and young adults (AYAs) the median probability of overall survival (OS) was 44 months, whereas the 5-year OS was 48 %. In adults, the median probability of OS was 24 months, and the 5-year OS was 32 %. Patients with T-cell ALL did significantly worse than those with a B cell phenotype (OS at 5 years 17 versus 40 %, respectively). These figures are better than those informed in our country employing more aggressive, in-hospital schedules such as the hyper-CVAD. We found that, in AYAs and adult patients with ALL, the use of an asparaginase-containing PICC delivered on an outpatient basis renders acceptable results, better than those obtained in similar socioeconomic circumstances employing adult-oriented schedules. Additional studies are needed to assess the usefulness of these PICC treatments in adult individuals with ALL treated in underprivileged circumstances, such as those prevailing in LMIC.

High dose melphalan is an adequate preparative regimen for autologous hematopoietic stem cell transplantation in relapsed/refractory lymphoma.

INTRODUCTION: High-dose melphalan (HD-Mel) has been successfully employed in autografting patients with multiple myeloma. An advantage of this regimen is that the total dose of Mel can be delivered in a single day, being particularly useful when non-frozen hematopoietic stem cells are employed in the autograft. MATERIAL AND METHODS: All consecutive patients with R/R lymphomas, both HL and NHL studied and treated at two different centers were prospectively included in a study of ASCT employing a single dose of HD-Mel (200 mg/m2). A group of R/R HL or NHL autografted employing BEAM-like preparative regimens was constructed matched by diagnosis and age. The primary endpoint of the study was overall survival (OS), the secondary endpoint was event-free survival (EFS). RESULTS: Twenty-five R/R HL/NHL patients were prospectively accrued in the study. There were 8 (32%) females, 13 (52%) patients had at least 1 adverse effect: 7 (28%) developed mucositis, 5 (20%) neutropenic fever, and 6 (24%) grade IV nausea. In the HD-Mel group, median overall survival (OS) was not achieved and OS at 36 months was 71%, the transplant-related mortality being 0%. In the control group, median OS was not achieved and the 36-month OS was 76%, results not statistically significant (p 0.5). The EFS was also similar in both groups (p 0.5). CONCLUSION: HD-Mel alone is non-inferior to a BEAM-like regimen as a preparative regimen for autografting patients with R/R HL and NHL. The regimen is adequate to graft persons with non-frozen stem cells.

Long term survival in multiple myeloma: a single institution experience in underprivileged circumstances.

There is data suggesting that the clinical behavior of multiple myeloma (MM) may be different in Latin Americans than in Caucasian or African-Americans, consistent with a less aggressive course of MM in Latinos. We analyzed the overall survival (OS) of 139 persons with MM in a single institution in México, as well the variables which were associated with long-term OS. Of all patients, the median OS was 11 years whereas the 5-year and 10-year OS were 75% and 55% respectively. The analysis of variables showed that the variable related with five-year survival was having hematopoietic stem cell transplantation (HSCT), whereas the variables related with 10-year survival were HSCT, age at diagnosis (patients younger than 50 survived longer), light chain type (kappa survived longer) and ISS stage (stage I patients survived longer). The only variable associated with both 5 and 10-year survival was HSCT. A plateau in the OS was reached after 10 years, both in grafted and non-grafted patients. We have confirmed the critical role of HSCT in the prognosis of persons with MM, independent of the induction treatment or the maintenance post-transplant, and we have identified a better prognosis in this cohort, as compared with African-Americans or Caucasians, since the proportion of long-term survivors in our group is seemingly better than those in other populations.

An Aggressive Case of Sinonasal Squamous Cell Carcinoma, Invasive to Bone, Arising Within Inverted Papilloma with Intracranial Extension: A Case Report.

Sinonasal squamous cell carcinoma represents a rare and aggressive disease. Clinical presentation usually mimics other benign entities and consequently this malignancy is seldom diagnosed in early stages. Surgical management, although is standard of care, is rarely amenable due to the structures involved, usually intracranially. This article encompasses a case report of squamous cell carcinoma involving the ethmoidal, maxillary, and sphenoid sinuses invasive to bone and extending intracranially.

A Fatal Case of Large Cell Neuroendocrine Lung Cancer Metastatic to the Brain: A Case Report.

Large cell neuroendocrine carcinoma (LCNEC) is part of lung neuroendocrine tumors. LCNEC represents an extremely rare entity with aggressive behavior and poor prognosis. Primary surgery is the mainstream of treatment, although it is rarely amenable due to local or systemic tumor metastasis at the time of the diagnosis. We present a case report of a female patient diagnosed with large cell neuroendocrine lung cancer metastatic to the brain. Noting the low incidence of the disease, the lack of relevant clinical data has resulted in a challenge in diagnosis and management.

Cerebellar Cavernous Malformation (Cavernoma): A Case Report.

Cavernous malformations are congenital or acquired vascular abnormalities. They are uncommon entities with an incidence of 0.5% of the general population and usually are unnoticed until a hemorrhagic event occurs. Cavernomas can be concurrently seen with developmental venous anomalies (DVAs) in 20% (range 20%-40%) of cases, in which case they are known as mixed vascular malformations. We report a case of a healthy young adult, who presented with acute onset of headache, dizziness, and nausea with intermittent episodes of vomiting for four days. Brain tomography imaging at presentation revealed likely multiple foci of intracranial hemorrhage; however, magnetic resonance imaging (MRI) showed findings suggestive of an underlying cavernoma that had bled, in addition to a coexisting DVA. The patient was discharged home with no deficits. Outpatient follow-up five months later revealed no symptoms or neurologic deficits.