Kasi, Pashtoon Murtaza

Developing a systematic approach to hospital discharges can lead to improvements and serve a model for other inpatient wards.

The liver is the dominant site of metastases for patients with metastatic colorectal cancer (mCRC). Depending on the timing of diagnosis and the biology of the disease, it is not uncommon for these patients to present with visceral crisis in the form of severe liver dysfunction. Treatment of these individuals is, however, difficult and challenging. The decision to consider chemotherapy in these dire circumstances entails consideration of numerous factors. If we were to focus on just the metabolism of the different drugs and biologic agents available to treat mCRC, both 5-fluorouracil and oxaliplatin alone or in combination with a monoclonal antibody are reasonable choices. Specifically, FOLFOX is a feasible and safe option in patients with mCRC with severe liver dysfunction. Choice of the biologic agent to add to the doublet chemotherapy could be individualized based on the RAS status and the clinical scenario. Based on the divergent experience of treating 2 cases and other prior reports, a summary of recommendations with a model in the form of a “therapeutic triad” is presented. The paper highlights the therapeutic challenges in patients with mCRC and severe liver dysfunction. The choice of chemotherapeutic agents and reports of other cases/series is also presented.

Nelarabine (ara-G; Arranon; compound 506U78) is an antineoplastic purine analog used for the treatment of refractory or relapsed T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). The drug was granted accelerated approval in October 2005 by the US Food and Drug Administration (FDA) given the efficacy (induction of complete responses) noted in 2 single-arm trials (one in pediatric setting and one in adult patient population). The main spectra of toxicities that have been reported in these clinical trials and subsequent studies are hematological and neurological. Nelarabine induced rhabdomyolysis and increased creatinine phosphokinase (CK; CPK) levels apparently have been reported and this side effect has been added as an adverse reaction in the product monograph from the drug company during postmarketing surveillance. However, the true extent and incidence of the myotoxicity from the drug are unclear. In this paper we report a grade IV CK elevation and rhabdomyolysis in a patient with T-ALL treated with nelarabine. Given the reported finding, we examined the literature further for myotoxicity, increased CK, and/or rhabdomyolysis associated with the use of the nelarabine and report our findings.

Abstract Background: Esophageal Adenocarcinoma (EAC) continues to rise in incidence, with prognosis remaining poor despite advances in multimodality therapy. Several novel target agents are now being explored as an option for treating EAC. One potential target is heat shock protein 90 (Hsp90), a chaperone protein that is involved in many diverse biological processes including cell signaling, proliferation, and survival. Many of the client proteins are known oncoproteins that allow Hsp90 to stabilize cancer cell growth by supporting proliferation and preventing apoptosis. The isoform, Hsp90β, is constituently expressed, while Hsp90α is inducible during times of stress, with expression increased 2-10 fold in cancers. Our hypothesis is that Hsp90 inhibition, in combination with standard chemotherapeutic drugs, will cause EAC cancer cells to be more susceptible to apoptosis and reduce the rate of proliferation. Methods: EAC cell lines, OE19 and OE33, were used to evaluate the effects of Hsp90 inhibitor, AUY-922, in cancer cell growth and apoptosis. ELISA of WST-1 and BrdU were used to determine the effective dosage and assess proliferation. Pathway inhibition was evaluated by Western Blot of Hsp90α and Hsp70. OE19, OE33, and patient samples of EAC tumor and gastroesophageal reflux tissue were used to assess the gene expression of Hsp90 and several client protein pathways by reverse transcription polymerase chain reaction (RT-PCR). Results: The ED50 of AUY-922 was determined to be 30ηM. A combination of chemotherapeutic drugs, cisplatin and 5-fluorouracil (5-Fu), along with AUY-922 showed significantly decreased proliferation compared to untreated and single agent treated cell lines. Western blot demonstrated that Hsp90 was inhibited by AUY-922 treatment, by a decrease in expression of Hsp90α, and an increase in the expression of Hsp70. RT-PCR in the cell line treatment groups showed an impact on many client oncoproteins involved in cancer cell survival and Hsp90 was shown to be upregulated in tumor samples when compared to normal GERD samples. Conclusion: The use of Hsp90 inhibitor, AUY-922, leads to reduced Hsp90 pathway expression, resulting in a degradation of many Hsp90 client proteins involved in cancer genesis. Cell proliferation was decreased with AUY-922 treatment, with the greatest demonstrated effect when used in combination with cisplatin and 5-Fu. Therefore, Hsp90 inhibition may have an application in multimodal EAC chemotherapy. Citation Format: Christina L. Rotoloni, Jaclyn M. LaRosa, Michael J. Porter, Lori A. Kelly, Katherine Nega, Emily Wolfson, Yoshihiro Komastu, Juliann E. Kosovec, Pashtoon M. Kasi, Toshitaka Hoppo, Ali H. Zaidi, Blair A. Jobe. Enhanced efficacy of cisplatin and 5-fluorouracil combination with AUY-922 in esophageal adenocarcinoma cells. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A48.

Background. Understanding the predictors of mortality in individuals with human immunodeficiency virus and hepatitis C virus (HIV/HCV) coinfection can be useful in management of these patients. Methods. We used the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) for these analyses. Multivariate Cox-regression models were used to determine predictors of mortality. Results. Among 8,039 HIV infected veterans, 5251 (65.3%) had HCV coinfection. The all-cause mortality rate was 74.1 (70.4–77.9) per 1000 person-years (PY) among veterans with HIV/HCV coinfection and 39.8 (36.3–43.6) per 1000 PY for veterans with HIV monoinfection. The multivariable adjusted hazard ratio (95% confidence interval) of all-cause mortality for HCV infection was 1.58 (1.36–1.84). Positive predictors of mortality included decompensated liver disease (2.33 (1.98–2.74)), coronary artery disease (1.74 (1.32–2.28)), chronic kidney disease (1.62 (1.36–1.92)), and anemia (1.58 (1.31–1.89)). Factors associated with reduced mortality included HCV treatment (0.41 (0.27–0.63)) and higher CD4 count (0.90 (0.87–0.93) per 100 cells/μL higher count). Data were insufficient to make informative analyses of the role of HCV virologic response. Conclusion. HCV coinfection was associated with substantial increased risk of mortality among HIV infected veterans. HCV treatment was associated with significantly lower risk of mortality.

Pegfilgrastim (Neulasta) is a recombinant filgrastim (human granulocyte colony-stimulating factor (G-CSF)) attached to a polyethylene glycol (PEG) molecule and is given as part of chemotherapy regimens that are associated with significant myelosuppression and risk for febrile neutropenia. Prescribing information available on manufacturer’s website for the drug warns us about possible severe sickle cell crises related to the medication but does not report the actual incidence or the use in patients with sickle cell trait. Caution is advised when using it in patients with sickle cell disease. Here we present a case of a Caucasian female with known sickle cell trait (SCT) with no prior complications who developed a presumed sickle cell crisis after getting Neulasta, as a part of the chemotherapy regimen used to treat her breast cancer. Based on our literature review, this appears to be the first case report of a patient with SCT developing a sickle cell crisis with the pegylated form of recombinant filgrastim. Given the dearth of literature regarding the use of G-CSF and its related pegylated forms in patients with sickle cell anemia and sickle cell trait, a discussion of potential mechanisms and review of current literature and guidelines is also presented.