Damian A. Laber

Clinical Efficacy and Toxicity of Anti-EGFR Therapy in Common Cancers

Epidermal growth factor receptor (EGFR) is a cell surface molecule and member of the ErbB family of receptor tyrosine kinases. Its activation leads to proliferation, antiapoptosis, and metastatic spread, making inhibition of this pathway a compelling target. In recent years, an increasing number of clinical trials in the management of solid malignancies have become available indicating the clinical efficacy of anti-EGFR monoclonal antibodies and oral small molecule tyrosine kinase inhibitors (TKIs). This review addresses frequently used EGFR inhibitors, summarizes clinical efficacy data of these new therapeutic agents, and discusses their associated toxicity and management.

The Role of Human Papilloma Virus in Lung Cancer: A Review of the Evidence

Papillomaviruses are small nonenveloped DNA viruses that infect squamous epithelial cells. These viruses have been found in many organisms. Human papillomaviruses (HPVs) give rise to a large spectrum of epithelial lesions, mainly benign hyperplasia (eg, warts and papillomas) with low malignant potential. There is a subgroup of HPV, the “high-risk” HPV, which is associated with precancerous and cancerous lesions. A small fraction of people infected with high-risk HPV will develop cancers that usually arise many years after the initial infection (Psyrri and Dimaio, Nat Clin Pract Oncol. 2008;5:24–31). Nonsmall cell lung cancer is a heterogeneous disease. The most common histologic subtypes include squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Despite different histologies, nonsmall cell lung cancers are often classified together because of similarities in approach and management of the disease. In this article, we reviewed the current literature on lung cancer and HPV. On the basis of this data, we suggested a possible mechanism of carcinogenesis induced by HPV.

Argatroban for anticoagulation during cardiac surgery.

Background: The aim of this study was to report our experience and review the published data on argatroban administration during adult cardiac surgery. Methods: The information on all reported cases of argatroban use in adults, during cardiac surgery was reviewed, including that of the patient described here. This analysis focused on patient characteristics, type of surgery, argatroban dosing schedule, monitoring of anticoagulation and outcomes. Results: Twenty‐one cases have been reported. Fifteen patients underwent off‐pump surgical procedures with the argatroban dose adjusted to maintain an activated clotting time (ACT) range between 200 and 300 s. Three intraoperative thrombi occurred in two patients when the ACT was <280 s. None had coagulopathy. Six cases reported the use of argatroban during on‐pump cardiac surgery dosed to keep the ACT >400 s. Intraoperative thrombotic complications were not reported in this group; however, one clot in the pump was noted after the procedure when the ACT was between 300 and 350 s. All six cases required larger volumes of perioperative blood products and three had severe coagulopathy. Of the 21 cases, seven had an indication for continued anticoagulation following surgery. Four cases did not report further use of argatroban after surgery. Three patients received argatroban after surgery without complications. Recommendations for how to use argatroban during cardiac surgery are proposed. Conclusions: Argatroban, with ACT monitoring, might be safely used for anticoagulation during cardiac surgery.

Risk factors, classification, and staging of renal cell cancer

Knowledge about renal cell carcinoma (RCC) has increased exponentially over the last decades. A clear understanding of RCC is of utmost importance to prevent the disease and improve the outcomes. Large epidemiologic studies have identified cigarette smoking, chemical agents, obesity, hypertension, and end-stage renal disease as risk factors associated with RCC. Identification and confirmation of risk factors may be projected into preventive strategies. Genetic studies of inherited disorders associated with an enhanced risk of RCC have elucidated many important targets for anticancer therapy. The World Health Organization (WHO) has recently developed a new histologic classification of renal cell tumors that has demonstrated prognostic utility. A refined clinical staging system is improving our ability to prognosticate the outcome of RCC patients. This article provides a practical yet comprehensive review of the risk factors, classification, and staging of RCC focussing on recent updates.

Mobilization of Hematopoietic Progenitor Cells by Yeast-Derived β-Glucan Requires Activation of Matrix Metalloproteinase-9

Poly‐(1,6)‐β‐d‐glucopyranosyl‐(1,3)‐β‐d‐glucopyranose (PGG) β‐glucan is a soluble yeast‐derived polysaccharide that has previously been shown to induce hematopoietic progenitor cell (HPC) mobilization. However, the mobilizing mechanism of action remains unknown. Here, we confirmed that PGG β‐glucan alone or in combination with granulocyte colony‐stimulating factor (G‐CSF) mobilizes HPC into the periphery. Optimal mobilizing effects were seen 24–48 hours after PGG β‐glucan doses of 4.8–9.6 mg/kg. Animals treated with G‐CSF and PGG β‐glucan showed a collaborative effect in HPC mobilization compared with G‐CSF treatment alone. Additional studies demonstrated that neither complement 3 nor complement receptor 3 played a role in this effect and that PGG β‐glucan treatment did not induce proinflammatory cytokine secretion. However, bone marrow cells from PGG β‐glucan‐treated mice secreted abundant matrix metalloproteinase‐9 (MMP‐9), and PGG β‐glucan‐induced HPC mobilization was abrogated in MMP‐9 knockout mice. Moreover, we demonstrated that both hematopoietic and nonhematopoietic cells contributed to MMP‐9 secretion upon PGG β‐glucan treatment. In addition, HPCs mobilized by PGG β‐glucan had similar levels of engraftment in host and lineage differentiation capability compared with those mobilized by G‐CSF. Thus, PGG β‐glucan is an agent that enhances HPC mobilization and may improve the outcome of clinical stem cell transplantation.

Digitalis, A Targeted Therapy for Cancer?

The clinical benefit of digitalis for patients with heart disease is well established. However, recent studies have also suggested that digitalis has antineoplastic activities at clinically relevant serum concentrations. Much of the early evidence supporting the anticancer activity of digitalis has been circumstantial. Observational studies suggest a protective benefit and improved outcomes in patients who develop cancer while they are taking digitalis. The mechanism by which digitalis selectively affects the growth of malignant cells is complex, involving several important signaling pathways. Experiments to determine its mechanism of action have demonstrated that digitalis inhibits cell growth and angiogenesis and induces apoptosis in multiple cancer cell lines. Most, if not all, of these effects are mediated through its target enzyme, sodium- and potassium-activated adenosine triphosphatase. This article reviews the literature, which supports the use of digitalis in patients with malignancies with a discussion of the potential mechanisms of action. We hypothesize that sodium- and potassium-activated adenosine triphosphatase is an important new target for cancer therapy. It is reasonable to expect that the addition of digitalis to current cancer treatments will improve the clinical outcomes.

Spontaneous complete regression of hepatocellular carcinoma

In medical terminology, spontaneous regression of cancer refers to exceptional and unexplained partial or complete disappearance of cancer without medical intervention. This phenomenon has been described in various malignancies with no well established causative factors, except perhaps immune mediated. Here we present a rare case of hepatocellular carcinoma with possible metastasis to the lung by computed tomography with complete regression of both the primary tumor and the pulmonary nodules without medical intervention. Our patient may represent the first case of complete regression of the HCC with possible lung metastasis by computed tomography caused by abstinence from alcohol. This phenomenon was confirmed by surgical resection and pathologic evaluation.

Etiology of thrombocytopenia in all patients treated with heparin products

Abstract:  Purpose: To characterize the cause of thrombocytopenia in all patients treated with heparin products, to determine the incidence of heparin‐induced thrombocytopenia (HIT) in unselected hospitalized patients, and to have modern data of the magnitude of this problem. Methods: Retrospective hospital‐based cohort study. During a random 2‐month period, we reviewed the medical records of all patients treated with heparin agents, screened them for thrombocytopenia, and determined the cause of it. Results: Out of 674 patients who received heparin products, 110 (16%) had thrombocytopenia. The most common causes included cancer chemotherapy, surgery, sepsis, and medications. Three patients met the clinical criteria for HIT. One had antibodies for heparin‐platelet factor‐4, and received a direct thrombin inhibitor. The other two individuals had a clinical syndrome that resembled immune HIT, but were not tested for HIT antibodies. One suffered a thrombotic episode that led to the death of her fetus. The other died of a possible thromboembolism. Conclusions: This study provides evidence‐based data for the differential diagnosis of thrombocytopenia after treatment with heparin products. Our findings suggest that increased awareness of the HIT syndrome might reduce morbidity and mortality. Patients exposed to heparin products, who develop thrombocytopenia, should not be overlooked.

IL-4 production by CD8+ lymphomatoid papulosis, type C, attracts background eosinophils

There are two subsets of CD8+ T cells: Tc1 and Tc2. INF‐γ production by Tc1 cells causes granulomatous inflammation. IL‐4 production by Tc2 cells attracts eosinophils. A 76‐year‐Caucasian female presented with CD8+ lymphomatoid papulosis (LyP), type C. We hypothesized that the LyP cells belonged to the Tc2 subset because of abundant background eosinophils. Hematoxylin and eosin and immunohistochemical stains were carried out on tissue sections from a skin punch biopsy. Antibodies for immunohistochemical stains included CD3, CD4, CD5, CD7, CD8, CD30, CD56, ALK‐1, clusterin and IL‐4. There was involvement of the dermis by a dense lymphoid infiltrate composed of large atypical cells and numerous eosinophils. The LyP cells expressed CD5, CD8, CD30 and IL‐4. Keratinocytes showed a membranous pattern of immunoreactivity for IL‐4. IL‐4 production by CD8+ LyP, type C indicates that it belongs to the Tc2 subset. The cytokine milieu produced by the LyP cells attracted eosinophils. The IL‐13R complex on keratinocytes bound IL‐4 and produced a membranous staining pattern. Although CD8+ LyP is rare, we believe that this CD30+ lymphoproliferative disorder should be included in the World Health Organization‐European Organization for Research and Treatment of Cancer classification of cutaneous T‐cell lymphomas.

Pure red-cell aplasia secondary to pregnancy, characterization of a syndrome

The aim of this study was to characterize the syndrome of pure red-cell aplasia (PRCA) secondary to pregnancy. All published cases of PRCA induced by pregnancy were reviewed. Additionally, we reported a patient who developed PRCA on three occasions; two were triggered by pregnancy and one after medroxyprogesterone administration. Ten patients with 13 pregnancy-induced PRCA episodes were reported. The PRCA occurred at any gestational age. All patients received blood transfusions, and six of them were treated corticosteroids. The PRCA resolved in all subjects postpartum. Five women had subsequent pregnancies; three were complicated by PRCA, one was normal, and one had spontaneous abortion without PRCA. One subject developed a PRCA after long-term exposure to medroxyprogesterone. Infant blood values were normal in the nine reported cases. Pregnancy-induced PRCA is a self-limited syndrome with a high risk for relapse during subsequent pregnancies. It can be managed by blood transfusions. Progestins might cause PRCA in these women.