Juan J. Cruz

Reversible Posterior Leukoencephalopathy Syndrome Induced by Sunitinib

TO THE EDITOR: We would like to report the occurrence of reversible posterior leukoencephalopathy that we believe is directly attributable to sunitinib malate (Sutent; Pfizer Pharmaceuticals Group, New York, NY), a receptor tyrosine kinase inhibitor with antiangiogenic activity that is approved for the treatment of advanced renal cell carcinoma. A 70-year-old woman diagnosed with renal cell carcinoma and bone metastasis was first treated with palliative nefrectomy and interferon plus vinblastine. Afterwards, she was enrolled in a phase II clinical trial with sunitinib malate (50 mg daily for 4 weeks every 6 weeks). Two weeks after starting the treatment, she was admitted to the hospital because of partial seizures affecting her left superior extremity, headache, and vision loss in the previous 2 days. The physical examination was normal except for cortical blindness and hypertension (170/100 mmHg). Blood tests, including coagulation study and gasometry, were unremarkable. Computed tomography of the brain showed symmetric subcortical hypodense lesions in the occipital lobes, consistent with reversible posterior leukoencephalopathy syndrome (RPLS). Magnetic resonance imaging was requested to rule out brain micrometastasis and it confirmed the findings of RPLS: symmetric hyperintense T2 signal involving bilateral occipital and parietal lobes in the subcortical distribution (Fig 1). Sunitinib administration was withheld and the patient was treated with anticonvulsants and antihypertensives. She recovered completely, was discharged in a few days and had a normal brain computed tomography performed 1 month later. The RPLS was initially reported by Hinchey et al. It is a clinical condition characterized by headache, seizures, impaired vision, acute hypertension, and typical magnetic resonance imaging and computed tomography imaging findings (symmetric and reversible). This syndrome has been described related to different circumstances: hypertensive encephalopathy, eclampsia, collagen vascular disorders (systemic lupus erythematosus, polyarteritis nodose, Behcet), trombotic thrombocytopenic purpura, acute porphyria, postcarotid endarterectomy, and Guillain-Barre syndrome. However, it is most commonly caused by immunosuppressive agents and cytotoxic drugs as cyclosporine A, tacrolimus, interferon alfa, cisplatin, cytarabine, IV immunoglobulins, L-asparaginase, and more recently by bevacizumab (antiangiogenic agent) and sorafenib (tyrosine kinase inhibitor). Its pathogenesis is not precisely known. It is postulated that the alterations can be related with the appearance of vasogenic edema because of elevation in the blood pressure (vasospasm) or because of toxic damage to blood-brain barrier or vascular endothelium. Sunitinib has a dual activity: extracellular action against vascular endothelial growth factor receptor (antiangiogenic) and intracellular action against tyrosine kinase domains, which can produce hypertension. In our case, the set of symptoms could be caused through both mechanisms.

Evaluation of Multiparameter Flow Cytometry for the Detection of Breast Cancer Tumor Cells in Blood Samples

We comparatively evaluated different cytokeratin (CK) reagents analyzed by flow cytometry (FCM) for the identification of the best combination of DNA/CK staining for detecting minimal numbers of breast cancer cells in peripheral blood (PB). In 59 primary breast cancer tumors, we comparatively analyzed the reactivity for up to 6 different anti-CK reagents using multiparameter FCM: anti-CK7, anti-CK20, anti-pan-CK, anti-CK8/CK18, anti-CK8, and anti-CK18. Afterward, dilutional experiments of Michigan Cancer Foundation (MCF)7 breast cancer cells in PB were performed, and the sensitivity of a DNA/CK18 staining was evaluated. Our results showed that anti-CK18 reagents were those providing the brightest and more sensitive staining for primary breast cancer tumor cells by FCM. Dilutional experiments of MCF cells in PB showed that the DNA/anti-CK18 double staining was highly specific for the identification of epithelial cells; its sensitivity ranged between 10(-6) and 10(-7) (detection of 1 tumor cell among 10(6) to 10(7) nucleated blood cells). Combined assessment of DNA cell contents and reactivity for CK18 by FCM is a sensitive method for the specific identification of breast cancer cells in PB.

Neuregulin Expression Modulates Clinical Response to Trastuzumab in Patients With Metastatic Breast Cancer

PURPOSE Human epidermal growth factor receptor 2 (HER-2) overexpression has been associated with the genesis and progression of a subset of breast cancers. The function of HER-2 may be upregulated by overexpression or by the availability of neuregulins (NRGs), a group of transmembrane growth factors. Transmembrane NRGs strongly activated HER-2 and cell proliferation in breast cancer cells that did not overexpress HER-2, and treatment with trastuzumab prevented the proliferative action of transmembrane NRG. This raised the relevant clinical question of whether patients considered as HER-2 negative, but expressing transmembrane NRG, may benefit from treatment with trastuzumab. PATIENTS AND METHODS MCF7 cells expressing transmembrane NRG (MCF7-NRG2c) were injected into mice, and their sensitivity to trastuzumab was assessed. A retrospective study of 124 patients with early-stage or metastatic breast cancer was conducted. Expression of transmembrane NRG was evaluated by immunohistochemistry. In 11 patients, Western blot for NRGs was also carried out. Statistics were performed to analyze possible correlations between NRG expression and response to trastuzumab-based therapies, event-free survival, and overall survival (OS). RESULTS Trastuzumab inhibited tumor growth in mice injected with MCF7-NRG2c cells. Transmembrane NRG was frequently expressed in breast cancer patients. Overexpression of transmembrane NRG significantly correlated with a longer event-free survival and OS in patients with low or normal HER-2 expression who were treated with trastuzumab-based therapies but not in patients with HER-2 overexpression. CONCLUSION We suggest that the spectrum of patients who may benefit from trastuzumab-based therapies may be widened to include patients with metastatic breast cancer without HER-2 amplification but who express transmembrane NRGs.

Cancer as a reprogramming-like disease: implications in tumor development and treatment.

Cancer is a clonal malignant disease originated in a single cell and characterized by the accumulation of partially differentiated cells that are phenotypically reminiscent of normal stages of differentiation. Given the fact that human cancer is diagnosed at later stages and cannot be monitored during its natural evolution, the origin of tumors has been a subject of continuing discussion. Animal models provide a means to determine the identity of the cell-of-origin leading to malignancy and to develop new treatments. Recent findings in mice have shown that cancer stem cells could arise through a reprogramming-like mechanism, suggesting that genetic lesions that initiate the cancer process might be dispensable for tumor progression and maintenance. This review addresses the impact of these results toward a better understanding of carcinogenesis and proposes research avenues for tackling these issues in the future.

The Emerging Picture of Human Breast Cancer as a Stem Cell-based Disease

There are increasing data supporting the existence of a cell hierarchy within the mammary gland. At the top or this hierarchy a small population of cells with self-renewal properties maintains the tissue architecture and remodeling, and they are known as stem cells. Also, recent evidences indicate that breast cancer is originated and maintained by its own cancer stem cells reminding the normal mammary gland. The existence of this small population of cells with self-renewal capability has important biological and clinical significances. So, the interpretation of tumors as hierarchical cellular structures has changed our vision of the breast cancer scenario. Here, we review the current knowledge about normal and breast cancer stem cells, and their implications in cancer development, together with their consequences in breast cancer susceptibility, dissemination and treatment response.

Phase II study of capecitabine as palliative treatment for patients with recurrent and metastatic squamous head and neck cancer after previous platinum-based treatment

Background:Platinum-based therapy (PBT) is the standard therapy for recurrent and/or metastatic head and neck cancer (HNC), but the incidence of recurrence remains high. This study evaluates the efficacy and tolerability of capecitabine as palliative monotherapy for recurrent HNC previously treated with PBT.Methods:Patients aged 18–75 years, with Eastern Cooperative Oncology Group performance status 0–2, squamous HNC with locoregional and/or metastatic recurrence previously treated with PBT and adequate organ functions, were included. Capecitabine (1.250 mg m−2 BID) was administered on days 1–14 every 21 days for at least two cycles.Results:A total of 40 male patients with a median age of 58 years were analysed. All patients received a median number of four cycles of capecitabine (range: 1–9) and the median relative dose intensity was 91%. Seven patients were not evaluable for response. Overall response rate was 24.2%. Median time to progression and overall survival were 4.8 and 7.3 months, respectively. Haematological adverse events (AEs) grade 3/4 were reported in six patients. Most common grade 3/4 non-haematological AEs were asthenia (12.5%), palmar-plantar eritrodisestesia (10%), mucositis (10%), dysphagia (10%) and diarrhoea (7.5%).Conclusions:Capecitabine seems to be an active, feasible and well-tolerated mode of palliative treatment for advanced HNC patients who have previously received PBT schedules.

Trastuzumab and antiestrogen therapy: focus on mechanisms of action and resistance.

Objective:In breast cancer, 2 molecular targets are well established (ER/PR and HER2), and therapies directed to these proteins have demonstrated to be clinically useful. Methods:Despite the presence of the ER and PR, only half of the patients will respond to endocrine therapy, and less than 35% of patients with ErbB2-overexpressing metastatic breast cancer will respond to trastuzumab as a single agent. Results:To improve survival of metastatic breast cancer patients with ER/PR positive and HER2 positive is critical to elucidate the mechanism of resistance or sensitivity of these tumors for a better selection depending on biologic molecular alterations. Conclusions:Recently, several studies addressing this issue have been reported. Here, we will focus on a comprehensive review of the currently available data.

Flow cytometry in the diagnosis of cancer

Flow cytometry has rapidly expanded from basic research to clinical laboratories mainly due to its unique characteristics regarding cell analysis. Among the clinical uses of flow cytometry cancer represents one of the most relevant. Several applications of flow cytometry can currently be applied to the study of cancer, including the detection of tumour cell DNA aneuploidy, the analysis of tumour cell proliferation and the immunophenotyping of leukemias. Although standardized flow cytometry protocols for these applications are scanty, the clinical value has been clearly established. The presence of DNA aneuploidy and a high proportion of S-phase tumour cells have been associated with tumour malignancy and a poor prognosis. The immunophenotype of leukaemia is of great help both for the diagnosis and classification of chronic lymphoproliferative disorders and acute leukaemias, especially in acute lymphoblastic leukemia cases and the M0, M3-variant, M6 and M7 acute myeloblastic leukaemia subtypes. In addition, it allows the identification of relatively rare leukemia cases such as the biphenotypic and the Nk-cell lineage leukemias. The development of flow cytometry is continuously bringing new applications into the clinical laboratory in the area of cancer diagnosis.

Breakthrough cancer pain – still a challenge

Breakthrough cancer pain is defined as transient pain exacerbation in patients with stable and controlled basal pain. Although variable, the prevalence of breakthrough cancer pain is high (33%–95%). According to the American Pain Foundation, breakthrough pain is observed in 50%–90% of all hospitalized cancer patients, in 89% of all patients admitted to homes for the elderly and terminal-patient care centers, and in 35% of all ambulatory care cancer patients. The management of breakthrough cancer pain should involve an interdisciplinary and multimodal approach. The introduction of new fentanyl formulations has represented a great advance and has notably improved treatment. Among these, the pectin-based intranasal formulation adjusts very well to the profile of breakthrough pain attacks, is effective, has a good toxicity profile, and allows for convenient dosing – affording rapid and effective analgesia with the added advantage of being easily administered by caregivers when patients are unable to collaborate.

New options in the treatment of locally advanced head and neck cancer: Role for induction chemotherapy

Advanced locoregional disease is the most frequent clinical situation in Head and Neck cancer. The standard of care for most clinicians is a multidisciplinary treatment with concomitant chemotherapy plus radiotherapy (CRT). However, retrospective studies have shown that in patients treated with CRT there was a relative increase in systemic relapse due to a lack of systemic control. For this reason a renewed interest has appeared for the incorporation of induction chemotherapy in the treatment of locally advanced Head and Neck Cancer. Furthermore new combination regimens with taxanes have shown to be more active than the classical cisplatin and 5-fluorouracil induction regimen. For these reasons ongoing trials are comparing induction chemotherapy followed by chemoradiotherapy with chemoradiotherapy alone. In this review, we will discuss the currently available data that support the design of these clinical trials as well as the future role of new agents in this clinical situation.