Sercan Aksoy

Rituximab-related viral infections in lymphoma patients.

Recently, a human/mouse chimeric monoclonal antibody, rituximab, has been successfully used to treat cases of B-cell non-Hodgkins lymphoma and some autoimmune diseases. However, several viral infections related to rituximab have been reported in the literature, but were not well characterized. To further investigate this topic, relevant English language studies were identified through Medline. There were 64 previously reported cases of serious viral infection after rituximab treatment. The median age of the cases was 61 years (range: 21 – 79). The median time period from the start of rituximab treatment to viral infection diagnosis was 5.0 months (range: 1 – 20). The most frequently experienced viral infections were hepatitis B virus (HBV) (39.1%, n = 25), cytomegalovirus infection (CMV) (23.4%, n = 15), varicella-zoster virus (VZV) (9.4%, n = 6), and others (28.1%, n = 18). Of the patients with HBV infections, 13 (52.0%) died due to hepatic failure. Among the 39 cases that had viral infections other than HBV, 13 died due to these specific infections. In this study, about 50% of the rituximab-related HBV infections resulted in death, whereas this was the case in only 33% of the cases with other infections. Close monitoring for viral infection, particularly HBV and CMV, in patients treated with rituximab should be recommended.

Infectious complications of rituximab in patients with lymphoma during maintenance therapy: a systematic review and meta-analysis.

Rituximab maintenance therapy has emerged as an effective treatment for low-grade lymphomas. No major acute or cumulative toxicities were observed in patients receiving rituximab maintenance therapy compared with observation arms in clinical trials. However, B-cells are completely depleted throughout the maintenance period and even longer, which may render patients at high risk for infections. Several infections related to rituximab have been reported in the literature. Yet it is not clear whether rituximab maintenance therapy increases the infectious complications or not. To further investigate this topic, we have performed a systematic review and meta-analysis of randomised controlled trials (RCT). The meta-analysis of five RCTs showed that rituximab maintenance therapy significantly increased the relative risk of both infection and neutropenia in patients with lymphoma. On the basis of the available evidence, patients who received rituximab maintenance treatment have higher risk of neutropenia and infection than those who did not. Previously treated patients particularly with fludarabine containing regimens are more susceptible to infectious complications and require extended vigilance.

Trastuzumab emtansine (T-DM1) for HER2-positive breast cancer

Abstract Background: Trastuzumab emtansine (T-DM1), a novel drug developed for the treatment of HER2-positive breast cancer, is a human epidermal growth factor receptor (HER2) targeted antibody drug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine). It has been shown that, in preclinical studies, it has anti-tumor activity in trastuzumab refractory cancer cells. In this review, we aim to show the clinical data about trastuzumab-DM1 (T-DM1) therapy and to discuss the therapy advantages for the management of patients with HER2-positive breast cancer. Scope: T-DM1 showed positive results in clinical studies of HER2-positive metastatic breast cancer. PubMed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts were searched up to September 2012 by using the terms ‘trastuzumab emtansine (T-DM1) and anti-HER2 treatment’; papers which were considered relevant for the aim of this review were selected by the authors. Findings: The phase III randomized trial EMILIA has shown that T-DM1 provided objective tumor responses and significantly improved progression free survival and overall survival compared to lapatinib and capacitabine combination in HER2-positive metastatic breast cancer patients treated with a prior taxane and trastuzumab regimen. It is believed that T-DM1 will play a role in the management of patients with advanced and early stage HER2-positive breast cancer, but this awaits further study. In particular, the ongoing phase III trials MARIANNE and TH3RESA will further give information about the place of T-DM1 in the treatment algorithms for HER2-positive disease. Conclusion: The trials of T-DM1 as a single agent and in combination with other chemotherapies have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. There are ongoing studies of T-DM1 showing an increasing tendency towards moving the study of these agents to earlier stages of HER2-positive breast cancer.

Sonographic and Electrodiagnostic Evaluations in Patients With Aromatase Inhibitor-Related Arthralgia

PURPOSE To investigate the prevalence of arthralgia in breast cancer patients taking aromatase inhibitors (AIs) and perform a detailed rheumatologic assessment including autoimmune serology, musculoskeletal sonography, and electromyography (EMG) in these patients. PATIENTS AND METHODS Postmenopausal patients with stage I to III breast cancer who were taking adjuvant AIs were enrolled (n = 92). Patients who were not receiving hormone treatment were included as a control group (n = 28). Musculoskeletal sonography and EMG were applied to the patients and the controls along with markers of autoimmunity. RESULTS Thirty patients (32.6%) reported to have AI-related new-onset or worsening arthralgia. The most commonly affected joints were knee (70%), wrist (70%), and small joints of the hand (63%). Patients taking AIs had increased tendon thicknesses compared with those who never received AIs (P < .001). Patients with AI-related arthralgia had higher rates of effusion in hand joints/tendons than those without arthralgia (P = .033). More patients with AI-related arthralgia had EMG findings consistent with carpal tunnel syndrome (CTS) than those without arthralgia (P = .024). No significant difference was observed in erythrocyte sedimentation rates, C-reactive protein, antinuclear antibody, antidouble stranded DNA antibody, rheumatoid factor, or anticyclic citrullinated peptide levels between patients and controls or between those with and without arthralgia. CONCLUSION Patients with AI-related arthralgia often show tenosynovial changes suggesting tenosynovitis, exerting local problems but lacking a systemic inflammatory component. Our finding of increased CTS frequency also supports this hypothesis.

Cardiotoxicity of novel HER2-targeted therapies

Abstract Background: Trastuzumab, an anti-HER2 humanized monoclonal antibody, is the standard treatment for both early and metastatic HER2-positive breast cancer. In addition to other chemotherapeutic agents, trastuzumab significantly improves response rate and survival in HER2-positive early and metastatic breast cancer. Although it is well known that trastuzumab therapy is closely associated with both symptomatic and asymptomatic cardiotoxicity, less is known about novel HER2-targeted therapies. The aim of this review is to discuss the cardiac safety data from recent studies of novel anti-HER2 drugs other than trastuzumab. Scope: Novel HER2-targeted therapies showed favorable results in HER2 positive metastatic breast cancer patients. Pubmed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts were searched until January 2013 using the following search keywords; ‘trastuzumab, trastuzumab cardiotoxicity, HER-2 targeted therapies, lapatinib, pertuzumab, trastuzumab emtansine, afatinib and neratinib’; papers which were considered relevant for the aim of this review were selected by the authors. Lapatinib, pertuzumab, T-DM1, neratinib and afatinib molecules are evaluated in the study. Findings: In a comprehensive analysis, 3689 lapatinib treated patients enrolled in 49 trials; asymptomatic cardiac events were reported in 53 patients (1.4%) and symptomatic grade III and IV systolic dysfunction was observed only in 7 patients (0.2%) treated with lapatinib. In phase I–III trials of pertuzumab, cardiac dysfunction was seen in 4.5–14.5% of patients with pertuzumab treatment and cardiac dysfunction was usually grade I and II. Cardiotoxicity of pertuzumab was usually reported with the trastuzumab combination and no additive cardiotoxicity was reported with addition of pertuzumab to trastuzumab. T-DM1 had a better safety profile compared to trastuzumab, no significant cardiotoxicity was observed with T-DM1 in heavily pre-treated patients. In the EMILIA study, only in 1.7% of patients in the T-DM1 group experienced reduction of left ventricular ejection fraction (LVEF) and grade III LVEF reduction developed only in one patient (0.2%) in the T-DM1 group compared to the lapatinib plus capacitabine group. In phase I–II trials with neratinib no cardiotoxicity was reported whereas cardiotoxicity was seen between 0–5.3% with afatinib treatment. Conclusion: Although cardiac toxicity has been reported as an adverse event for novel HER2-targeted therapies, cardiac dysfunction rate of the novel HER2-targeted therapies is significantly lower than the trastuzumab and combination of these agents with trastuzumab did not significantly increase the cardiac adverse events.

Variation in hormone receptor and HER-2 status between primary and metastatic breast cancer: review of the literature.

Importance of the field: Hormone and human epidermal growth factor receptor 2 (HER-2) receptors are two important pharmaceutical targets that affect the survival of patients with metastatic breast cancer. Discordance of hormone and HER-2 receptors were reported in a series of studies. Receptor status was reported to change in both directions, yet alteration occurs mostly in the loss of positivity for both receptors. We do not know both the exact mechanism of this process or the contribution rate of technical mistakes; a number of mechanisms might be responsible. Factors suggested include: tumor heterogeneity, clonal selection of tumor cell subpopulations, genetic instability of tumor cells, local or systemic treatments, the time interval between primary tumor and metastasis, receptor status determination techniques, and the site of metastasis. Areas covered in this review: Studies of estrogen, progesterone and HER-2 receptor discordance between primary and metastasis of breast cancer are summarized. Laboratory evaluation of estrogen, progesterone and HER-2 receptors, and possible causes of receptor discordance, are summarized. Literature data are reviewed; the major shortcoming of these studies is that they are mostly retrospective. What the reader will gain: The reader will read a concise literature review about the studies on estrogen, progesterone and HER-2 receptor discordances between primary and metastasis of breast cancer. Take home message: We do not know whether the changes in receptor expression account for a true biological phenomenon or may result from inconsistent measurement. However, in light of current data, for the treatment plans that target the receptors, biopsy specimen from the metastatis of breast cancer must also be evaulated for alterations in the receptor status.

Breast cancer subtypes and outcomes of central nervous system metastases

Central nervous system (CNS) metastases are detected in up to one third of patients with advanced breast cancer, but their incidence and outcomes by breast cancer subtypes are not precisely documented. Herein, we retrospectively analyzed clinicopathologic data of 259 breast cancer patients with CNS metastases to evaluate the association between breast cancer subtypes and CNS metastasis. The patient groups were classified according to their hormone receptor status and HER-2 expression. Median follow-up time among the patients was 42 months and median survival after CNS metastasis detection was 7.8 months. In HER-2 overexpressing group, median time period between the diagnosis of breast cancer and the detection of CNS metastasis (15.9 months) was significantly shorter compared to the other groups (p = 0.01). The triple negative group had the shortest median survival time after CNS metastasis (6.6 months), although statistically not significant (p = 0.3). In multivariate Cox regression analyses, having solitary CNS metastasis (HR 0.4, 95% CI; 0.2-0.7, p = 0.004), and receiving chemotherapy after CNS metastasis (HR 0.4, 95% CI; 0.287-0.772, p = 0.003) were independent prognostic factors for increasing survival after CNS metastasis. In conclusion, new and effective treatment strategies are required for breast carcinoma patients with brain metastasis considering the positive effect of the treatment on survival.

Platelet size has diagnostic predictive value for bone marrow metastasis in patients with solid tumors

Though not very common, solid tumor involvement of the bone marrow (BM) may have serious consequences. Recent studies have shown that mean platelet volume (MPV) is a good indicator for BM disease in the differential diagnosis of thrombocytopenia. We investigated the significance of MPV in the diagnosis of BM metastasis in patients with solid tumors. Patients with histologically‐verified solid tumors for whom BM biopsy specimens were available (n = 121) and healthy controls (n = 62) were included in this retrospective study. A total of 183 individuals were analyzed. Of the patients, 61 had a diagnosis of BM metastasis (Group A), 60 did not have BM metastasis (Group B). Group B and C (healthy controls) constituted the control group without BM metastasis (n = 122). The mean MPV was 7.0 ± 0.8 fl in patients with BM metastasis and 8.4 fl in the control group (P < 0.001). A cut‐off point of <7.4 fl was found to have significant predictive value according to receiver‐operating characteristics curve analysis. This cut‐off point had 85% positive predictive value and 90% negative predictive value in the diagnosis of BM metastasis (odds ratio: 53; 95% confidence interval: 20–135), and a sensitivity of 82.7% and specificity of 89.6%. MPV can be used as a reliable marker to guide the clinician as to the likely presence or absence of BM metastasis in patients with solid tumors.

Which One Is Better: AIDS Related or HIV Associated?

TO THE EDITOR: We have read the article by Francois Boue et al on AIDS-related lymphoma. The authors stated that rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is a simple and effective schedule for HIV-associated lymphoma. The authors used the terms HIV-associated and AIDS-related interchangeably throughout their article. Although everybody who read it surely understood that they are more or less the same entity, it is crucial to use the most correct terminology for scientific communication, in our point of view. Which one defines malignancies developing in individuals infected with HIV better? We have some comments. Caused by HIV, AIDS is the profound immunodeficiency state characterized by opportunistic infections and Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and cervical cancer—the AIDS-defining cancers. By definition, when they are diagnosed in a patient infected with CD4 count less than 200 cells/uL that patient has AIDS. Therefore, the term AIDS-related seems better suited for AIDS-defining cancers. However, non–AIDS-defining cancers do occur in individuals infected with HIV. Several population-based studies indicated that relative risks for such malignancies with the exception of anal cancer is minimally increased during the pre-AIDS period, meaning that HIV positivity does not substantially increase risk of malignancy before inducing AIDS. Therefore, the term AIDS related seems more correct for non–AIDS-defining cancers, as well. Furthermore, highly active antiretroviral therapy prevents immunodeficiency and decreased incidences of malignancies, but can not eradicate HIV. This observation means that AIDS is necessary for the development of most cancers. In conclusion, we kindly suggest that AIDS related be preferred over HIV associated when referring to all malignancies in individuals with HIV infection.

Characteristics of Breast Cancer Patients with Central Nervous System Metastases: A Single-Center Experience

The aim of this study was to assess the characteristics of breast cancer patients with central nervous system (CNS) metastases and factors associated with survival after development of CNS metastasis. One-hundred-forty-four patients with brain metastases were retrospectively analyzed. Median age at the time of brain metastasis diagnosis was 48.9. Median time between initial diagnosis and development of brain metastasis was 36 months. Fourteen cases had leptomeningeal involvement. Twenty-two patients (15.3%) had single metastasis. Ten percent of the patients had surgery, 94% had radiotherapy and 63% had chemotherapy. Median survival after development of brain metastasis was 7.4 months. Survival of patients with single metastasis was significantly longer than those with multiple metastases (33.5 vs. 6.5 months, p = 0.0006). Survival of patients who received chemotherapy was significantly longer than those who received radiotherapy alone (9.9 vs. 2 months, p < 0.0001). In multivariate Cox regression analyses, presence of single metastasis and application of chemotherapy were the only significant factors associated with better survival (p = 0.047 and p < 0.0001, respectively). Age at initial diagnosis or at the time of brain metastasis, time from initial diagnosis to development of brain metastasis, menopausal status, tumor stage, grade, hormone receptor or HER2 status individually were not associated with survival. In this study, survival after the diagnosis of CNS metastases appeared to be affected by patient characteristics rather than biologic characteristics of the tumor. This is probably secondary to the lack of effective treatment options in these patients and overall poor prognosis.