Disorders of the Lymph System

The potential effect of statins on rituximab immunotherapy.

Tue, 22 Apr 2008 14:44:25 GMT

The potential effect of statins on rituximab immunotherapy.

Mark S. Cragg

Abbreviations: ADCC, antibody-dependent cellular cytotoxicity; CDC, complement-dependent cytotoxicity; HMG-CoAR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; mAb, monoclonal antibody

Mark Cragg is in the Cancer Sciences Division, University of Southampton, Southampton, United Kingdom. E-mail: msc@soton.ac.uk

Background

CD20 is a cell surface marker expressed on mature B cells and most malignant B cells. It does not modulate rapidly, is not shed, and is highly expressed, leading to its use as a target for immunotherapy. In 1997, rituximab, a chimeric anti-CD20 monoclonal antibody (mAb), was approved for use in the treatment of cancer following its efficacy (46% response rate) in a phase II trial involving 37 patients with relapsed low-grade non-Hodgkin lymphoma . Since then, rituximab has been approved for the treatment of numerous other B cell malignancies and is now being actively investigated for use in the treatment of autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus . As a result, rituximab has been administered to more than a million patients worldwide, making it the most successful immunotherapeutic (commercially and clinically) used to date.

Importantly, much of the therapeutic efficacy of rituximab is seen when it is used in combination with other drugs. In the treatment of non-Hodgkin lymphoma, rituximab is routinely given in conjunction with chemotherapy, which greatly enhances the therapeutic outcome in terms of response rates, durations of remissions, and improvements in survival . A similar synergy is observed between rituximab and cyclophosphamide or methotrexate in the treatment of autoimmune conditions. In part, these effective combinations are afforded bythe distinct toxicity profiles of the different drugs and the relatively mild side effects observed with rituximab treatment. For these reasons rituximab is an ideal drug for investigating powerful combination therapies.

One group of drugs that could potentially be useful in combination with rituximab is the statins. Statins target 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR), which is the rate-limiting enzyme of the mevalonate pathway required for the synthesis of isoprenoids such as cholesterol. As such, the main clinical use of statins to date has been in the treatment of hypercholesterolemia. However, in addition to inhibiting cholesterol synthesis, statins also have cytotoxic effects on tumor cells These cytotoxic effects are likely achieved through one of two downstream effects of HMG-CoAR inhibition. First, by reducing isoprenoid synthesis, statins impair protein prenylation, a critical process for the correct cellular localization and signaling activity of numerous proteins such as Ras that may be important for tumor cell survival. Second, reducing cholesterol synthesis can interfere with the formation of cholesterol-rich lipid microdomains, or “rafts,” within the plasma membrane. These lipid rafts are thought to represent localized signaling platforms and may be particularly important in providing cell survival signals to tumor cells . Moreover, as prenylated proteins commonly localize to lipid raft regions, statin treatment may therefore doubly compromise the biological activity of these proteins, providing potent cytostatic and cytotoxic effects. Clearly statins have an obvious anti-tumor potential, and it seems sensible to consider whether they provide a useful drug combination in conjunction with rituximab.

Statins Decrease the Efficacy of Anti-CD20 mAb by Preventing Their Binding

In a new study published in this issue of PLoS Medicine, Jakub Golab and colleagues address this very issue: namely, how do statins affect rituximab treatment? Perhaps surprisingly, they show that instead of enhancing the ability of rituximab to kill target cells, statins are inhibitory.

Rituximab has three main effector mechanisms: Complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity (CDC and ADCC, respectively) and direct cytotoxic signaling. Using a number of well-established in vitro assays, Golab and colleagues clearly show that statins impair the ability of rituximab to lyse lymphoma cell lines with the help of either complement (CDC) or, to a lesser degree, effector cells (ADCC), and that this impairment occurs because surface binding of CD20 is greatly reduced in these cells . The researchers did not examine the ability of statins to inhibit direct cytotoxic signaling, but presumably this was also reduced due to diminished mAb binding. Therefore, at least two (and likely all) of the main effector mechanisms of rituximab were reduced by statin treatment. After establishing that the loss of CD20 binding was due to a change in conformation of surface CD20 after statin treatment, the authors then performed experiments to examine the effect of statins on CD20 in vivo. Although the effects here were more marginal, again the evidence suggests that statins reduce the binding of rituximab to its target.

Statins as a Contraindication for Rituximab Treatment?

Given the potential implications of these findings, the next steps are to confirm them and then to establish the CD20 status of patients on long-term statin treatment. Subsequently, it will be important to address whether equivalent effects on CD20 binding are observed in patients suffering from malignant or autoimmune disease to determine whether B cells in these conditions are more or less susceptible to the effects of cholesterol depletion through statin treatment. Previous in vitro experiments with methyl-beta-cyclodextrin indicate that the effects of cholesterol depletion on CD20 mAb binding are highly dependent upon both the mAb and cell type. Presumably, data on the effects of statins on rituximab use are already available through retrospective analysis, as it is likely that among the million patients treated with rituximab a proportion were also receiving statins. To date, very few cases of co-administration have been reported, but it is important to note that in at least one of these, long-term statin treatment did not appear to impair the normal therapeutic effect of rituximab . These data, coupled with the limited effects seen in Figure 9 of Golab andcolleagues' study , suggest that the pronounced effects of statin treatment on anti-CD20 binding observed on lymphoma cell lines in vitro may not translate to equivalent effects in vivo. However, note that the CD20 binding shown in was assessed after only a three day treatment with atorvastatin; potentially greater effects would be observed after more protracted treatment. The definitive answer to the question of whether statins substantially affect CD20 binding and function in vivo awaits clinical investigation.

Assuming long-term statin treatment does indeed substantially reduce CD20 detection in vivo, two obvious changes to clinical management should be made. First, extensive use of statins for the treatment of hypercholesterolemia should be a contraindication for the use of CD20 as a diagnostic marker for mature B cells. Second, statins should be removed from the treatment of patients with either malignant or autoimmune disease who are required to undergo CD20-specific therapy.

Other Combinations?

Interestingly, Golab and colleagues reported (but did not show) that inhibitors of farnesyltransferase and geranylgeranyltransferase did not decrease CD20-mediated CDC , indicating that the effect of statins on anti-CD20 mAb binding is independent of their effects on impaired protein prenylation. As prenylation inhibition is a central component of the anti-tumor effect of statins, it is possible that farnesyltransferase and geranylgeranyltransferase inhibitors such as tipifarnib may work well in combination with rituximab. To discover if this is the case, a sensible way forward would be to examine the direct cell-killing activity of these reagents in combination with rituximab. Whether this combination will also fall foul of unexpected complications remains to be seen.

PLOS Journals

Tags: rituximab, immunotherapy, statins, CD20

Re-emergence of lymphogranuloma venereum.

Sat, 29 Mar 2008 02:48:54 GMT

Re-emergence of lymphogranuloma venereum.

J Eur Acad Dermatol Venereol. 2008 Apr

Kapoor S.

glossomed@gmail.com

Keywords: anal strictures, chlamydia trachomatis, genital ulcers, inguinal lymphadenopathy, proctitis

Lymphogranuloma venereum (LGV) is a sexually transmitted infection caused by the L1, L2 and L3 serotypes of Chlamydia trachomatis. The disease has been in the spotlight recently because of recent outbreaks in Europe as well as the USA. A unique feature of the recent outbreaks has been that most cases have been caused by the L2 strain. Another unique feature of these outbreaks is the fact that most cases have occurred in men having sex with men, and most patients have presented with proctitis. Interestingly, most recent cases have occurred in human immunodeficiency virus-seropositive patients. Usually, the disease is divided into three phases: the primary stage characterized by a self-healing papule, the secondary stage characterized by proctitis or lymphadenopathy and the tertiary stage characterized by lymphedema and anal strictures. Tests used for diagnosis include polymerase chain reactions and compliment fixation tests. The treatment of choice is doxycycline.

Blackwell

Tags: lymphogranuloma venereum, Chlamydia trachomatis, proctitis, lymphadenopathy, doxycycline, genital ulcers,

Folliculotropic mycosis fungoides responding to bexarotene gel

Fri, 14 Mar 2008 13:49:45 GMT

Folliculotropic mycosis fungoides responding to bexarotene gel

J Drugs Dermatol. 2008 Feb

Walling HW, Swick BL, Gerami P, Scupham RK.

Town Square Dermatology, Coralville, IA 52241, USA. hobartwalling@yahoo.com

Folliculotropic mycosis fungoides (FMF) is an uncommon and potentially aggressive form of cutaneous T cell lymphoma (CTCL). Phototherapy, radiotherapy, and systemic chemotherapy are the most commonly employed treatment options, but may have limited success and common adverse reactions. Bexarotene gel is a topical retinoid X receptor (RXR) agonist with activity on the follicular unit that has not been previously reported in the management of FME The case of a 73-year-old male with FMF that responded to bexarotene gel is presented.

PMID: 18335654 [PubMed - in process]

Tags: Folliculotropic mycosis fungoides, bexarotene gel, cutaneous T cell lymphoma, Phototherapy, radiotherapy, chemotherapy,

Treatment of Transformed Mycosis Fungoides with Intermittent Low-Dose Gemcitabine

Fri, 14 Mar 2008 13:46:46 GMT

Treatment of Transformed Mycosis Fungoides with Intermittent Low-Dose Gemcitabine

Oncology. 2008 Mar

Awar O, Duvic M.

Department of Internal Medicine, UCLA Medical Center, Los Angeles, Calif., USA.

The malignant helper T cells of mycosis fungoides, a type of cutaneous T cell lymphoma, are capable of transforming into large cerebriform cells. Large cell transformation usually renders the disease more resistant to treatment and prone to relapse. Currently investigated treatment modalities for transformed mycosis fungoides are few and include phototherapy, chemotherapy, biologic response modification, targeted molecular therapy and combinations thereof. A tolerable and reliable modality has yet to be identified. Gemcitabine, a novel purine analogue, is gaining recognition as a potent agent for advanced nontransformed cutaneous T cell lymphoma. Here we present a brief review of the literature with 3 illustrative cases that additionally reveal gemcitabine monotherapy to be a practical, safe and efficacious option for mycosis fungoides that has undergone large cell transformation. Copyright (c) 2008 S. Karger AG, Basel.

PMID: 18337626 [PubMed - as supplied by publisher]

Tags: Mycosis Fungoides, Low-Dose Gemcitabine, malignant helper T cells, cutaneous T cell lymphoma, phototherapy, chemotherapy

Mesenteric lymphadenitis

Mon, 03 Mar 2008 04:31:31 GMT

Mesenteric lymphadenitis

Introduction

Mesenteric lymphadenitis is an inflammation of the lymph nodes in the fold of membranes that attaches organs, such as your colon, to your abdominal wall (mesentery). Mesenteric lymphadenitis occurs mainly in children and adolescents.

Commonly caused by a viral or bacterial infection, mesenteric lymphadenitis may mimic the signs and symptoms of appendicitis. Unlike appendicitis, however, mesenteric lymphadenitis usually requires no treatment.

Signs and Symptoms

Signs and symptoms of mesenteric lymphadenitis may last a few days or as long as a few weeks. They include:

Abdominal pain, often centered on the lower, right side, but the pain can be more diffuse
Fever

Depending on what's causing the ailment, other signs and symptoms may include:

Diarrhea
Nausea and vomiting
General unwell feeling (malaise)

Causes

The most common cause of mesenteric lymphadenitis is a viral infection, such as adenovirus, a common cause of intestinal infection (gastroenteritis) in children. But it can also result from a bacterial infection. The type of bacterium commonly associated with mesenteric lymphadenitis is yersinia, which may come from eating undercooked pork or drinking unpasteurized milk or contaminated water.

Some children may develop an upper respiratory infection beforeor during their course of mesenteric lymphadenitis. Other conditions associated with inflamed mesenteric nodes include:

Epstein-Barr virus (EBV) — one of the most common human viruses
Cat-scratch fever — a bacterial infection from a cat scratch or bite

When to seek medical advice

The signs and symptoms of mesenteric lymphadenitis usually resolve on their own within a few days to a few weeks. However, it may be important for your child to see a doctor to rule out appendicitis and other possible causes of abdominal pain. Take your child to a doctor if fever, low blood pressure (hypotension), bloody stools or inability to keep fluids down accompany the abdominal pain.

Screening and diagnosis

Your doctor is likely to take your child's medical history and ask when and how signs and symptoms developed. In addition, your doctor may request laboratory tests to help pin down the diagnosis, including:

Blood tests. Certain blood tests can help determine whether your child has an infection and what type of infection it is.
Imaging studies. A computerized tomography (CT) scan of your child's abdomen can help differentiate between appendicitis and mesenteric lymphadenitis. Abdominal ultrasound also may be used.

Complications

Mesenteric lymphadenitis usually resolves on its own and rarely causes complications. However, if the cause is a bacterial infection and it isn't treated, the infection could spread to the bloodstream, causing an overwhelming infection (sepsis). Sepsis may result in organ failure and death. Treatment of sepsis involves hospitalization and administration of antibiotics through a vein (intravenously).

Treatment

Mild, uncomplicated cases of mesenteric lymphadenitis and those caused by a virus usually resolve on their own within days or weeks. To help ease discomfort, over-the-counter (OTC) pain relievers and fever reducers may help.

If your child has a bacterial infection that's causing moderate to severe signs and symptoms, your doctor may prescribe antibiotics.

Self-care

For the pain and fever of mesenteric lymphadenitis, have your child:

Get plenty of rest. Adequate rest can help your child recover.
Drink fluids. This can help prevent dehydration from vomiting or diarrhea.
Take OTC pain relievers. These include ibuprofen (Advil, Motrin, others) and acetaminophen (Tylenol, others). Don't give your child aspirin without consulting your doctor because of its link to Reye's syndrome in children. Reye's syndrome is a rare but serious illness that can affect the blood, liver and brain of children and teenagers recovering from a viral infection.

Mayo Clinic
Tags: Mesenteric lymphadenitis, inflammation, lymph nodes, adenovirus, epstein-barr virus, cat-scratch fever, yersinia

Feline bartonellosis and cat scratch disease

Sun, 02 Mar 2008 13:32:40 GMT

Feline bartonellosis and cat scratch disease

Vet Immunol Immunopathol. 2008 Jan 19

Breitschwerdt EB.

College of Veterinary Medicine, North Carolina State University, Dipl. ACVIM, 4700 Hillsborough Street, Raleigh, NC 27606, United States.

Bartonella species are important emerging zoonotic pathogens. Transmission of these organisms in nature may be much more complex than is currently appreciated. Cats can be infected with five Bartonella species, including, Bartonella henselae, Bartonella clarridgeae, Bartonella bovis, Bartonella koehlerae and Bartonella quintana. In addition to cats, numerous domestic and wild animals, including bovine, canine, human, and rodent species can serve as chronically infected reservoir hosts for various intra-erythrocytic Bartonella species. In addition, an increasing number of arthropod vectors, including biting flies, fleas, keds, lice, sandflys and potentially ticks have been implicated in the transmission of various Bartonella species to animals or human beings.

In the reservoir host, Bartonella species cause chronic intra-erythrocytic and vascular endothelial infections, with a relapsing bacteremia documented in experimentally infected cats. Although the immunopathology induced by Bartonella infection requires additional study, the organisms can localize to the heart valve (endocarditis), cause granulomatous inflammation in lymph nodes, liver or spleen, induce central nervous system dysfunction with or without cerebrospinal fluid changes, and may contribute to inflammatory polyarthritis. Hematological abnormalities are infrequent, but thrombocytopenia, lymphocytosis, neutropenia, and eosinophilia have been reported in B. henselae-infected cats. Serology, PCR and culture can be used to support a diagnosis of feline bartonellosis, however, due to the high rate of sub-clinical infections among various cat populations, documenting causation in an individual cat is difficult, if not impossible.

Response to treatment can be used in conjunction with serology or organism isolation to support a clinical diagnosis of feline bartonellosis. As fleas are involved in the transmission among cats, the use of acaracide products to eliminate fleas from the environment is of critical importance to decrease the risk of B. henselae transmission among cats and to humans.

Elsevier

Tags: Feline bartonellosis, cat scratch disease, zoonotic pathogens, Bartonella henselae, Bartonella clarridgeae, Bartonella bovis, Bartonella koehlerae, Bartonella quintana, endocarditis, granulomatous inflammation, inflammatory polyarthritis, bacteremia, thrombocytopenia, lymphocytosis, neutropenia, eosinophilia

Pathobiology of the sentinel node

Sun, 02 Mar 2008 13:26:35 GMT

Pathobiology of the sentinel node

Melanoma and other skin neoplasms

Current Opinion in Oncology. 20(2):190-195, March 2008.
Cochran, Alistair J a,b; Ohsie, Steven J a; Binder, Scott W a

Abstract:

Purpose of review: Lymphatic mapping and sentinel lymph node biopsy have been established as definitive procedures for the staging of cutaneous melanoma. Large-scale studies that have been recently conducted and that are ongoing suggest a therapeutic role for lymphatic mapping/sentinel node biopsy in the management and prognosis of melanoma patients with early lymph node metastases.

Recent findings: Sentinel node biopsy has been shown to extend disease free survival and increase melanoma-specific survival for patients with early nodal metastases according to interim analysis of the Multicenter Selective Lymphadenectomy Trial 1 (MSLT-1). The proper evaluation of sentinel lymph nodes requires histologic and immunohistochemical analysis of multiple levels. Immune modulation has been shown to play an important role in nodal metastasis.

Summary: There is increasing evidence for the efficacy of lymphatic mapping and sentinel lymph node biopsy in predicting prognosis, reducing the morbidity traditionally associated with regional lymph node dissection and increasing survival in subgroups of patients with cutaneous melanoma. Further study is needed to determine the role of the immune system in the spread of nodal metastases and the role of immunomodulatory therapy to prevent or possibly even reverse nodal metastases.

2008 Lippincott Williams & Wilkins, Inc.

Tags: sentinel lymph node, Lymphatic mapping, Lymphadenectomy, immunomodulatory therapy, Melanoma, skin neoplasms, lymph node metastases, regional lymph node dissection

Mediastinal cavernous lymphangioma in an adult

Wed, 27 Feb 2008 11:43:23 GMT

Mediastinal cavernous lymphangioma in an adult

Gen Thorac Cardiovasc Surg. 2008 Feb

Teramoto K, Suzumura Y.

Department of Surgery, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan, teramoto@belle.shiga-med.ac.jp.

Key words: Mediastinal tumor - Lymphangioma - Cavernous - Thoracotomy

Cavernous lymphangioma is a rare mediastinal benign tumor. A 43-year-old woman presented with cough and dyspnea for 1 month. Computed tomography of the chest showed a 3-cm well-circumscribed cystic mass in the posterior mediastinum. At thoracotomy, a cystic tumor in the mediastinum that was adherent to the descending aorta and esophagus was removed completely. The tumor, the cystic space of which was filled with lymph fluid, was diagnosed as cavernous lymphangioma based on pathological findings. Mediastinal lymphangiomas may insinuate into surrounding organs. As incomplete resection can result in recurrence, complete tumor removal should be performed based on accurate preoperative evaluation.

SpringerLink

Tags: Mediastinal tumor, Lymphangioma, Cavernous, Thoracotomy, posterior mediastinum, cystic mass, cough, dyspnea

Laser excision of multiple esophageal lymphangiomas: A case report and review of the literature

Wed, 27 Feb 2008 11:39:12 GMT

Laser excision of multiple esophageal lymphangiomas: A case report and review of the literature

Auris Nasus Larynx. 2008 Feb 1

Best SR, Coelho DH, Ahrens WA, Atez G, Sasaki CT.

Yale University School of Medicine Division of Otolaryngology, Head & Neck Surgery, New Haven, CT, USA.

Lymphangiomas of the gastrointestinal tract are rare and benign submucosal tumors. We present the first case of multiple lymphangiomas in the cervical esophagus and only the 15th case of an esophageal lymphangioma. A 63-year-old male presented to our clinic with two years of dysphagia and an esophageal mass noted on MRI. A barium swallow confirmed a polypoid mass of the upper esophagus with operative findings of two smooth pedunculated lymphangiomas occupying the entire lumen of the esophagus. Previous reports have documented successful surgical intervention through open or endoscopic techniques, whereas the favorable location of the tumors in this case allowed for the first successful excision utilizing a CO(2) laser. We demonstrate here that esophageal laser surgery can provide an accurate, complete, and minimally invasive excision technique for lymphangiomas of the upper digestive tract with minimal morbidity for the patient. A complete review of all published cases is presented, with a focus on the clinical presentation and surgical treatment of this disease.

Pub Med

Tags: Laser excision, esophageal lymphangiomas, benign submucosal tumors, CO(2) laser, gastrointestinal tract

Accuracy of fine-needle aspiration cytology of axillary lymph nodes in breast cancer

Sat, 23 Feb 2008 10:03:37 GMT

Accuracy of fine-needle aspiration cytology of axillary lymph nodes in breast cancer patients: a study of 115 cases with cytologic-histologic correlation.

Cancer. 2008 Feb 19

Alkuwari E, Auger M.

Department of Pathology, McGill University Health Center, McGill University, Montreal, Quebec, Canada.

BACKGROUND: Fine-needle aspiration (FNA) cytology of axillary lymph nodes is a simple, minimally invasive technique that can be used to improve preoperative determination of the status of the axillary lymph nodes in patients with breast cancer, thereby serving as a tool with which to triage patients for sentinel versus full lymph node dissection procedures. The aim of the current study was to determine the sensitivity and specificity of FNA cytology to detect metastatic breast carcinoma in axillary lymph nodes.

METHODS: A total of 115 FNAs of axillary lymph nodes of breast cancer patients with histologic follow-up (subsequent sentinel or full lymph node dissection) were included in the current study. The specificity and sensitivity, as well as the positive and negative predictive values, were calculated.

RESULTS: The positive and negative predictive values of FNA cytology of axillary lymph nodes for metastatic breast carcinoma were 1.00 and 0.60, respectively. The overall sensitivity of axillary lymph node FNA in all the cases studied was 65% and the specificity was 100%. The sensitivity of FNA was lower in the sentinel lymph node group than in the full lymph node dissection group (16% vs 88%, respectively), which was believed to be attributable to the small size of the metastatic foci in the sentinel lymph node group (median, 0.25 cm). All false-negative FNAs, with the exception of 1 case, were believed to be the result of sampling error. There was no 'true' false-positive FNA case in the current study.

CONCLUSIONS: FNA of axillary lymph nodes is a sensitive and very specific method with which to detect metastasis in breast cancer patients. Because of its excellent positive predictive value, full axillary lymph node dissection can be planned safely instead of a sentinel lymph node dissection when a preoperative positive FNA result is rendered. Cancer (Cancer Cytopathol) 2008. (c) American Cancer Society.

PMID: 18286535 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/pubmed/18286535?ordinalpos=14&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Tags: fine-needle aspiration; small needle biopsy; axillary lymph nodes; breast cancer; metastatic breast carcinoma; lymph node dissec