Prescribing Exercise for Cancer Survivors:Time for Physicians to Become More Proactive.

Survivorship has become an integral component of the cancer care continuum. Advances in diagnosis and treatment have resulted in decreasing cancer mortality and a subsequent increase in the cancer survivorship population. International guidelines recommend counselling these patients with regards to healthy lifestyle changes. Increased physical activity has been shown to have profound impacts on quality of life and has also been shown to reduce recurrence rates in patients with breast, colon and prostate cancer. However physicians remain reluctant to prescribe exercise for these patients. Contributing factors include inadequate understanding of the benefits of these programmes, as well as uncertainty with regards to their patients' ability to tolerate such an intervention. It is thus imperative to raise awareness of the benefits of exercise, to guide physicians' selection of patients for exercise and to outline the available options to promote and increase physical activity as part of a healthy lifestyle.

Leptomeningeal Relapse of Embryonal Rhabdomyosarcoma after 15 years.

Aim Rhabdomyosarcoma (RMS) is the most common malignant soft tissue tumour of childhood. We present the case of a late relapse of RMS to the leptomeninges after 15 years. Methods A 20 year old male presented with a 3 week history of headaches and nausea. He previously had RMS of his right ear diagnosed at age 5 years which was treated with concurrent chemoradiotherapy. An MRI Brain and Spine confirmed extensive leptomeningeal disease and CSF analysis confirmed the presence of recurrent embryonal RMS. Results He completed two cycles of cyclophosphamide and topotecan followed by 45Gy/25Fr of craniospinal radiotherapy. Conclusion Late relapses beyond five years can be seen in up to 9% of patients, however very late recurrences (>10 years) are exceedingly rare. Molecular based methods such as gene expression profiling can aid risk stratification and survivorship clinics may become increasingly useful in following patients with high risk features.

Synchronous diffuse large B cell lymphomas of the endometrium and breast: a staging dilemma.

BACKGROUND: A 66 years old presented with abnormal postmenopausal vaginal bleeding and was diagnosed with an endometrial lymphoma (diffuse large B cell type, DLBCL). A left breast lesion was found on PET CT which was subsequently biopsy-proven as a separate stage IE DLBCL, but she had no lymph node, bone marrow or spleen involvement. AIMS: This study aimed to review the available literature and discuss the management and staging of synchronous extra-nodal DLBCL's. RESULTS: Our patient was staged as having synchronous stage IE DLBCL's of the endometrium and breast. Subsequent molecular analysis (IgH gene rearrangement analysis) on both lesions, confirmed the two lesions to be clonally unrelated. CONCLUSIONS: Staging of synchronous extra-nodal lymphomas, particularly when they arise in rare sites such as the endometrium and breast, is difficult and previously unreported. We present our rationale for defining our patient's disease as synchronous stage IE DLBCL's.

An unusual case of basal cell carcinoma of the vulva with lung metastases.

Basal cell carcinoma (BCC) is the most common non-melanomatous skin cancer, typically arising in sun-exposed areas such as the head and neck. Defective signaling through the Hedgehog (HH) signaling pathway forms the molecular basis for BCC. Surgery remains the mainstay of treatment. Basal cell carcinoma of the genital tract is rare as is metastatic BCC. We report a case of metastatic BCC in a young woman with previously resected vulval BCC presenting six years later with inguinal nodal recurrence and multiple lung metastases.

Enteroscopic Management of Ectopic Varices in a Patient with Liver Cirrhosis and Portal Hypertension.

Portal hypertension and liver cirrhosis may predispose patients to varices, which have a propensity to bleed and cause significant morbidity and mortality. These varices are most commonly located in the gastroesophageal area; however, rarely ectopic varices may develop in unusual locations outside of this region. Haemorrhage from these sites can be massive and difficult to control; thus early detection and management may be lifesaving. We present a case of occult gastrointestinal bleeding in a patient with underlying alcoholic liver disease where an ectopic varix was ultimately detected with push enteroscopy.

Get the GIST? An overview of gastrointestinal stromal tumours.

GISTs are the most common mesenchymal neoplasms of the gastrointestinal tract. The last 20 years have been revolutionary in the understanding of these tumours and began with the discovery of c-KIT, a proto oncogene that when mutated forms the molecular basis for the growth and development of these malignancies. Surgery was previously considered to be the only treatment modality in both local and advanced disease, however, the introduction of immunotherapy agents such as tyrosine kinase inhibitors has had profound effects on how we now approach and manage these tumours. These novel agents have significantly reduced the frequency of disease recurrence and dramatically improved survival, and serve as a model for the study of targeted therapies in other solid tumors. We present a review of gastrointestinal stromal tumours and consider the current evidence based detection and management of these unique tumors.

Nonoperative management of blunt splenic injury: what is new?

The majority of splenic injuries are currently managed nonoperatively. The primary indication for operative management of blunt splenic injury is hemodynamic instability. Findings which correlate with failure of nonoperative management include grade IV or V splenic injury, high Injury Severity Scores, or active extravasation. The role of angiograph/embolization is becoming better defined, appropriate in the patient with pseudoaneurysm or active extravasation or the stable patient with grade IV or V splenic injury.

Interferon regulatory factor-1-induced apoptosis mediated by a ligand-independent fas-associated death domain pathway in breast cancer cells.

Interferon (IFN) regulatory factor-1 (IRF-1) is a transcription factor that has apoptotic anti-tumor activity. In breast cancer cell types, IRF-1 is implicated in mediating apoptosis by both novel and established anti-tumor agents, including the anti-estrogens tamoxifen and faslodex. Here we demonstrate that in MDA468 breast cancer cells, apoptosis by IFN-gamma is mediated by IRF-1 and IFN-gamma, and IRF-1-induced apoptosis is caspase-mediated. IRF-1 induction results in cleavage of caspase-8, -3 and -7, and application of caspase inhibitors attenuate activated cleavage products. IRF-1-induced apoptosis involves caspase-8 since apoptosis is significantly decreased by the caspase-8-specific inhibitor IETD, c-FLIP expression and in caspase-8-deficient cancer cells. Furthermore, we demonstrate that IRF-1-induced apoptosis requires fas-associated death domain (FADD) since dominant-negative FADD expressing cells resist IRF-1-induced apoptosis and activated downstream products. Immunofluorescent studies demonstrate perinuclear colocalization of FADD and caspase-8. Despite the known role of FADD in mediating death-ligand induced apoptosis, neutralizing antibodies against classical death receptors do not inhibit IRF-1 induced apoptosis, and no secreted ligand appears to be involved since MDA468 coincubated with IRF-1 transfected cells do not apoptose. Therefore, we demonstrate that IRF-1 induces a ligand-independent FADD/caspase-8-mediated apoptosis in breast cancer cells.

Multidisciplinary management of pediatric low-grade gliomas.

Low-grade gliomas comprise a heterogeneous group of tumors accounting for 30% to 40% of all primary central nervous system (CNS) neoplasms in the pediatric population. Management of these patients has evolved significantly over the past 2 decades, the present emphasis being on surgery. Adjuvant therapies, such as radiation and/or chemotherapy are generally withheld until symptomatic or radiographic progression is evident. The goal of surgery is gross total resection, while preserving maximal neurologic function. The goal of radiation and chemotherapy is to provide symptom and tumor control with minimal acute and late toxicities. Chemotherapy has the additional goal of deferring radiation to allow maximal development and maturation of the child's CNS. The incorporation of these 3 modalities into the overall care of the pediatric low-grade glioma patient involves the multidisciplinary input of the neurosurgeon, radiation oncologist, and pediatric neuro-oncologist both at time of diagnosis and throughout the course of their disease.

Generalized ridge analysis with application to population pharmacokinetics/dynamics.

Given a set of measurements on a patient in clinical studies or on a drug response in bioassays and immunoassays, the data series for the individual can be incomplete, noisy, and haphazard. Hence, meaningful analysis on such limited data is at best difficult given the typical assumptions on the nonlinear structure of systematic and random components involving both individual and population effects. This paper describes a simple direct semiparametric procedure to incorporate population-wide information from as many individuals as required to support analysis of data on any specific individual. This notion is motivated by the pattern-processing capabilities of experts as they evaluate data on an individual based on their reservoir of accumulated knowledge of the given application on many individuals.

Aberrant antigen presentation by macrophages from tumor-bearing mice is involved in the down-regulation of their T cell responses.

Splenic T cells from BALB/c mice bearing mammary adenocarcinomas initially demonstrate a primed response to tumor-associated Ags (TAA), which declines to presensitization levels within 4 wk after tumor implantation. Associated with this decline in responses to TAA is the expansion of a subpopulation of Mac-1+ 2+ splenic macrophages (M phi). These Mac-1+ 2+ cells present TAA inefficiently to normal T cells primed to TAA by footpad injection, as compared with the Ag presenting ability of M phi from normal mice. The addition of anti-I-Ed, but not anti-I-Ad, Ab blocked the ability of Ag-pulsed Mac-1+ 2+ cells to present TAA to primed T cells. The converse was observed with macrophages from normal mice. However, presentation of human gamma-globulin or OVA was restricted by I-Ad molecules when APC from normal mice or tumor bearers were used, although less efficiently in the latter. Using cell depletion techniques, it was determined that the I-Ed-restricted presentation preferentially expanded CD8+ T cells, and not CD4+ cells, as was the case for I-Ad-restricted normal macrophages. These CD8+ cells were poor effectors of cytotoxicity against tumor cells; instead they down-regulated the proliferative activity of T cells. Limiting dilution assays indicated that Mac-1+ 2+ macrophages preferentially present TAA to a low frequency inhibitory T cell population that expanded and inhibited further responses to TAA. Thus, alterations of Ag presentation in tumor bearers may help the tumor to subvert potential beneficial host responses and allow the progression of the neoplastic process.

Regulation of leukocyte binding to endothelial tissues by tumor-derived GM-CSF.

The adherence of leukocytes to endothelial cells is the first step in the migration of these cells into tumor tissues. Specific binding to the endothelial cells by leukocytes is mediated by the development and maintenance of adhesion molecules on the endothelium; however, the mechanisms of leukocyte traffic into tumors and of their interactions with neoplastic tissue are not clearly understood. The infiltration of leukocytes occurs in most spontaneous and transplanted solid tumors and we have previously reported that not only are murine mammary tumors heavily infiltrated by leukocytes but tumor-derived factors alter the development and function of leukocytes in tumor-bearing mice. We now present evidence that a tumor-derived cytokine, namely granulocyte-macrophage-colony-stimulating factor, appears to be of importance in the regulation of leukocyte binding to endothelial cells. The data suggest that tumor-derived factors may influence leukocyte trafficking within tumor tissue.

Splenic macrophages from tumor-bearing mice co-expressing MAC-1 and MAC-2 antigens exert immunoregulatory functions via two distinct mechanisms.

Tumor burden has been shown to induce a variety of phenotypic and functional changes in the cellular constituents of the host's immune system. These changes have been implicated as mechanisms by which tumors avoid rejection. Studies of BALB/c mice bearing a D1-DMBA-3 mammary adenocarcinoma showed alterations of the splenocyte populations. There was a five-fold increase of macrophages (M phi) that were phenotypically and functionally analyzed to establish their role in tumor-induced modifications of the host's immune response. Monoclonal antibody staining defined a Mac-1+2+ population which comprised up to 20% of the splenocytes in tumor-bearers (TB), but is negligible in spleens from normal mice. These Mac-1+2+ M phi were found to mediate down-regulation of both polyclonal and antigen-specific T and B cell responses in vitro and in vivo. Although B cell responses were suppressed via prostaglandin E2 (PGE2) production by the TB M phi, T cell responses were relatively refractory to PGE2-mediated down-regulation. Instead, they were suppressed by a contact-dependent T cell-M phi interaction. Furthermore, tumor-derived factors such as granulocyte-M phi colony-stimulating factor (GM-CSF) seem to play an important role in the induction and expansion of the Mac-1+2+ M phi. These cells appear to mediate down-regulation of the host immune responses by at least two distinct mechanisms: 1) PGE2 production and 2) a cell contact-dependent, but non-major-histocompatibility-complex-specific, interaction.

The role of tumor-derived cytokines on the immune system of mice bearing a mammary adenocarcinoma. I. Induction of regulatory macrophages in normal mice by the in vivo administration of rGM-CSF.

Using a dimethylbenzanthracene-induced immunogenic nonmetastatic murine mammary adenocarcinoma in BALB/c mice, our previous work has shown that splenocytes from tumor bearers have reduced responses to both mitogens and Ag including tumor-associated Ag. NK and cytotoxic T cell activities are also reduced in splenocytes of tumor bearers. Mac-1+2+ macrophages induced in mammary tumor bearers are capable of down-regulating lymphocyte responses to mitogens and tumor-associated Ag by cell to cell contact interaction and increased PGE2 production. We have found that the tumor constitutively releases a granulocyte-macrophage (GM)-CSF-like factor in vivo and in vitro, which may be responsible for the systemic increase in cells of the macrophage lineage in tumor-bearing mice. A tumor cell line established from the in vivo tumor expresses and releases GM-CSF as shown by Northern and Western blot analyses. Daily i.p. injections for 3 wk of 10,000 U of rGM-CSF into normal mice induces hemopoietic and immunologic alterations similar to those observed in tumor bearers. Mac-1+ and/or Mac-2+ macrophages can also be detected in the spleens and bone marrow of the mice treated with rGM-CSF. Additionally, splenocytes from rGM-CSF-treated mice have reduced responses to mitogens and their peritoneal exudate cells can cause in vitro down-regulation of proliferative responses of lymphocytes from normal mice. The suppression can be partially reversed by the addition of indomethacin to the cultures suggesting that PGE2 may contribute to the effect. rGM-CSF enhances the in vitro release of PGE2 by the spleen, bone marrow, and peritoneal cells of normal mice. These data indicate that the high levels of GM-CSF constitutively produced by the tumor may be responsible for the hemopoietic changes and immunologic alterations observed in tumor-bearing mice.

Emergence of a B lymphocyte population with ADCC effector function in mammary tumor bearing mice.

Differential expression of antibody dependent cellular cytotoxicity (ADCC) effectors was studied in normal Balb/cCrgI mice and those bearing a chemically induced 7, 12 dimethylbenzanthracene mammary adenocarcinoma. Depletion of macrophages from normal mouse splenocytes by Sephadex G-10 columns resulted in elimination of ADCC. Further separation of the normal G-10 nonadherent splenocytes on nylon wool columns did not result in any population with significant cytotoxicity. However, Balb/c mice bearing mammary tumors showed enhanced levels of ADCC which were not eliminated by macrophage removal. Lymphocytes from tumor bearers further separated on nylon wool yielded nonadherent and adherent populations both capable of effecting significant ADCC. Treatment of the nylon nonadherent cells of both normal and tumor bearing mice with anti-asialo GM1 (AGM1) and complement decreased the ADCC responses. The same treatment only marginally affected cytotoxic levels of nylon adherent cells from tumor bearers, indicating that these effectors are primarily of non-NK lineage. In addition, G-10 nonadherent, nylon adherent cells from tumor bearers separated on a fluorescence activated cell sorter based on the presence of surface immunoglobulins (slg) revealed that both the slg- and slg+ (98% pure) sorted cells were capable of functioning in ADCC. To determine whether in the tumor mice the 2% of slg- cells present in the slg+ sorted population were the ADCC effectors, mixing experiments were done in which up to 10% of slg- cells from tumor bearers were added to nylon adherent cells from normal mice. No significant increases in ADCC levels were found over that of normal mice. These experiments indicate that the 2% slg- cells were not the ADCC effectors nor were they inducing normal B cells to exert this type of cytotoxic reaction in vitro. To further substantiate the B cell lineage of the slg+ ADCC effectors, surface immunoglobulins were removed with protease treatment. After a 36 hr incubation, 92% of the cells had regenerated their slg. The results presented in this paper demonstrate that various splenic lymphoreticular populations from tumor bearers possess an enhanced cytolytic activity against antibody coated target cells. Among these is a unique nylon adherent slg+ cell that is capable of functioning as an ADCC effector.