Mojtaba Akhtari

Biology of breast cancer bone metastasis.

Breast carcinoma ranks among the most prevalent malignancies in women. Breast carcinoma frequently metastasizes to bone and approximately 70% of patients with breast cancer have bone metastases, which generally are osteolytic lesions. They cause major morbidity and mortality in patients; and the available treatment options are limited. Bone-specific homing and colonization of cancer cells are important and interesting features of metastasis. There are complex and multiple steps in the process of bone metastasis; and the elaborate interaction between breast carcinoma and bone involves various cytokines, growth factors and cellular signals, which results in a vicious cycle and promotes tumor cell accumulation and osteolysis. Recent advances in molecular biology have resulted in major breakthroughs in our understanding of the pathogenesis of bone metastasis in breast cancer, which is critical in preventing metastasis, designing novel and targeted treatments and prolonging survival in this devastating condition.

Fecal microbiota transplantation for fulminant Clostridium difficile infection in an allogeneic stem cell transplant patient

We present a case of severe Clostridium difficile infection (CDI) in a non‐neutropenic allogeneic hematopoietic stem cell transplant recipient who was treated successfully with fecal microbiota therapy after standard pharmacologic therapy had failed. Following naso‐jejunal instillation of donor stool, the patients symptoms resolved within 48 h. Bowel resection was averted. This is the first case in the literature, to our knowledge, to describe fecal microbiota therapy in a profoundly immunocompromised host with severe CDI. We propose that fecal microbiota therapy be considered as a therapeutic option in immunosuppressed patients with refractory severe CDI.

Neutropenia in a Patient Treated With Ipilimumab (anti-CTLA-4 Antibody)

A 42-year-old white woman with a diagnosis of metastatic melanoma developed severe neutropenia during treatment with ipilimumab (anticytotoxic T-lymphocyte-associated antigen-4 antibody). Bone marrow aspiration and biopsy specimens revealed marked myeloid hypoplasia, with unremarkable erythropoiesis and megakaryopoiesis. The patients neutropenia did not respond to therapy with a combination of colony stimulating factors and steroids; however, it rapidly improved after administration of intravenous immunoglobulin. Treatment with ipilimumab has not been reported to be associated with hematologic toxicities, and to our knowledge, no case of neutropenia has previously been reported. This report of acute grade 4 neutropenia associated with ipilimumab and clinically consistent with an autoimmune process emphasizes the importance of monitoring complete blood count during treatment with this new monoclonal antibody.

Targeting TGF beta signaling for cancer therapy

Transforming growth factor (TGF)?s are multifunctional polypeptides that regulate several cellular functions, including cell growth and differentiation, extra cellular matrix production, motility and immunosuppression. The growth-inhibiting properties of TGF? have gained much attention into its role as a tumor suppressor. There is, however, now increasing evidence that TGF? switches roles, from tumor suppressor to tumor promoter, as the tumor progresses. Given the integral role of TGF? in the tumor progression, it follows that TGF? signaling offers an attractive target for cancer therapy. Several strategies including the use of antisense oligonucleotides for TGF?, TGF? antibodies, dominant negative TGF? receptor II, and small drug-molecules to inhibit TGF? receptor I kinase have shown great promise in the preclinical studies. These new findings, coupled with progressing clinical trials indicate that inhibition of TGF? signaling may, indeed, be a viable option to cancer therapy. This review summarizes the TGF? signaling, the dual role of TGF? - as a tumor suppressor and tumor promoter, and various strategies targeted against TGF?signaling for cancer therapy. The next few years promise to better our understanding of approaching cancer therapy with an eye to the inhibition of TGF? signaling.

Autoimmune neutropenia in adults.

Autoimmune neutropenias (AIN) in adults are a heterogeneous group of diseases with clinical manifestations varying from being asymptomatic to having infectious complications with considerable morbidity and mortality. They are characterized by autoantibodies directed against neutrophils, resulting in destruction of neutrophils. AIN can be divided into two forms. In primary AIN, neutropenia is usually the sole hematologic abnormality and it is more common in children. Secondary AIN, which is more prevalent in adults, is associated with underlying autoimmune diseases, malignancies, infections, particularly viral, neurological diseases or drug exposure. This article is an overview of these conditions with emphasis on secondary AIN; it also discusses the available serological methods for antibody detection and recent therapeutic developments including colony stimulating factors, rituximab and Campath-1H.

The locus for combined factor V-factor VIII deficiency (F5F8D) maps to 18q21 , between D18S849 and D18S1103

Combined factor V-factor VIII deficiency (F5F8D) is a rare, autosomal recessive coagulation disorder in which the levels of both coagulation factor V and coagulation factor VIII are diminished. In order to map and subsequently clone the gene responsible for this phenotype, DNAs from 19 families (16 from Iran, 2 from Pakistan, and 1 from Algeria) with a total of 32 affected individuals were collected for a genomewide linkage search using genotypes of highly informative DNA polymorphisms. All pedigrees except two contained at least one consanguineous marriage. A maximum LOD score (Zmax) of 14.82 for theta = .02 was generated with marker D18S1129 in 18q21; LOD scores > 9 were obtained for several other markers-D18S849, D18S1103, D18S64, and D18S862. Multipoint analysis resulted in Zmax = 18.91 for the interval between D18S1129 and D18S64. Informative recombinants placed the locus for F5F8D between D18S849 and D18S1103, in an interval of approximately 1 cM. These results are similar to the recently reported linkage of this disease to chromosome 18q in Jewish families (Nichols et al. 1997) and provide evidence that the same gene is responsible for all F5F8D among human populations. The difference in clinical severity of the phenotype in unrelated families, as well as the failure to detect a specific haplotype of DNA polymorphisms in the consanguineous Iranian families, suggests the existence of different molecular defects in the F5F8D gene. There exists an apparently gap-free contig with CEPH YACs linking the two markers on either side of the critical region. Positional cloning efforts are now in progress to clone the F5F8D gene.

Management of immune cytopenias in patients with systemic lupus erythematosus — Old and new

There are various immune cytopenias associated with systemic lupus erythematosus (SLE). The most common one is anemia; however, there are different etiologies for the anemia caused by SLE. Anemia could be due to chronic disease, secondary to renal insufficiency, blood loss, drug induced or autoimmune hemolysis. There are other very rare causes of anemia secondary to SLE which include red cell aplasia, aplastic anemia, and microangiopathic hemolytic anemia. Treatment of the anemia would be according to the cause. Leukopenia, neutropenia, and lymphopenia are hematologic complications associated with SLE, and in majority of cases no treatment is required. Thrombocytopenia is one of the complications of SLE and is usually treated by steroids. However, there are significant numbers of patients which will either not respond to or relapse after treatment. This article summarizes immune cytopenias seen in patients with SLE, and it also discusses management of these cytopenias.

Hematologic toxicities associated with intravenous immunoglobulin therapy.

Intravenous immunoglobulin (IVIG) is an immunomodulating agent that induces beneficial therapeutic responses in children and adults. IVIG is not only used for prophylaxis and therapy of infections in patients with primary and secondary immunodeficiencies associated with defective antibody production, but also used for treatment of patients with systemic inflammatory disorders, autoimmune diseases, and neuroimmunologic conditions. IVIG is generally considered a safe and efficacious therapeutic modality. However, it is associated with certain adverse effects including hematologic complications such as hemolytic anemia, leukopenia, neutropenia, monocytopenia, disseminated intravascular coagulation, and changes in blood rheology. Venous and arterial thrombotic complications can also occur following treatment with IVIG in high risk patients. It is very important for clinicians to have the knowledge of those adverse events profiles; and this article summarizes hematologic toxicities associated with IVIG therapy reported in the literature; and describes strategies for their identification and management.

Management of autoimmune neutropenia in Felty's syndrome and systemic lupus erythematosus

Autoimmune neutropenia, caused by neutrophil-specific autoantibodies is a common phenomenon in autoimmune disorders such as Feltys syndrome and systemic lupus erythematosus. Feltys syndrome is associated with neutropenia and splenomegaly in seropositive rheumatoid arthritis which can be severe and with recurrent bacterial infections. Neutropenia is also common in systemic lupus erythematosus and it is included in the current systemic lupus classification criteria. The pathobiology of the autoimmune neutropenia in Feltys syndrome and systemic lupus erythematosus is complex, and it could be a major cause of morbidity and mortality due to increased risk of sepsis. Treatment should be individualized on the basis of patients clinical situation, and prevention or treatment of the infection. Recombinant human granulocyte colony-stimulating factor is a safe and effective therapeutic modality in management of autoimmune neutropenia associated with Feltys syndrome and systemic lupus erythematosus, which stimulates neutrophil production. There is a slight increased risk of exacerbation of the underlying autoimmune disorder, and recombinant human granulocyte colony-stimulating factor dose and frequency should be adjusted at the lowest effective dose.

Therapy-related myeloid neoplasms after autologous hematopoietic stem cell transplantation in lymphoma patients

Lymphoma patients treated with autologous transplantation (ASCT) live an increasingly long life with the recent advancement in therapeutic modalities. This has resulted in an increase in the incidence of therapy-related myeloid neoplasms (t-MN), which is one of the leading causes of non-relapse mortality. Several observational studies have linked the development of t-MN after ASCT with the intensity and frequency of chemotherapy, particularly alkylating agents, use of total body irradiation (TBI), and peripheral blood progenitor cells. In addition, role of genetic factors is increasingly being identified. It is postulated that the use of chemotherapy prior to ASCT results in DNA damage of progenitor cells, mitochondrial dysfunction, and altered gene expression related to DNA repair, metabolism as well as hematopoietic regulation. Cytogenetic studies have shown the presence of abnormalities in the peripheral blood progenitor cells prior to ASCT. It is, therefore, likely that the reinfusion of peripheral blood progenitor cells, proliferative stress on infused progenitor cells during hematopoietic regeneration and associated telomere shortening ultimately result in clonal hematopoiesis and blastic transformation. Cytopenias, myelodysplasia, or cytogenetic abnormalities are common and can be transient after ASCT; therefore, only when present together, they do confirm the diagnosis of t-MN. Attempts to reduce the occurrence of t-MN should be directed toward minimizing the exposure to the identified risk factors. Although the median survival is few months to less than a year, studies have shown the promising role of allogeneic transplantation in select young t-MN patients without high-risk cytogenetics. In this review we will explain the recent findings in the field of t-MN in lymphoma patients that have implications for identifying the molecular and genetic mechanisms of leukemogenesis and discuss potential strategies to reduce the risk of t-MN in this patient population.