Nicholas D'Cunha

Gamma-radiation upregulates MHC class I/II and ICAM-I molecules in multiple myeloma cell lines and primary tumors

SummaryThe γ-irradiation of normal cells causes an increased synthesis of specific proteins. However, few studies have described the effects of high doses of irradiation on the expression of cell surface antigens in tumor cells. This study analyzed the effects of high doses of γ-irradiation on the surface antigen expression of Major Histocompatability Complex (MHC) class I/II and intercellular adhesion molecule-1 (ICAM-I) in human multiple myeloma (MM) cell lines ARP-1, ARK-RS, and 10 MM primary tumors. The expression of surface antigens was evaluated by fluorescence-activated cell sorter analysis at different time points, following the exposure to high doses of γ-irradiation. Doses of 10,000 and 15,000 cGy were no0105 sufficient to totally block cell replication in both cell lines and primary tumors; cell replication was able to be inhibited completely only at 18,000 cGy. Lower doses (10,000 cGy) and lethal doses of irradiation (i.e., 15,000 and 18,000 cGy) increased the expression of all surface antigens present on the cells before irradiation. Essentially, such upregulation was shown to be dose dependent, with higher radiation doses resulting in higher antigen expression. Furthermore, when the kinetics of this upregulation were studied 3 and 6 d after irradiation, there was a constant increase in antigen expression in MM cells. These findings suggest that upregulation of costimulatory molecules, such as of MHC class I/II antigens and ICAM-1 molecules in MM patients treated by γ-radiation, can increase the immunogenicity of the tumor cells. In light of these findings, radiotherapy combined with immunotherapy might be considered in relapsing patients after receiving the standard treatment.

Identification of AKAP-4 as a new cancer/testis antigen for detection and immunotherapy of prostate cancer†

Prostate cancer (PC) is the second most common cancer in older men, after skin cancer. PC is difficult to diagnose because the prostate‐specific antigen screening method is associated with many false positives. In addition there is a need to develop new and more effective treatments. Among presently available new treatments, immunotherapy is a promising approach. We investigated the expression of the cancer/testis antigen, AKAP‐4, in PC patients to evaluate the possibility of exploiting AKAP‐4 as a target for immunotherapy.

Chimeric Antigen Receptor Engineering: A Right Step in the Evolution of Adoptive Cellular Immunotherapy

Cancer immunotherapy comprises different therapeutic strategies that exploit the use of distinct components of the immune system, with the common goal of specifically targeting and eradicating neoplastic cells. These varied approaches include the use of specific monoclonal antibodies, checkpoint inhibitors, cytokines, therapeutic cancer vaccines and cellular anticancer strategies such as activated dendritic cell (DC) vaccines, tumor-infiltrating lymphocytes (TILs) and, more recently, genetically engineered T cells. Each one of these approaches has demonstrated promise, but their generalized success has been hindered by the paucity of specific tumor targets resulting in suboptimal tumor responses and unpredictable toxicities. This review will concentrate on recent advances on the use of engineered T cells for adoptive cellular immunotherapy (ACI) in cancer.

The pituitary tumor transforming gene 1 (PTTG-1): An immunological target for multiple myeloma

BackgroundMultiple Myeloma is a cancer of B plasma cells, which produce non-specific antibodies and proliferate uncontrolled. Due to the potential relapse and non-specificity of current treatments, immunotherapy promises to be more specific and may induce long-term immunity in patients. The pituitary tumor transforming gene 1 (PTTG-1) has been shown to be a novel oncogene, expressed in the testis, thymus, colon, lung and placenta (undetectable in most other tissues). Furthermore, it is over expressed in many tumors such as the pituitary adenoma, breast, gastrointestinal cancers, leukemia, lymphoma, and lung cancer and it seems to be associated with tumorigenesis, angiogenesis and cancer progression. The purpose was to investigate the presence/rate of expression of PTTG-1 in multiple myeloma patients.MethodsWe analyzed the PTTG-1 expression at the transcriptional and the protein level, by PCR, immunocytochemical methods, Dot-blot and ELISA performed on patients sera in 19 multiple myeloma patients, 6 different multiple myeloma cell lines and in normal human tissue.ResultsWe did not find PTTG-1 presence in the normal human tissue panel, but PTTG-1 mRNA was detectable in 12 of the 19 patients, giving evidence of a 63% rate of expression (data confirmed by ELISA). Four of the 6 investigated cell lines (66.6%) were positive for PTTG-1. Investigations of protein expression gave evidence of 26.3% cytoplasmic expression and 16% surface expression in the plasma cells of multiple myeloma patients. Protein presence was also confirmed by Dot-blot in both cell lines and patients.ConclusionWe established PTTG-1s presence at both the transcriptional and protein levels. These data suggest that PTTG-1 is aberrantly expressed in multiple myeloma plasma cells, is highly immunogenic and is a suitable target for immunotherapy of multiple myeloma.

Genistein inhibited proliferation and induced apoptosis in acute lymphoblastic leukemia, lymphoma and multiple myeloma cells in vitro

Abstract Genistein is one of the major isoflavones in soy products. It has been reported that genistein has apoptotic effects on certain hematological malignancies. However, so far there have been no completely comparative studies of the effect of genistein on malignant hematological diseases, especially multiple myeloma. We investigated genisteins inhibitory effect on the growth of acute lymphoblastic leukemia (RS4;11 and CEM), lymphoma (Toledo and GA10) and multiple myeloma (OPM-2 and U266) cell lines in vitro. We observed that genistein dose- and time-dependently inhibited proliferation of these cells. The cell line sensitivity to genistein treatment based on the 50% inhibitory concentration (IC50) values in decreasing order of toxicity was found to be as follows: RS4;11 (4.89 ± 4.28 μM) > GA10 (13.08 ± 3.49 μM) > Toledo (16.94 ± 3.89 μM) > CEM (17.31 ± 0.72 μM) > OPM-2 (46.76 ± 2.26 μM) > U266 (128.82 ± 1.90 μM). The mechanism of growth inhibition was through induction of apoptosis and cell cycle arrest. The concomitant altered expression of apoptosis pathway proteins and cell cycle modulators (caspases 9, 3, 7, PARP [poly(ADP-ribose) polymerase], cIAP1 [inhibitor of apoptosis protein 1], Bcl-2 and cyclin B1) were observed by Western blot and real-time polymerase chain reaction (PCR) analyses. In addition, some malignancy-related embryologic pathway proteins, e.g. Notch1 and Gli1, were modulated by genistein treatment in sensitive cell lines.

Sigmoid plasmacytoma mimicking colon cancer in a patient with multiple myeloma: case report and review of literature

Congenital duodenal occlusion presenting as a neonatal emergency may be caused by a diaphragm or a complete obliteration of the duodenal lumen. Complete obliteration may result from vascular occlusion in utero. A diaphragm may represent incomplete vacuolation of the proliferating epithelial lining of the duodenum between the sixth and eighth weeks of gestation. 1 If the occlusion caused by the diaphragm is complete, symptoms appear from birth. In some cases, a lumen persists in the diaphragm, and presentation is delayed. The lumen is rarely wide enough to avoid symptoms or for symptomstobedelayeduntiladultlife.Thehistoryinadults isusuallyoneofpersistent vomitingandweightloss.Twenty adult patients with duodenal web were reported in a large series of congenital duodenal anomalies from one center in the United States. 3 The onset of symptoms in adult life seems to be the effect of progressive decompensation of the peristaltic force of the stomach and proximal duodenum.

Perspective for prophylaxis and treatment of cervical cancer: an immunological approach.

As the second most common cause of cancer-related death in women, human papilloma virus (HPV) vaccines have been a major step in decreasing the morbidity and mortality associated with cervical cancer. An estimated 490,000 women are diagnosed with cervical cancer each year. Increasing knowledge of the HPV role in the etiology of cervical cancer has led to the development and introduction of HPV-based vaccines for active immunotherapy of cervical cancer. Immunotherapies directed at preventing HPV-persistent infections. These vaccines are already accessible for prophylaxis and in the near future, they will be available for the treatment of preexisting HPV-related neoplastic lesions.

Reactive Thrombocytosis Associated with Acute Myocardial Infarction following STEMI with Percutaneous Coronary Intervention.

The etiology of thrombocytosis can be classified into reactive and essential forms. The rate of thromboembolic events is higher in essential thrombocytosis, and these events include strokes, transient ischemic attacks, retinal artery or retinal vein occlusions, digital ischemia, and acute coronary syndrome. In a study of 732 medical and surgical patients with thrombocytosis, 88% had reactive thrombocytosis. Patients with reactive thrombocytosis do not require cytoreductive medications or antiplatelet treatment. We report a healthy 40-year-old man without any medical problems who developed a new episode of myocardial infarction associated with thrombocytosis after an episode of myocardial infarction followed by percutaneous coronary intervention. He had thrombocytosis, and his platelet function test did not reveal adequate inhibition. To treat his acute coronary syndrome, therapeutic enoxaparin was added, and clopidrogel was substituted with ticagrelor. We decided to start hydroxyurea to reduce platelets counts. Enoxaparin and hydroxyurea were discontinued when platelet count returned to baseline. JAK-2 and BCR/ABL mutations were negative. This case report highlights a clinical dilemma (reactive thrombocytosis), which is challenging in terms of management and pathophysiology.

A Systematic Review and Meta-Analysis of Randomized Controlled Trials to Evaluate the Risk of Hematological Toxicities in Patients with Multiple Myeloma Treated with Daratumumab

S242 p 1⁄4 0.70); asthenia, 0.84 (95% CI: 0.38 e 1.85, p 1⁄4 0.66); and insomnia, 1.05 (95% CI: 0.80 e 1.36; p 1⁄4 0.71). The RR of highgrade adverse effects were as follows: nausea, 1.92 (95% CI: 0.17 e 21.60; p 1⁄4 0.59); diarrhea, 1.43 (95% CI: 0.75 e 2.74, p 1⁄4 0.27); fatigue, 1.87 (95% CI: 0.99 e 3.52; p 1⁄4 0.051); asthenia, 0.81 (95% CI: 0.30 e 2.14, p 1⁄4 0.67); and insomnia, 0.30 (95% CI: 0.04 e 1.93; p 1⁄4 0.20). Conclusions: Addition of daratumumab did not increase the risk of gastrointestinal toxicities and healthrelated quality of life events in patients with multiple myeloma compared to control arm, while contributing substantial survival benefits.

Giant-cell tumor of bone with pathological evidence of blood vessel invasion

Giant cell tumor of bone is a rare but aggressive benign tumor that arises at the end of long tubular bones. The tumor rarely metastasizes; however, we report a case in which a giant cell tumor of bone presented with progressive pulmonary metastases. There has been no clear pathologic evidence of the definitive cause or route of metastasis. In our case, the primary tumor site was located in the left femur with pathological evidence of blood vessel invasion. The histological and pathological features of this entity are discussed in this letter to the editor.