Myelodysplastic syndrome and immunotherapy novel to next in-line treatments.

Patients with Myelodysplastic syndromes (MDS) have few therapy options for sustainable responses in the frontline setting, and even less after hypomethylating agent (HMA) failure in relapsed and refractory setting. The only potential cure is an allogeneic hematopoietic stem cell transplant which is an unrealistic option for the majority of MDS patients. Immunotherapy with checkpoint inhibition, CAR-T cells, and vaccine therapy few have shown promise in a variety cancer and have now been tested in patients with MDS. Most trials have focused on AML patients and included small numbers of MDS patients. Until now, a dedicated review of immunotherapy outcomes in MDS patients has been lacking. Thus, herein we review outcomes of MDS patients after immunotherapies on a variety of clinical trials reported to date.

Inpatient burden of gastric cancer in the United States.

BACKGROUND: Gastric cancer is associated with significant morbidity and mortality. Over one-half of patients have advanced disease at the time of presentation, leading to a significant burden on the healthcare system. Limited epidemiological data exists on national inpatient hospitalization trends. The aim of this study is to determine the inpatient burden of gastric cancer in the United States. METHODS: We analyzed the Nationwide Inpatient Sample (NIS) database for all subjects with the diagnosis of malignant neoplasm of the stomach (ICD-9 code 151.x) as primary diagnosis during the period from 2001-2011. NIS is the largest all-payer inpatient care database in the U.S. Statistical significance of variation in the number of hospitalizations, patient demographics, and comorbidity measures was determined using Cochran-Armitage trend test. RESULTS: From 2001 to 2011, the number of hospitalizations with the diagnosis of malignant neoplasm of the stomach ranged between 22,430 and 25,371, however, the trend was not significant. Men were always more affected than women with no significant change in overall proportion (P<0.0001). Overall, in-hospital mortality decreased from 11.19% in 2001 to 6.47% in 2011 (P<0.0001). However, average cost of care per hospitalization increased from $21,710 in 2001 to $24,706 in 2011 (adjusted for inflation, P<0.0001). CONCLUSIONS: The total number of hospitalizations remained relatively stable throughout the study period with higher proportion of men affected every year. Although in-hospital mortality in patients with the diagnosis of gastric cancer decreased over the study period, there was a significant rise in the cost of care.

SRSF2 mutations in myelodysplasia/myeloproliferative neoplasms.

Recurrent gene mutations have been described with varying frequencies in myelodysplasia (MDS) /myeloproliferative neoplasm (MPN) overlap syndromes (MMOS). Recent work has placed significant focus on understanding the role of gene lesions involving the spliceosomal machinery in leukemogeneis. SRSF2 is a gene encoding critical spliceosomal proteins. SRSF2 mutations appear to play an important role in pathogenesis of MMOS, particularly in chronic myelomonocytic leukemia. Inhibition of splicing may be a new therapeutic approach. E7107, a spliceosome inhibitor, has been shown to differentially inhibit splicing more in SRSF2-mutant cells leading to decreased leukemia burden in mice. H3B-8800 is a small molecule modulator of spliceosome complex and has been shown to lower leukemia burden in SRSF2-P95H mutant mice. This review focuses on the incidence of mutant SRSF2 across various MMOS as well as recent clinical development of spliceosome inhibitors.

Percutaneous pleural drainage in patients taking clopidogrel: real danger or phantom fear?

Despite being categorized as a procedure associated with a low risk of iatrogenic hemorrhage, percutaneous pleural drainage in patients taking the ubiquitous antiplatelet agent clopidogrel is still commonly perceived as a risky proposition. There is mounting evidence, however, in support of the safety of percutaneous needle procedures in persons receiving this medication. Establishing that these pleural interventions can be performed safely without clopidogrel interruption would be of great clinical significance, especially in those taking it for recent cardiac stenting and therefore in danger of stent thrombosis should antiplatelet therapy (APT) be withheld. The purpose of the present review is to summarize the available data from published studies and series of thoracentesis and chest tube insertion in patients exposed to clopidogrel. Also incorporated into this review are relevant investigations from the thoracic surgery and interventional radiology experience, which contribute indirect evidence and help shape the context for interpreting the safety data reported in the pleural literature. At the end, an attempt is made to synthesize the current knowledge on this topic into conclusions for guiding practice.

A 54-year-old Woman with Myelofibrosis and Massive Hemothorax Due to Primary Extramedullary Hematopoiesis of the Pleura.

Extramedullary hematopoiesis, which represents ectopic blood cell production, is usually an incidental finding accompanying hematologic pathology. The liver and spleen are the most common sites of extramedullary hematopoiesis, but thoracic involvement is likewise observed. Pleural effusions in the setting of intrathoracic extramedullary hematopoiesis have been attributed to mechanical interactions between the pleural surface and neighboring paravertebral masses consisting of hematopoietic tissue. Rupture of these highly vascularized lesions into the adjacent pleural space has been the putative mechanism in cases complicated by hemothorax. Histologically proven instances of islets of extramedullary hematopoiesis occurring on the pleural surface itself are exceedingly rare. Our case of a patient with myelofibrosis and massive pleural effusion is only the third such example described in the literature and the second to result in a confirmed hemothorax requiring surgery. As expected, technetium-99m sulfur (Tc-99m sulfur) colloid scanning accurately localized sites of extramedullary hematopoiesis in our patient, and there was a salutary response to radiation therapy.

SETBP1 mutations as a biomarker for myelodysplasia /myeloproliferative neoplasm overlap syndrome.

Myelodysplasia (MDS) /myeloproliferative neoplasm (MPN) overlap syndrome has been described since the 2001 WHO classification as disorders that have both proliferative and dysplastic changes simultaneously. Specific disorders include chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), BCR-ABL negative atypical chronic myeloid leukemia (aCML) and unclassifiable MDS/MPN (MPN/MDS-U). Recurrent gene mutations in these conditions have been described. Among them, SETBP1 mutations have been identified in up to 32% of aCML, 24% of JMML, 18% of CMML and 10% of MDS/MPN-U patients. The mutation hotspot lies in the amino acid residues 858-871 in the SETBP1 protein. SETBP1 mutations in MDS/MPN overlap syndrome is associated with accelerated transformation to leukemia and poor prognosis. In this review, we summarized the latest data on the role of SETBP1 mutations in the overlap syndrome. SETBP1 mutations may serve as a biomarker for the diagnosis and poor prognosis of the overlap syndrome.

Atypical hemolytic uremic syndrome in first trimester pregnancy successfully treated with eculizumab.

BACKGROUND: Atypical hemolytic uremic syndrome is a rare disorder which is known to cause acute thrombotic microangiopathy during pregnancy with poor maternal and fetal outcomes. Atypical hemolytic uremic syndrome is caused mostly by dysregulation of alternative complement pathway secondary to genetic mutations. Most of the cases reported have been in the post-partum period. We report a rare case of a patient who presents with thrombotic microangiopathy in the first trimester of her eleventh pregnancy and was successfully treated with eculizumab. CASE PRESENTATION: A 30-year-old woman presented at 10 weeks of gestation with hypertension, hemolytic anemia, thrombocytopenia, and acute kidney injury, consistent with thrombotic microangiopathy. She was managed initially with daily plasmapheresis. However, her kidney function did not recover, requiring hemodialysis. ADAMTS13 activity was later found to be within normal limit, hence diagnosis of atypical hemolytic uremic syndrome was strongly considered at that time and she was immediately treated with anti-C5 humanized monoclonal antibody (eculizumab). The patient responded well (resolution of thrombotic microangiopathy and recovery of renal function) to eculizumab, with continued remission after discharge and successfully delivered a healthy baby at term without any peripartum complications. CONCLUSION: Early recognition of atypical hemolytic uremic syndrome is often difficult as several other conditions also manifest as thrombotic microangiopathy during pregnancy, causing delay in initiating appropriate treatment. Our case suggests that treatment of atypical hemolytic uremic syndrome in early trimester of pregnancy with eculizumab results in good outcome to mother and fetus.

Complete remission after single agent blinatumomab in a patient with pre-B acute lymphoid leukemia relapsed and refractory to three prior regimens: hyperCVAD, high dose cytarabine mitoxantrone and CLAG.

BACKGROUND: The current standard of care for relapsed and refractory acute lymphoblastic leukemia (ALL) is combination chemotherapy. CASE PRESENTATION: We report a case of highly refractory ALL who was treated with blinatumomab. The ALL in this patient relapsed within a month after completion of hyperCVAD regimen and was refractory to high dose mitoxantrone/cytarabine and CLAG regimens. CONCLUSION: This highly refractory pre-B Ph(-) ALL was induced to complete remission after one course of single agent blinatumomab.

Polymorphic variation in choline transporter gene (CHT1) is associated with early, subclinical measures of carotid atherosclerosis in humans.

Atherosclerosis is a heritable trait with little known about specific genetic influences on preclinical measures of plaque formation. Based on relations of parasympathetic-cholinergic function to atherosclerosis and to a choline transporter gene [CHT1 (G/T)] polymorphism, we investigated whether the same allelic variant predicts variation in carotid intima-media thickness (IMT) and plaque formation. Carotid IMT and plaque occurrence as well as genotyping for the CHT1 (G/T) variant were measured in a sample (N = 264) of generally healthy adults (age 30-55) of European ancestry. CHT1 GG homozygotes had greater IMT (P < 0.005) and plaque occurrence (P < 0.020) than T allele carriers. This is the first study showing polymorphic variation in the CHT1 gene to predict early, subclinical measures of carotid atherosclerosis which may aid in understanding cholinergic-vagal processes potentially underlying atherosclerotic risk.

Focal electrically administered therapy: device parameter effects on stimulus perception in humans.

BACKGROUND: Focal electrically administered therapy is a new method of transcranial electrical stimulation capable of focal modulation of cerebral activity. Other than invasive studies in animals and examination of motor output in humans, there are limited possibilities for establishing basic principles about how variation in stimulus parameters impact on patterns of intracortical stimulation. This study used a simpler paradigm and evaluated the effects of different stimulation parameters on subjective perception of the quality and location of scalp pain. METHODS: In 2 studies, 19 subjects were randomly stimulated over the left forehead, varying the anode-cathode arrangement, the intensity of stimulation, the electrode size and placement, and whether the current flow was unidirectional or bidirectional. Subjects rated the location of the sensation and its quality. RESULTS: The perceived center of stimulation moved toward the cathode, regardless of placement. This shift in subjective sensation was more prominent when the electricity was unidirectional. In addition, more intense stimulation, as well as stimulation with a smaller electrode, caused greater perceived pain. Unidirectional stimulation was rated more painful when traveling from a large anode to a small cathode and less painful when traveling from a small anode to a large cathode. Finally, participants were more likely to perceive the electrical stimulation as moving toward a specific direction when the intensity was high than when it was low. CONCLUSIONS: The intensity and location of sensations can be manipulated by varying the intensity, current direction, or geometry of electrodes.

Focal electrical stimulation as a sham control for repetitive transcranial magnetic stimulation: Does it truly mimic the cutaneous sensation and pain of active prefrontal repetitive transcranial magnetic stimulation?

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a novel, noninvasive method of stimulating selected regions of the brain that has both research applications and potential clinical utility, particularly for depression. To conduct high-quality clinical studies of rTMS, it is necessary to have a convincing placebo (or sham) treatment. Prefrontal rTMS causes cutaneous discomfort and muscle twitching; therefore, an optimal control condition, ie, sham condition, would mimic the cutaneous sensation and muscular discomfort of rTMS without stimulating the brain. Ideally, the quality and intensity of the sham condition would feel identical to the quality and intensity of the rTMS condition, except that the sham would have no effect on cortical activity. We designed and built a focal electrical stimulation system as a sham rTMS condition. Although this electrical sham system is superior to methods used in previous studies, little is known about how the new electrical sham system compares with active rTMS in terms of the level of discomfort and type of sensation it produces. METHODS: We hypothesized that the electrical sham system may not mirror the experimental condition sufficiently. We studied this hypothesis under single-blind conditions in 15 healthy adults by administering either the real or sham rTMS at high and low intensities while subjects, who were unaware of condition, rated subjective qualities of the stimulation (such as tingling, pinching, and piercing), the scalp location of the perception, and the painfulness of the stimuli. RESULTS: At low-intensity stimulation, the two techniques (active and sham) differ with respect to the subjective quality of the sensation. The differences between real and sham rTMS were less dramatic at higher intensities. The best sham condition that most closely mimics real prefrontal rTMS requires individual titration of the intensity of electrical stimulation across a broad range. Performing this titration without unblinding patients is likely possible, but technically challenging. We propose a new approach to do this. CONCLUSION: We conclude that it is possible to create a truly indistinguishable sham condition (with appropriate acoustic masking as well), but more work is needed beyond these initial attempts.