The introduction of CD38-targeting monoclonal antibodies (CD38 MoABs), daratumumab and isatuximab, has significantly impacted the management of patients with multiple myeloma (MM). Outcomes of patients with MM refractory to CD38 MoABs have not been described. We analyzed outcomes of 275 MM patients at 14 academic centers with disease refractory to CD38 MoABs. Median interval between MM diagnosis and refractoriness to CD38 MoAB (T 0) was 50.1 months. The median overall survival (OS) from T 0 for the entire cohort was 8.6 [95% C.I. 7.5-9.9] months, ranging from 11.2 months for patients not simultaneously refractory to an immunomodulatory (IMiD) agent and a proteasome inhibitor (PI) to 5.6 months for "penta-refractory" patients (refractory to CD38 MoAB, 2 PIs and 2 IMiDs). At least one subsequent treatment regimen was employed after T 0 in 249 (90%) patients. Overall response rate to first regimen after T 0 was 31% with median progression-free survival (PFS) and OS of 3.4 and 9.3 months, respectively. PFS was best achieved with combinations of carfilzomib and alkylator (median 5.7 months), and daratumumab and IMiD (median 4.5 months). Patients with MM refractory to CD38 MoAB have poor prognosis and this study provides benchmark for new therapies to be tested in this population.

Stromal or mesenchymal neoplasms affecting the gastrointestinal (GI) tract have undergone a remarkable evolution in how they are perceived, classified, approached, diagnosed and managed over the last 30 years. Gastrointestinal stromal tumors (GIST) account for approximately 1% to 3% of all malignant GI tumors. The clinical features can vary depending on the anatomic location, size and aggressiveness of the tumor. Metastatic GIST represents a successful example of molecular targeted therapy. In this comprehensive review, we discuss the epidemiology, clinical features and diagnostic modalities for GIST. We also describe treatment options for early stage, locally advanced and metastatic GIST. Indications for neoadjuvant and adjuvant therapy along with duration of therapy are also explained. A brief discussion of latest biomarkers and updates from recent meetings is also provided.

Allogeneic hematopoietic cell transplantation (HCT) is associated with significant morbidity and mortality, making advance care planning (ACP) and management especially important in this patient population. A paucity of data exists on the utilization of ACP among allogeneic HCT recipients and the relationship between ACP and intensity of healthcare utilization in these patients. We performed a retrospective review of patients receiving allogeneic HCT at our institution from 2008 to 2015 who had subsequently died after HCT. Documentation and timing of advance directive (AD) completion were abstracted from the electronic medical record. Outcomes of interest included use of intensive care unit (ICU) level of care at any time point after HCT, within 30 days of death, and within 14 days of death; use of mechanical ventilation at any time after HCT; and location of death. Univariate logistic regression was performed to explore associations between AD completion and each outcome. Of the 1031 patients who received allogeneic HCT during the study period, 422 decedents (41%) were included in the analysis. Forty-four percent had AD documentation prior to death. Most patients (69%) indicated that if terminally ill, they did not wish to be subjected to life-prolonging treatment attempts. Race/ethnicity was significantly associated with AD documentation, with non-Hispanic white patients documenting ADs more frequently (51%) compared with Hispanic (22%) or Asian patients (35%; P = .0007). Patients with ADs were less likely to use the ICU during the transplant course (41% for patients with ADs versus 52% of patients without ADs; P = .03) and also were less likely to receive mechanical ventilation at any point after transplantation (21% versus 37%, P < .001). AD documentation was also associated with decreased ICU use at the end of life; relative to patients without ADs, patients with ADs were more likely to die at home or in hospital as opposed to in the ICU (odds ratio, .44; 95% confidence interval, .27 to .72). ACP remains underused in allogeneic HCT. Adoption of a systematic practice to standardize AD documentation as part of allogeneic HCT planning has the potential to significantly reduce ICU use and mechanical ventilation while improving quality of care at end of life in HCT recipients.

Most of the information about spinal cord and nerve root involvement in tuberculous meningitis is available in the form of isolated case reports or case series. In this article, we evaluated the incidence, predictors, and prognostic impact of spinal cord and spinal nerve root involvement in tuberculous meningitis.In this prospective study, 71 consecutive patients of newly diagnosed tuberculous meningitis were enrolled. In addition to clinical evaluation, patients were subjected to magnetic resonance imaging (MRI) of brain and spine. Patients were followed up for at least 6 months.Out of 71 patients, 33 (46.4%) had symptoms/signs of spinal cord and spinal nerve root involvement, 22 (30.9%) of whom had symptoms/signs at enrolment. Eleven (15.4%) patients had paradoxical involvement. Paraparesis was present in 22 (31%) patients, which was of upper motor neuron type in 6 (8.4%) patients, lower motor neuron type in 10 (14%) patients, and mixed type in 6 (8.4%) patients. Quadriparesis was present in 3 (4.2%) patients. The most common finding on spinal MRI was meningeal enhancement, seen in 40 (56.3%) patients; in 22 (30.9%), enhancement was present in the lumbosacral region. Other MRI abnormalities included myelitis in 16 (22.5%), tuberculoma in 4 (5.6%), cerebrospinal fluid (CSF) loculations in 4 (5.6%), cord atrophy in 3 (4.2%), and syrinx in 2 (2.8%) patients. The significant predictor associated with myeloradiculopathy was raised CSF protein (>250 mg/dL). Myeloradiculopathy was significantly associated with poor outcome.In conclusion, spinal cord and spinal nerve root involvement in tuberculous meningitis is common. Markedly raised CSF protein is an important predictor. Patients with myeloradiculopathy have poor outcome.

No abstract

Most paramyxovirus fusion proteins require coexpression of and activation by a homotypic attachment protein, hemagglutinin-neuraminidase (HN), to promote membrane fusion. However, the molecular mechanism of the activation remains unknown. We previously showed that the incorporation of a monohistidylated lipid into F-virosome (Sendai viral envelope containing only fusion protein) enhanced its fusion to hepatocytes, suggesting that the histidine residue in the lipid accelerated membrane fusion. Therefore, we explored whether a histidine moiety in HN could similarly direct activation of the fusion protein. In membrane fusion assays, the histidine substitution mutants of HN (H247A of Sendai virus and H245A of human parainfluenza virus 3) had impaired membrane fusion promotion activity without significant changes in other biological activities. Synthetic 30-mer peptides corresponding to regions of the two HN proteins containing these histidine residues rescued the fusion promoting activity of the mutants, whereas peptides with histidine residues substituted by alanine did not. These histidine-containing peptides also activated F-virosome fusion with hepatocytes both in the presence and in the absence of mutant HN in the virosome. We provide evidence that the HN-mimicking peptides promote membrane fusion, revealing a specific histidine "switch" in HN that triggers fusion.

Infection with hepatitis C virus (HCV) is a major cause of transfusion-associated hepatitis, cirrhosis and hepatocellular carcinoma. The present study was conducted with an objective to evaluate the prevalence of anti-HCV antibody in New Delhi, India using a large number of healthy voluntary blood donors. A total of 15,898 healthy voluntary blood donors were subjected to anti-HCV testing (using a commercially available third generation anti-HCV ELISA kit) and 249 were found to be reactive for anti-HCV antibody, yielding an overall prevalence of 1.57%. No significant difference was found between the HCV positivity rate of male (1.57%; 238/15,152) vs. female (1.47%; 11/746) donors, family (1.58%; 213/13,521) vs. altruistic (1.51%; 36/2377) donors and first-time (1.55%; 180/11,605) vs. repeat (1.61%; 69/4293) donors. The age distribution of anti-HCV reactivity showed a maximum prevalence rate of 1.8% in the age group of 20-29 years. In addition, there was a clear trend of decreasing positivity for anti-HCV with increasing age and this trend was statistically significant. The results of the present study show that the prevalence of anti-HCV antibodies in the healthy voluntary blood donors of New Delhi, India is considerably higher than the reported seroprevalence of HCV in majority of the industrialized nations and this represents a large reservoir of infection capable of inflicting significant disease burden on the society. In addition, donors of New Delhi, India showed a trend of decreasing seroprevalence with increasing age, possibly implying a higher exposure rate to HCV in younger subjects.

The disease is usually treated surgically, although a more expectant approach consisting of antibiotics and observation has also been proposed.