Gaps and opportunities in the treatment of relapsed-refractory multiple myeloma: Consensus recommendations of the NCI Multiple Myeloma Steering Committee

A wide variety of new therapeutic options for Multiple Myeloma (MM) have recently become available, extending progression-free and overall survival for patients in meaningful ways. However, these treatments are not curative, and patients eventually relapse, necessitating decisions on the appropriate choice of treatment(s) for the next phase of the disease. Additionally, an important subset of MM patients will prove to be refractory to the majority of the available treatments, requiring selection of effective therapies from the remaining options. Immunomodulatory agents (IMiDs), proteasome inhibitors, monoclonal antibodies, and alkylating agents are the major classes of MM therapies, with several options in each class. Patients who are refractory to one agent in a class may be responsive to a related compound or to a drug from a different class. However, rules for selection of alternative treatments in these situations are somewhat empirical and later phase clinical trials to inform those choices are ongoing. To address these issues the NCI Multiple Myeloma Steering Committee formed a relapsed/refractory working group to review optimal treatment choices, timing, and sequencing and provide recommendations. Additional issues considered include the role of salvage autologous stem cell transplantation, risk stratification, targeted approaches for genetic subsets of MM, appropriate clinical trial endpoints, and promising investigational agents. This report summarizes the deliberations of the working group and suggests potential avenues of research to improve the precision, timing, and durability of treatments for Myeloma.Subject terms: Combination drug therapy, Cancer therapeutic resistance, Targeted therapies     

Neural processing associated with cognitive empathy in pedophilia and child sexual offending

Behavioral studies found evidence for superior cognitive empathy (CE) in pedophilic men without a history of child sexual offending (P − CSO) compared to pedophilic men with a history of child sexual offending (P + CSO). Functional magnetic resonance imaging (fMRI) studies also point to differences between P − CSO and P + CSO. Neural processing associated with CE has not yet been investigated. Therefore, the present study aimed to explore the neural correlates of CE in subjects with pedophilia with (P + CSO) and without (P − CSO) child sexual offending. 15 P + CSO, 15 P − CSO and 24 teleiophilic male controls (TC) performed a CE task during fMRI. We observed reduced activation in the left precuneus (Pcu) and increased activation in the left anterior cingulate cortex (ACC) in P − CSO compared to P + CSO. P − CSO also showed stronger connectivity between these regions, which might reflect a top-down modulation of the Pcu by the ACC toward an increased self-focused emotional reaction in social situations. There was also evidence for increased right superior temporal gyrus activation in P − CSO that might constitute a potentially compensatory recruitment due to the dampened Pcu activation. These findings provide first evidence for altered neural processing of CE in P − CSO and underline the importance of addressing CE in pedophilia and CSO in order to uncover processes relevant to effective prevention of child sexual abuse.     

Cognitive and functional deficits are associated with white matter abnormalities in two independent cohorts of patients with schizophrenia

European Archives of Psychiatry and Clinical Neuroscience - Significant evidence links white matter (WM) microstructural abnormalities to cognitive impairment in schizophrenia (SZ), but the...     

Evaluation of 5‐Year Risk of Cardiovascular Events in Patients after Acute Myocardial Infarction Using Synchronization of 0.1‐Hz Rhythms in Cardiovascular System

Background: Synchronization between 0.1‐Hz rhythms in cardiovascular system is deteriorated at acute myocardial infarction (AMI) leading to a disruption of natural functional couplings within the system of autonomic regulation. Objective: This study evaluates the prognostic value of autonomic regulation indices for the 5‐year risk of fatal and nonfatal cardiovascular events in patients after AMI. Methods and Results: We studied 125 patients (53 [42%] female) after AMI aged between 30 and 83 years. The period of observation was 5 years with checkpoints at the first week after AMI and after each year after AMI. We compared the prognostic value of established clinical characteristics and degree S of synchronization between 0.1‐Hz rhythms in heart rate and microcirculation for evaluation of the 5‐year risk of mortality and recurrent myocardial infarction (MI) in patients after AMI. Acute heart failure Killip 2–4 at AMI and S < 20% at the first week after AMI were identified as the most important factors for evaluation of the risk of 5‐year mortality in patients after AMI (χ²= 14.2, P = 0.003). Sensitivity and specificity of low S (<20%) at the first week after AMI were 76% and 43%, respectively. For evaluation of the 5‐year risk of recurrent MI index S had no advantage over established clinical characteristics. Conclusion: The value of S below 20% in patients with AMI is a sensitive marker of high risk of mortality during the subsequent five years. It is characterized by better prognostic value than most of established clinical characteristics.     

Contrast-enhanced T1-weighted fluid-attenuated inversion-recovery BLADE magnetic resonance imaging of the brain: an alternative to spin-echo technique for detection of brain lesions in the unsedated pediatric patient?

RATIONALE AND OBJECTIVES: We compared contrast-enhanced T1-weighted magnetic resonance (MR) imaging of the brain using different types of data acquisition techniques: periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER, BLADE) imaging versus standard k-space sampling (conventional spin-echo pulse sequence) in the unsedated pediatric patient with focus on artifact reduction, overall image quality, and lesion detectability. MATERIALS AND METHODS: Forty-eight pediatric patients (aged 3 months to 18 years) were scanned with a clinical 1.5-T whole body MR scanner. Cross-sectional contrast-enhanced T1-weighted spin-echo sequence was compared to a T1-weighted dark-fluid fluid-attenuated inversion-recovery (FLAIR) BLADE sequence for qualitative and quantitative criteria (image artifacts, image quality, lesion detectability) by two experienced radiologists. Imaging protocols were matched for imaging parameters. Reader agreement was assessed using the exact Bowker test. RESULTS: BLADE images showed significantly less pulsation and motion artifacts than the standard T1-weighted spin-echo sequence scan. BLADE images showed statistically significant lower signal-to-noise ratio but higher contrast-to-noise ratios with superior gray-white matter contrast. All lesions were demonstrated on FLAIR BLADE imaging, and one false-positive lesion was visible in spin-echo sequence images. CONCLUSION: BLADE MR imaging at 1.5 T is applicable for central nervous system imaging of the unsedated pediatric patient, reduces motion and pulsation artifacts, and minimizes the need for sedation or general anesthesia without loss of relevant diagnostic information.     

"Endoview" project of intrapartum endoscopy.

INTRODUCTION: The change in obstetrical practices over the last decade in favor of trials of labor in patients with uterine scars has resulted in increased incidences of uterine ruptures. Although neither repeat cesarean delivery nor a trial of labor is risk free, evidence from a large multicenter study shows vaginal birth after the cesarean (VBAC) is associated with shorter hospital stays, fewer postpartum blood transfusions, and a decreased incidence of postpartum maternal fever. The uterine rupture remains the most serious complication associated with VBAC. Factors associated with uterine rupture include excessive exposure to oxytocin, dysfunctional labor, and a history of more than 1 cesarean delivery.2 Because uterine rupture may be a life-threatening event, intrapartum surveillance and the ability to perform an emergency surgery are both necessary when trial of labor is allowed. Until now, no early symptoms pathognomonic to uterine rupture had been described. We share our experiences with the novel approach to the problem - an intrapartum endoscopy. MATERIALS AND METHODS: Endoscopic examination was accomplished by using the intraoperational fiberscope (Olympus and Endoview system (Costa Mesa, CA, USA). A gas-sterilized 25-cm long fiberscope is introduced into the amniotic cavity through the cervical canal after rupture of the membranes. The distance between the fiberscope and the object varies from 3 to 50 mm. The fiberscope has a separate channel for the fluid infusion (normal saline) throughout the procedure; the surgeon looks through the eyepiece directly and exhibits control over the flexible scope. The duration of endoscopy is less than 15 minutes. The inserting of the endoscopic device is very similar to that of insertion of an intrauterine pressure catheter. The IRB Committees of both participating institutions approved the study protocol. Twenty-eight patients with an unknown or poorly documented site of the uterine scar were included in the study. An ultrasound examination had been performed on all patients prior to endoscopy to assess fetal wellbeing and placental location. The ages of the patients ranged from 21 to 38 years. Eighteen women had 1 previous cesarean delivery, and 10 had 2. The performance of intrapartum endoscopy did not interfere with fetal monitoring; 21 fetuses were monitored externally, 7 internally. Indications for previous cesarean deliveries were as follows: fetal distress in 11 cases, failure to progress in labor in 8, placenta previa in 2, and unknown in 7. Twenty-one patients delivered vaginally; 7 had had repeat cesarean deliveries. All neonates were born in satisfactory condition. The Apgar scores at 1 minute varied from 7 to 9 and at 5 minutes from 8 to 10. The integrity of the uterine wall was assessed by manual postpartum uterine exploration in each case of vaginal delivery and by visualization and palpation of the scar site in each abdominal delivery. RESULTS: The lower uterine segment and contractile portion of the anterior uterine wall were visualized successfully in all patients. In 25 patients, the presumed scar site looked totally indistinguishable from the rest of the lower uterine segment and anterior uterine wall. Two scars were identified as vertical in 2 patients who were delivered by a repeat abdominal operation. A vertical scar appears as a groove running in a cephalad-caudad direction from the lower uterine segment into the contractile portion of the anterior uterine wall. The usefulness of the intrapartum endoscopy is best demonstrated by the following case reports (2 of 28 study cases).     

Potassium-titanyl-phosphate laser assisted robotic partial nephrectomy in a porcine model: can robotic assistance optimize the power needed for effective cutting and hemostasis?

A potassium-titanyl-phosphate (KTP) laser through robotic endo-wrist instrument has been evaluated as an ablative and hemostatic tool in robotic assisted laparoscopic partial nephrectomy (RALPN). Ten RALPN were performed in five domestic female pigs. The partial nephrectomies were performed with bulldog clamping of the pedicle. Flexible glass fiber carrying 532-nm green light laser was used through a robotic endowrist instrument in two cases. Power usage from 4 to 10 W was tested. The laser probe was explored both as a cutting knife and for hemostasis. The pelvicalyceal system was closed with a running suture. Partial nephrectomies using KTP laser were performed without complications. Mean operative times and warm ischemia times for laser cases were 96 and 18 min, respectively. Mean estimated blood loss was 60 ml compared with 50 ml for non-laser cases. Complete hemostasis with the laser alone could be achieved with a power of 4 W and was found to be effective. In our hands the laser fiber powered up to 10 W was not effective as a quick cutting agent. Histopathologic analysis of the renal remnant revealed a cauterized surface effect with average laser penetration depth less than 1 mm and minimal surrounding cellular injury. The new robotic endowrist instrument carrying flexible glass fiber transmitting 532-nm green light laser is a useful addition to the armamentarium of the robotic urologic setup. Its control by the console surgeon enables quicker and more complete hemostasis of the cut surface in renal sparing surgery using a porcine model. Histologically proven lased depth of less than 1 mm suggests minimal parenchyma damage in an acute setting. Laser application as a cutting agent, however, requires further investigation with interval power settings beyond the limits of this preliminary study. We estimate that effective cutting should be possible with a setting lower than traditionally recommended for solid organs.     

Brain-specific small nucleolar RNAs

Small nucleolar RNAs (snoRNAs) are a group of noncoding RNAs that function mainly as guides for modification of ribosomal RNAs (rRNAs) and small nuclear RNAs (snRNAs). A subgroup of snoRNAs was found to be predominantly expressed in the brain; and interestingly, these brain-specific snoRNAs (b-snoRNAs) appear not to be involved in modification of rRNAs and snRNAs, raising the question of what their function and targets might be. Expression studies of b-snoRNAs in mice have shown potential involvement of two b-snoRNAs, MBII-48 and MBII-52, in learning and memory, HBII-52, the human homolog of MBII-52, appears to be involved with regulation of 5-HT_2c receptor subunit mRNA. Furthermore, several reports link the disruption of expression of a specific b-snoRNA, HBII-85, with a neurobehavioral disorder, Prader-Willi syndrome. This paper reviews the current knowledge of the properties, expression, and functions of b-snoRNAs.