Durable complete response to pembrolizumab in microsatellite stable colorectal cancer

IntroductionImmunotherapy by checkpoint inhibitors, i.e., anti-programmed death-1(PD-1) or anti-programmed death-ligand 1 (PD-L1) antibodies, has gained more attention managing solid tumors. Pembrolizumab (an anti-PD-1 antibody) in metastatic colorectal cancer (CRC) was approved in 2017 by the US FDA.Reason for the reportPembrolizumab is not effective in microsatellite stable, mismatch-repair-proficient (MSS-pMMR) molecular phenotype, which comprises most CRC patients. In this report, we present the first case of metastatic CRC with a dramatic and durable response to pembrolizumab despite being of MSS-pMMR phenotype.Case summaryA 34-year-old woman, presented seven years ago with T3N2bM0 colon cancer and an appendix carcinoid tumor. The last relapse with bilateral pulmonary metastases was refractory to all treatments. Although it seemed unresponsive to immunotherapy because of MSS molecular phenotype, due to the high expression level of PD-L1 (85%), we started treatment with pembrolizumab 200 mg every three weeks and continued for the overall 19 courses. Surprisingly, a rapid and complete response was observed that last until now, i.e., 17 months after discontinuation of pembrolizumab.OutcomeDespite non-promising results in the current clinical trials, MSS-pMMR colorectal cancer patients'' deprivation from immunotherapy seems not to be reasonable. There are ongoing clinical trials on checkpoint inhibitors either alone or in combination with other drugs. However, immunostaining for PD-L1 should be considered as a possible response predictor.Graphical abstractImmunotherapy either by cell-based approaches or by checkpoint inhibitors may revolutionize cancer treatmentPembrolizumab has been approved by the FDA in 2017 for colorectal cancer.However, MSS-pMMR molecular phenotype which comprises the majority of CRC patients, has not shown a good response to checkpoint inhibitors.We present a MSS-pMMR case with complete and durable response to pembrolizumabWe suggest immunostaining for PD-L1 as a possible response predictor to checkpoint inhibitors     

Canthaxanthin protects human sperm parameters during cryopreservation

Different antioxidants have been introduced to reduce oxidative stress during the cryopreservation. The main goal of this study was to evaluate the effects of canthaxanthin on human sperm parameters during the freeze‐thaw process. This study was performed on 25 normozoospermic semen samples dividing into five groups including 0, 0.1, 1, 10, and 25 µM of canthaxanthin. The prepared spermatozoa were cryopreserved by rapid freezing technique. Sperm motility, viability (eosin‐nigrosin), morphology (Papanicolaou), acrosome reaction (double staining), DNA denaturation (acridine orange), chromatin packaging (aniline blue and toluidine blue), and DNA fragmentation (sperm chromatin dispersion test) were evaluated before freezing and after thawing. All sperm parameters after thawing significantly were decreased compared to before freezing. Twenty‐five micromolar canthaxanthin could significantly improve the progressive and total motility, viability, normal morphology, chromatin packaging, acrosome integrity and DNA denaturation and fragmentation. Ten micromolar canthaxanthin significantly improved total motility, viability, normal morphology, chromatin packaging, acrosome integrity and DNA denaturation and fragmentation. Whereas, in 1 µM group, there were significant differences only in improvement of acrosome integrity, chromatin packaging (toluidine blue) and DNA denaturation and fragmentation. But, in 0.1 µM group, there were no significant differences in any of measured parameters. It seems that canthaxanthin ameliorates detrimental effects of cryopreservation on human sperm parameters.     

Hemoglobin optimization and transfusion strategies in patients undergoing cardiac surgery

Although red blood cells (RBCs) transfusion is sometimes associated with adverse reactions, anemia could also lead to increased morbidity and mortality in high-risk patients. For these reasons, the definition of perioperative strategies that aims to detect and treat preoperative anemia, prevent excessive blood loss, and define “optimal” transfusion algorithms is crucial. Although the treatment with preoperative iron and erythropoietin has been recommended in some specific conditions, several controversies exist regarding the benefit-to-risk balance associated with these treatments. Further studies are needed to better define the indications, dosage, and route of administration for preoperative iron with or without erythropoietin supplementation. Although restrictive transfusion strategies in patients undergoing cardiac surgery have been shown to effectively reduce the incidence and the amount of RBCs transfusion without increase in side effects, some high-risk patients (e.g., symptomatic acute coronary syndrome) could benefit from higher hemoglobin concentrations. Despite all efforts made last decade, a significant amount of work remains to be done to improve hemoglobin optimization and transfusion strategies in patients undergoing cardiac surgery.     

Virucidal mechanism of action of NVC-422, a novel antimicrobial drug for the treatment of adenoviral conjunctivitis

Human adenoviral conjunctivitis is a highly contagious eye infection affecting millions of people world-wide. If untreated, it can further develop into keratitis, corneal ulceration, scarring and possible blindness. Despite the significant patient morbidity and socio-economic costs, it is an unmet medical need with no FDA approved treatment. Here, we demonstrate the virucidal activity of NVC-422 (N,N-dichloro-2,2-dimethyltaurine) against adenovirus type 5 (Ad5) and investigated its mechanism of action of Ad5 inactivation. NVC-422 inhibits Ad5-induced loss of cell viability in vitro with 50% inhibitory concentration (IC₅₀) ranging from 9 to 23 μM. NVC-422 does not cause any cytotoxicity at concentrations as high as 250 μM. Invitro, NVC-422 inactivates Ad5 but does not interfere with viral replication, indicating that NVC-422 acts on the extracellular adenovirus as a virucidal agent. NVC-422 inactivates Ad5 by oxidative inactivation of key viral proteins such as fiber and hexon as evidenced by SDS–PAGE, Western blotting and reversed-phase HPLC. These data, combined with measurements of the kinetics of the NVC-422 reactivity with selected amino acids, indicate that the changes in the viral proteins are caused by the selective oxidation of sulfur-containing amino acids. The conformational changes of the viral proteins result in the destruction of the viral morphology as shown by transmission electron microscopy. In summary, NVC-422 exhibits virucidal activity against Ad5 by the oxidative inactivation of key viral proteins, leading to the loss of viral integrity and infectivity.     

Protective role of simvastatin on isolated rabbit atrioventricular node during experimental atrial fibrillation model: role in rate control of ventricular beats

The purpose of the present study was to determine (1) whether simvastatin (SV) modifies the rate-dependent conduction time and refractoriness of the atrioventricular (AV) node and (2) how it can change the protective mechanism of the AV node during atrial fibrillation (AF). Predefined stimulation protocols were applied to detect the electrophysiological parameters of the AV node, including atrial-His conduction time, effective refractory period (ERP), functional refractory period (FRP), concealed conduction, excitable index, and fatigue in two groups of isolated, perfused rabbit AV nodal preparations (N=16). The stimulation protocols (fatigue, recovery) were carried out during control and in the presence of SV (0.5, 0.8, 3, and 10 μM). Simulated AF was executed in a separate group (N=8), and specific indexes, including H-H mean, zone of concealment (ZOC), and concealed beats were recorded. SV, in a concentration-dependent manner, prolonged ERP, FRP, and Wenckebach cycle lengths. It (10 μM) significantly increased fatigue and the excitable index. In addition, SV elicited prolongation of ZOC and H-H mean at 3 and 10 μM. SV-evoked prolongation of nodal refractoriness and concealed conduction caused rate-dependent ventricular slowing effects during AF. The ability of simvastatin to decrease the excitable gap by its heterogeneous effects on nodal dual pathways proposes its protective role in AF.     

Muslim women having abortions in Canada: attitudes, beliefs, and experiences

Objective

To improve understanding of the attitudes, beliefs, and experiences of Muslim patients presenting for abortion.

Design

Exploratory study in which participants completed questionnaires about their attitudes, beliefs, and experiences.

Setting

Two urban, free-standing abortion clinics.

Participants

Fifty-three self-identified Muslim patients presenting for abortion.

Main outcome measures

Women’s background, beliefs, and attitudes toward their religion and toward abortion; levels of anxiety, depression, and guilt, scored on a scale of 0 to 10; and degree of pro-choice or anti-choice attitude toward abortion, assessed by having respondents identify under which circumstances a woman should be able to have an abortion.

Results

The 53 women in this study were a diverse group, aged 17 to 47 years, born in 17 different countries, with a range of beliefs and attitudes toward abortion. As found in previous studies, women who were less pro-choice (identified fewer acceptable reasons to have an abortion) had higher anxiety and guilt scores than more pro-choice women did: 6.9 versus 4.9 (P = .01) and 6.9 versus 3.6 (P = .004), respectively. Women who said they strongly agreed that abortion was against Islamic principles also had higher anxiety and guilt scores: 9.3 versus 5.9 (P = .03) and 9.5 versus 5.3 (P = .03), respectively.

Conclusion

Canadian Muslim women presenting for abortion come from many countries and schools of Islam. The group of Muslim women that we surveyed was so diverse that no generalizations can be made about them. Their attitudes toward abortion ranged from being completely pro-choice to believing abortion is wrong unless it is done to save a woman’s life. Many said they found their religion to be a source of comfort as well as a source of guilt, turning to prayer and meditation to cope with their feelings about the abortion. It is important that physicians caring for Muslim women understand that their patients come from a variety of backgrounds and can have widely differing beliefs. It might be helpful to be aware that patients who hold more anti-choice beliefs are likely to experience more anxiety and guilt related to their abortion than pro-choice patients do.     

Primary blood TSH/back up TSH measurements: an improved approach for neonatal thyroid screening

Objective: Neonatal hypothyroidism is one of the most common endocrine disorders related to mental impairment and growth retardation in newborns. In many countries, the neonatal thyroid screening programs are performed for rapid diagnosis and treatment of hypothyroidism. The major aim of this investigation was to improve the thyroid screening program using primary blood TSH/back up TSH measurements as some patients are missed due to technical and human errors. Methods: A total of 9,118neonates were evaluated on the protocol. On top of that, the quality control procedures were applied to improve the sampling technique and the laboratory results. Results: Three missed neonates by current programs using the cutoff point more than 20 mU/l for blood TSH were found by our approach. Conclusion: Results showed that the programs based on the primary blood TSH/back up TSH measurements improve the thyroid screening results. J. Clin. Lab. Anal. 25:61–63, 2011. © 2011 Wiley‐Liss, Inc.     

Foot Technology, Part 1 of 2: Assessing Postural Control and Postural Control Strategy in Diabetes Patients Using Innovative and Wearable Technology

Introduction

Currently, diagnosis of patients with postural instability relies on a rudimentary clinical examination. This article suggests an innovative, portable, and cost-effective prototype to evaluate balance control objectively.

Methods

The proposed system uses low-cost, microelectromechanical sensor, body-worn sensors (BalanSens™) to measure the motion of ankle and hip joints in three dimensions. We also integrated resulting data into a two-link biomechanical model of the human body for estimating the two-dimensional sway of the center of mass (COM) in anterior–posterior (AP) and medial–lateral (ML) directions. A new reciprocal compensatory index (RCI) was defined to quantify postural compensatory strategy (PCS) performance. To validate the accuracy of our algorithms in assessing balance, we investigated the two-dimensional sway of COM and RCI in 21 healthy subjects and 17 patients with diabetic peripheral neuropathic (DPN) complications using the system just explained. Two different conditions were examined: eyes open (EO) and eyes closed (EC) for duration of at least 30 seconds. Results were compared with center of pressure sway (COP) as measured by a pressure platform (Emed-x system, Novel Inc., Germany). To further investigate the contribution of the somatosensory (SOM) feedback to balance control, healthy subjects performed EO and EC trials while standing on both a rigid and a foam surface.

Results

A relatively high correlation was observed between COM measured using BalanSens and COP measured using the pressure platform (r = 0.92). Results demonstrated that DPN patients exhibit significantly greater COM sway than healthy subjects for both EO and EC conditions (p < 0.005). The difference becomes highly pronounced while eyes are closed (197 ± 44 cm² vs 68 ± 56 cm²). Furthermore, results showed that PCS assessed using RCI is significantly better in healthy subjects compared to DPN subjects for both EO and EC conditions, as well as in both ML and AP directions (p < 0.05). Alteration in SOM feedback in healthy subjects resulted in diminished RCI values that were similar to those seen in DPN subjects (p > 0.05).

Discussion/Conclusion

This study suggested an innovative system that enables the investigation of COM as well as postural control compensatory strategy in humans. Results suggest that neuropathy significantly impacts PCS.