A phase 2 study of polatuzumab vedotin + bendamustine + rituximab in relapsed/refractory diffuse large B-cell lymphoma

Polatuzumab vedotin (pola) is a CD79b-targeted antibody-drug conjugate delivering a potent antimitotic agent (monomethyl auristatin E) to B cells. This was an open-label, single-arm study of pola 1.8 mg/kg, bendamustine 90 mg/m², rituximab 375 mg/m² (pola + BR) Q3W for up to six cycles in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who received ≥1 prior line of therapy and were ineligible for autologous stem cell transplantation (ASCT) or experienced treatment failure with prior ASCT. Primary endpoint was complete response rate (CRR) at the end of the treatment (EOT) by positron emission tomography–computed tomography (PET-CT) using modified Lugano Response Criteria. Secondary endpoints included efficacy, safety, and pharmacokinetics. Thirty-five patients (median age 71 [range 46-86] years) were enrolled. Twenty-three (66%) patients had refractory disease, and 23 (66%) had ≥2 prior lines of therapy. At a median follow-up of 5.4 (0.7-11.9) months, patients received a median of five treatment cycles. CRR was 34.3% (95% confidence interval [CI] 19.1-52.2) at EOT. Overall response rate was 42.9% at EOT, and median progression-free survival was 5.2 months (95% CI 3.6-not evaluable). Median overall survival was not reached. No fatal adverse events (AEs) were observed. Grade 3-4 AEs were mainly hematological: anemia (37%), neutropenia (31%), white blood cell count decreased (23%), thrombocytopenia/platelet count decreased/neutrophil count decreased (20% each), and febrile neutropenia (11%). Grade 1-2 peripheral neuropathy (PN; sensory and/or motor) was reported in 14% of patients; there were no ≥grade 3 PN events. This study (JapicCTI-184048) demonstrated the efficacy and safety of pola + BR in Japanese patients with R/R DLBCL who were ineligible for ASCT.     

Acceptability of Elderly Cancer Patients and Tolerance to COVID-19 Vaccination in the Brittany Region<br/>L’acceptabilité du Patient Âgé Porteur de Cancer et la Tolérance à la Vaccination Anti-COVID-19 dans la Région Bretagne

Context: Since January 2021, vaccination for COVID-19 has been made possible in France for people aged 75 and over. Patients suffering from a cancer disease are part of a group at risk to develop severe complications to COVID-19. Method: The « Unité de coordination en Onco-Gériatrie région Bretagne » (the Brittany This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Coordinating Unit in Onco-Geriatrics) has wished to set up an inquest about the acceptability and the tolerance to COVID-19 vaccination by old-aged patients suffering from cancer in the Brittany region. Results: The study has been carried out between May 1, 2021 and August 31, 2021 in 7 Breton centers. 50 patients have been included in the study with an average age of 84 (72-93). At the time of inclusion, 43 patients had already been vaccinated (80% having had 2 injections and 8% only one). Among them, 86% have declared they had had a very good tolerance to the first injection of the vaccine, and 90% to the second injection. 12% of the patients had not been vaccinated. Conclusion: Overall, in our study, old-aged patients suffering from cancer haven’t been reluctant to the antiCOVID-19 vaccination and have shown a very good tolerance to these vaccines. However, seen the profile of these patients and the period of inclusion, the number of patients showing a complete vaccinal outline should have been more consistent, indeed even total.

RÉSUMÉ
Contexte: Depuis le 25 janvier 2021, la vaccination de la COVID-19 a pu être réalisée en France auprès des personnes âgées de 75 ans et plus. Les patients souffrant d’une maladie cancéreuse font partie des groupes à risque de développer des complications sévères à la COVID-19. Méthode: L’Unité de Coordination en Onco-Gériatrie région Bretagne a souhaité mettre en place une enquête sur l’acceptabilité du patient âgé porteur de cancer et sur la tolérance à la vaccination anti-COVID 19 dans la région Bretagne. Résultats: L’étude a été réalisée entre le 1^er mai 2021 et le 31 août 2021 dans 7 centres bretons. 50 patients ont été inclus avec un âge médian de 84 ans (72–93). 43 patients au moment de l’inclusion avaient été vaccinés (80% ayant eu 2 injections et 8% une seule injection). Parmi eux, 86% ont déclaré avoir eu une très bonne tolérance à la première injection du vaccin et 90 % à la seconde injection. 12% des patients n’étaient pas vaccinés. Conclusion: Globalement, dans notre étude, les patients âgés porteurs de cancer ne présentaient pas de réticence à lavaccination anti-COVID19 et ont eu une très bonne tolérance à ces vaccins. Cependant, au vu du profil de ces patients et de la période d’inclusion, le nombre de patients présentant un schéma vaccinal complet aurait pu être plus conséquent.     

Pre-transplant Screening for Non-HLA Antibodies: Who should be Tested?

Retrospective studies of angiotensin II type 1 receptor antibodies (AT1R-Ab) and anti-endothelial cell antibodies (AECA) have linked these antibodies to allograft injury. Because rising healthcare costs dictate judicious use of laboratory testing, we sought to define characteristics of kidney transplant recipients who may benefit from screening for non-HLA antibodies. Kidney recipients transplanted between 2011 and 2016 at Johns Hopkins, were evaluated for AT1R-Ab and AECA. Pre-transplant antibody levels were compared to clinical and biopsy indications of graft dysfunction. Biopsies were graded using the Banff' 2009–2013 criteria. AT1R-Ab and AECA were detected using ELISA and endothelial cell crossmatches, respectively. AT1R-Ab levels were higher in patients who were positive for AECAs. Re-transplanted patients (p?<?0.0001), males (p?=?0.008) and those with FSGS (p?=?0.04) and younger (p?=?0.04) at time of transplantation were more likely to be positive for AT1R-Ab prior to transplantation. Recipients who were positive for AT1R-Ab prior to transplantation had increases in serum creatinine within 3?months post-transplantation (p?<?0.0001) and developed abnormal biopsies earlier than did AT1R-Ab negative patients (126?days versus 368?days respectively; p?=?0.02). Defining a clinical protocol to identify and preemptively treat patients at risk for acute rejection with detectable non-HLA antibodies is an important objective for the transplant community.     

IL-1β induces expression of costimulatory molecules and cytokines but not immune feedback regulators in dendritic cells

Dendritic cells play an important role in the initiation of immune reactions. Due to their high capacity to prime T-cell responses, the activation of dendritic cells must be tightly controlled. Because Interleukin-1β (IL-1β) is a key player in autoinflammatory diseases, we compared the ability of IL-1β to activate human dendritic cells and induce immune-regulatory molecules versus the effects induced by pathogen-derived stimuli.Upon activation with either IL-1β or microbial stimuli, monocyte-derived dendritic cells showed enhanced expression of costimulatory molecules, increased secretion of chemokines and cytokines, and the ability to activate T cells. In contrast, immune-feedback molecules, including PD-L1, IL-1RA, IL-10 and SOCS1, were exclusively upregulated in response to microbial stimuli, whereas IL-1β treatment had no inducing effect on them. Thus, the limited capacity of IL-1β to induce potential feedback inhibitors may support its key etiologic role in chronic inflammation and autoinflammatory responses.     

The many ways to mend your liver: A critical appraisal

In the latter half of the 20th century, our understanding of mammalian liver regeneration was shaped by the manner of compensatory hyperplasia occurring after a partial rat liver resection. This response involves almost all hepatocytes and thus is unlikely to be the outcome of the multiple cycling of a small stem cell population. It was most intense in the outer third of lobule, the location closest to the afferent arterial blood supply. With the advent of heritable genetic labelling techniques, usually applied to mice, hitherto unrecognized hepatocytes with clonogenic potential have been discovered, contributing to homoeostatic renewal and/or regenerative responses after tissue loss. This review combines observations from cell lineage tracing studies with other data to summarize the Four proposed anatomical locations for hepatocyte stem cells: the periportal zone, the pericentral zone, a randomized distribution and finally within the intrahepatic biliary tree. As in other endodermal‐derived tissues, it appears that there are both homoeostatic stem cells and regenerative stem cells, while some normally homoeostatic stem cells can become more active to boost regeneration.     

Different involvement of the MAPK family in inflammatory regulation in human pulmonary microvascular endothelial cells stimulated with LPS and IFN-γ

Pulmonary endothelial injury is central in the pathogenesis of acute lung injury (ALI). The MAPK signaling cascades are generally thought to be involved in the molecular mechanism underlying the ALI development, but their roles in pulmonary endothelial injury is poorly understood. We thus examined the involvement of the MAPK family member in inflammatory responses of human pulmonary microvascular endothelial cells (HPMVECs) stimulated with LPS and IFN-γ. HPMVECs were found to exhibit the upregulation of expression of Toll-like receptor 4 by IFN-γ, resulting in potentiation of inflammatory cytokine release by LPS stimulation. All MAPKs, ERK1/2, JNK, and p38, were activated by simultaneous stimulation with LPS/IFN-γ. JNK activation in cells stimulated with LPS/IFN-γ was significantly potentiated by the two different p38 inhibitors, SB203580 and RWJ67657, suggesting the negative regulation of JNK activation by p38 in HPMVECs. The mRNA and protein expression levels of ICAM-1 were eliminated by the JNK inhibitor, suggesting that ICAM-1 expression is positively regulated by JNK. The p38 inhibitor significantly enhanced ICAM-1 expression. ERK1/2 activation was not responsible for the LPS/IFN-γ-induced ICAM-1 upregulation in HPMVECs. THP-1 monocyte adhesion to HPMVECs under LPS/IFN-γ stimulation was inhibited by the JNK inhibitor and enhanced by the p38 inhibitor. We conclude that, in HPMVECs stimulated with LPS/IFN-γ, JNK mediates ICAM-1 expression that can facilitate leukocyte adherence and transmigration, while p38 MAPK negatively regulates the upregulation of ICAM-1 through inhibition of JNK activation.     

全反式维甲酸对人类多发性骨髓瘤OPM-2细胞系抗增殖作用的研究

观察了全反式维甲酸(ATRA)对人类多发性骨髓瘤(MM)OPM-2细胞系作用,~3H-TdR掺入法显示ATRA使S及G_2/M期细胞标记指数下降,提示G_1→S期细胞增殖受抑制。抑制程度与其浓度呈依赖关系。当ATRA浓度在≤(1-2)×10~(-8)mol/L有时反有刺激生长的作用。外源性IL-6(rhIL-6)能刺激OPM-2细胞克隆生长,抗IL-6单克隆抗体(McAb)可抑制其生长,rhIL-6不能逆转ATRA致OPM-2细胞生长抑制,提示OPM-2细胞能自分泌IL-6。~(125)I标记IL-6测得细胞表面IL-6受体(IL-6R)密度降低及亲和性下降,RT-PCR测得IL-6RmRNA下降,但gp130 mRNA表达无改变,在培养上清液测不出IL-6活性。这进一步证明ATRA对OPM-2细胞增殖的抑制作用是通过下调IL-6R及抑制瘤细胞自分泌IL-6双重作用而实现的。本实验提出ATRA有可能作为一种新的抗增殖药物治疗MM及其它自/旁分泌IL-6依赖性生长特性的肿瘤。     

Enabling Task-Specific Volitional Motor Functions via Spinal Cord Neuromodulation in a Human With Paraplegia

We report a case of chronic traumatic paraplegia in which epidural electrical stimulation (EES) of the lumbosacral spinal cord enabled (1) volitional control of task-specific muscle activity, (2) volitional control of rhythmic muscle activity to produce steplike movements while side-lying, (3) independent standing, and (4) while in a vertical position with body weight partially supported, voluntary control of steplike movements and rhythmic muscle activity. This is the first time that the application of EES enabled all of these tasks in the same patient within the first 2 weeks (8 stimulation sessions total) of EES therapy.     

Suppression of pain and the R2 component of the blink reflex during optokinetic stimulation

The effect of exposure to a rotating optokinetic drum on the electrically evoked blink reflex was investigated in 20 healthy volunteers. Pain ratings and the area under the curve of the R2 component of the blink reflex to innocuous and nociceptive trigeminal stimulation decreased substantially during and after optokinetic stimulation. At low shock intensities, R2 decreased most during optokinetic stimulation in subjects who did not develop symptoms of motion sickness. In contrast, during the recovery period after optokinetic stimulation, suppression of R2 to moderate and intense stimuli was greatest in the most nauseated subjects. These findings suggest that a mechanism that suppresses symptoms of motion sickness during sensory conflict also inhibits activity in wide dynamic range neurones in the trigeminal nucleus caudalis. Nausea in the absence of sensory conflict may inhibit R2 to intense electrical stimulation by provoking diffuse noxious inhibitory controls.     

An improved assay with 4-(2-thiazolylazo)-resorcinol for non-esterified fatty acids in biological fluids

A simple and rapid colorimetric assay for non-esterified fatty acids (NEFA) was developed employing extraction of samples with 0.1 mol/l glycine (pH 2.7) and methoxyethanol : butyl ether, and formation of a copper-fatty acid soap detected with 4-(2-thiazolylazo)-resorcinol. The method developed is sensitive enough to detect as little as 11 nmol/0.25 ml sample. Results are not affected by marked molar excesses of phospholipids, cholesterol, cholesterol esters, triglycerides, bilirubin, or lactate. Recovery of palmitate in the extract averages 94.2 +/- 3.2% (S.D.) and other long chain fatty acids are recovered equally. The copper-NEFA-indicator complex formed is stable. Extracted samples can be stored for as long as 2 weeks without appreciable changes in measured NEFA content. The method developed is suitable for both manual and semi-automated procedures for determining NEFA content in biological fluids.