Standard therapy for advanced endometrial cancer after failure of platinum-based chemotherapy remains unclear.
In this phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced ...endometrial cancer who had previously received at least one platinum-based chemotherapy regimen to receive either lenvatinib (20 mg, administered orally once daily) plus pembrolizumab (200 mg, administered intravenously every 3 weeks) or chemotherapy of the treating physician's choice (doxorubicin at 60 mg per square meter of body-surface area, administered intravenously every 3 weeks, or paclitaxel at 80 mg per square meter, administered intravenously weekly with a cycle of 3 weeks on and 1 week off). The two primary end points were progression-free survival as assessed on blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1, and overall survival. The end points were evaluated in patients with mismatch repair-proficient (pMMR) disease and in all patients. Safety was also assessed.
A total of 827 patients (697 with pMMR disease and 130 with mismatch repair-deficient disease) were randomly assigned to receive lenvatinib plus pembrolizumab (411 patients) or chemotherapy (416 patients). The median progression-free survival was longer with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 6.6 vs. 3.8 months; hazard ratio for progression or death, 0.60; 95% confidence interval CI, 0.50 to 0.72; P<0.001; overall: 7.2 vs. 3.8 months; hazard ratio, 0.56; 95% CI, 0.47 to 0.66; P<0.001). The median overall survival was longer with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 17.4 vs. 12.0 months; hazard ratio for death, 0.68; 95% CI, 0.56 to 0.84; P<0.001; overall: 18.3 vs. 11.4 months; hazard ratio, 0.62; 95% CI, 0.51 to 0.75; P<0.001). Adverse events of grade 3 or higher occurred in 88.9% of the patients who received lenvatinib plus pembrolizumab and in 72.7% of those who received chemotherapy.
Lenvatinib plus pembrolizumab led to significantly longer progression-free survival and overall survival than chemotherapy among patients with advanced endometrial cancer. (Funded by Eisai and Merck Sharp and Dohme a subsidiary of Merck; Study 309-KEYNOTE-775 ClinicalTrials.gov number, NCT03517449.).
Use of organs from donors testing positive for hepatitis B virus (HBV) may safely expand the donor pool. The American Society of Transplantation convened a multidisciplinary expert panel that ...reviewed the existing literature and developed consensus recommendations for recipient management following the use of organs from HBV positive donors. Transmission risk is highest with liver donors and significantly lower with non‐liver (kidney and thoracic) donors. Antiviral prophylaxis significantly reduces the rate of transmission to liver recipients from isolated HBV core antibody positive (anti‐HBc+) donors. Organs from anti‐HBc+ donors should be considered for all adult transplant candidates after an individualized assessment of the risks and benefits and appropriate patient consent. Indefinite antiviral prophylaxis is recommended in liver recipients with no immunity or vaccine immunity but not in liver recipients with natural immunity. Antiviral prophylaxis may be considered for up to 1 year in susceptible non‐liver recipients but is not recommended in immune non‐liver recipients. Although no longer the treatment of choice in patients with chronic HBV, lamivudine remains the most cost‐effective choice for prophylaxis in this setting. Hepatitis B immunoglobulin is not recommended.
A multidisciplinary panel of experts from AST reviews the literature regarding the use of organs from donors who test positive for hepatitis B virus, and provides recommendations for their use in liver, kidney, heart, and lung transplant recipients.
Mycobacterium tuberculosis is a ubiquitous organism that infects one‐third of the world's population. In previous decades, access to organ transplantation was restricted to academic medical centers ...in more developed, low tuberculosis (TB) incidence countries. Globalization, changing immigration patterns, and the expansion of sophisticated medical procedures to medium and high TB incidence countries have made tuberculosis an increasingly important posttransplant infectious disease. Tuberculosis is now one of the most common bacterial causes of solid‐organ transplant donor‐derived infection reported in transplant recipients in the United States. Recognition of latent or undiagnosed active TB in the potential organ donor is critical to prevent emergence of disease in the recipient posttransplant. Donor‐derived tuberculosis after transplantation is associated with significant morbidity and mortality, which can best be prevented through careful screening and targeted treatment. To address this growing challenge and provide recommendations, an expert international working group was assembled including specialists in transplant infectious diseases, transplant surgery, organ procurement and TB epidemiology, diagnostics and management. This working group reviewed the currently available data to formulate consensus recommendations for screening and management of TB in organ donors.
This consensus report reviews current epidemiology and diagnostic testing for the identification of latent and active tuberculosis infection in deceased and living organ transplant donors and provides recommendations for the management of transplant donors and recipients, as well as suggested areas for future research.
Nucleic acid testing (NAT) for HIV, HBV and HCV shortens the time between infection and detection by available testing. A group of experts was selected to develop recommendations for the use of NAT ...in the HIV/HBV/HCV screening of potential organ donors. The rapid turnaround times needed for donor testing and the risk of death while awaiting transplantation make organ donor screening different from screening blood‐or tissue donors. In donors with no identified risk factors, there is insufficient evidence to recommend routine NAT, as the benefits of NAT may not outweigh the disadvantages of NAT especially when false‐positive results can lead to loss of donor organs. For donors with identified behavioral risk factors, NAT should be considered to reduce the risk of transmission and increase organ utilization. Informed consent balancing the risks of donor‐derived infection against the risk of remaining on the waiting list should be obtained at the time of candidate listing and again at the time of organ offer. In conclusion, there is insufficient evidence to recommend universal prospective screening of organ donors for HIV, HCV and HBV using current NAT platforms. Further study of viral screening modalities may reduce disease transmission risk without excessive donor loss.
This consensus report outlines several issues surrounding optimal testing of potential donors for HIV, HCV and HBV and includes suggestions regarding the use of Nucleic Acid Testing, its advantages and disadvantages, and areas for further research.
Recent molecular cloning studies have identified four distinct members (NHE-1,-2,-3,-4) of the Na/H exchanger gene family that are expressed in a tissue-specific pattern. To examine some of their ...functional properties, full-length cDNAs for two of these isoforms, rat NHE-1 and NHE-3, were stably transfected in Na/H exchanger-deficient Chinese hamster ovary cells (AP-1) and assayed for transport activity by measuring amiloride-inhibitable H(+)-activated 22Na+ influx. Pharmacological analyses revealed that the activity of NHE-1 was substantially more sensitive to inhibition by amiloride and its analogues than NHE-3. Similarly, both isoforms were differentially sensitive to inhibition by cimetidine, clonidine, and harmaline; agents also known to inhibit the activity of the Na/H exchanger. Their rank order of potency for NHE-1 was cimetidine > harmaline > or = clonidine whereas the reverse order was observed for NHE-3. The isoforms were also distinguished by their kinetic properties. While the extracellular Na+ (Na+o) dependence of both isoforms showed simple, saturating Michaelis-Menten kinetics, NHE-1 exhibited a 2-fold lower affinity for Na+o than NHE-3, with apparent KNa values of 10.0 +/- 1.4 and 4.7 +/- 0.6 mM, respectively. In contrast to Na+o, intracellular H+ (H+i) activated both isoforms by a positive cooperative mechanism. However, NHE-1 had a 2-fold higher apparent affinity for H+i compared to NHE-3, with half-maximal activation values of pK 6.75 +/- 0.05 and 6.45 +/- 0.08, respectively. Other external cations also interacted with both exchangers. Li+o and H+o inhibited 22Na+ influx by both isoforms with similar kinetics. In contrast, K+o inhibited 22Na+ influx by NHE-1, but had no effect on NHE-3. Thus NHE-1 and -3 exhibited diverse functional properties when expressed in the same cell type. Furthermore, the functional properties associated with NHE-3 closely mimicked those described for the apical membrane Na/H exchanger of renal proximal tubules, suggesting that these proteins are molecularly identical.
In the global phase 3 Study 309/KEYNOTE-775 (NCT03517449) at the first interim analysis, lenvatinib+pembrolizumab significantly improved progression-free survival (PFS), overall survival (OS), and ...objective response rate (ORR) versus treatment of physician's choice chemotherapy (TPC) in patients with previously treated advanced/recurrent endometrial cancer (EC). This exploratory analysis evaluated outcomes in patients enrolled in East Asia at the time of prespecified final analysis.
Women ≥18 years with histologically confirmed advanced, recurrent, or metastatic EC with progressive disease after 1 platinum-based chemotherapy (2 if 1 given in neoadjuvant/adjuvant setting) were enrolled. Patients were randomized 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks (≤35 cycles) or TPC (doxorubicin or paclitaxel). Primary endpoints were PFS per RECIST v1.1 by blinded independent central review and OS. No alpha was assigned for this subgroup analysis.
Among 155 East Asian patients (lenvatinib+pembrolizumab, n=77; TPC, n=78), median follow-up time (data cutoff: March 1, 2022) was 34.3 (range, 25.1-43.0) months. Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS (lenvatinib+pembrolizumab vs. TPC) were 0.74 (0.49-1.10) and 0.64 (0.44-0.94) in the mismatch repair proficient (pMMR) and all-comer populations, respectively. HRs (95% CI) for OS were 0.68 (0.45-1.02) and 0.61 (0.41-0.90), respectively. ORRs were 36% with lenvatinib+pembrolizumab and 22% with TPC (pMMR) and 39% and 21%, respectively (all-comers). Treatment-related adverse events occurred in 97% and 96% (grade 3-5, 74% and 72%), respectively.
Lenvatinib+pembrolizumab provided clinically meaningful benefit with manageable safety compared with TPC, supporting its use in East Asian patients with previously treated advanced/recurrent EC.
ClinicalTrials.gov Identifier: NCT03517449.
Axon degeneration is a critical pathological feature of many neurodegenerative diseases. Misregulation of local axonal ion homeostasis has been recognized as an important yet understudied mechanism ...for axon degeneration. Here we report a chemically induced, recessive mouse mutation, vacillator (vac), which causes ataxia and concomitant axon degeneration of cerebellar Purkinje cells. By positional cloning, we identified vac as a point mutation in the calcineurin-like EF hand protein 1 (Chp1) gene that resulted in the production of mutant CHP1 isoforms with an amino acid substitution in a functional EF-hand domain or a truncation of this motif by aberrant splicing and significantly reduced protein levels. CHP1 has been previously shown to interact with the sodium hydrogen exchanger 1 (NHE1), a major regulator of intracellular pH. We demonstrated that CHP1 assists in the full glycosylation of NHE1 that is necessary for the membrane localization of this transporter and that truncated isoforms of CHP1 were defective in stimulating NHE1 biosynthetic maturation. Consistent with this, membrane localization of NHE1 at axon terminals was greatly reduced in Chp1-deficient Purkinje cells before axon degeneration. Furthermore, genetic ablation of Nhe1 also resulted in Purkinje cell axon degeneration, pinpointing the functional convergence of the two proteins. Our findings clearly demonstrate that the polarized presynaptic localization of NHE/CHP1 is an important feature of neuronal axons and that selective disruption of NHE1-mediated proton homeostasis in axons can lead to degeneration, suggesting that local regulation of pH is pivotal for axon survival.
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