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Bortezomib, lenalidomide, and dexamethasone (VRd) is a standard therapy for newly diagnosed multiple myeloma. Carfilzomib, a next-generation proteasome inhibitor, in combination with lenalidomide and dexamethasone (KRd), has shown promising efficacy in phase 2 trials and might improve outcomes compared with VRd. We aimed to assess whether the KRd regimen is superior to the VRd regimen in the treatment of newly diagnosed multiple myeloma in patients who were not being considered for immediate autologous stem-cell transplantation (ASCT). In this multicentre, open-label, phase 3, randomised controlled trial (the ENDURANCE trial; E1A11), we recruited patients aged 18 years or older with newly diagnosed multiple myeloma who were ineligible for, or did not intend to have, immediate ASCT. Participants were recruited from 272 community oncology practices or academic medical centres in the USA. Key inclusion criteria were the absence of high-risk multiple myeloma and an Eastern Cooperative Oncology Group performance status of 0–2. Enrolled patients were randomly assigned (1:1) centrally by use of permuted blocks to receive induction therapy with either the VRd regimen or the KRd regimen for 36 weeks. Patients who completed induction therapy were then randomly assigned (1:1) a second time to either indefinite maintenance or 2 years of maintenance with lenalidomide. Randomisation was stratified by intent for ASCT at disease progression for the first randomisation and by the induction therapy received for the second randomisation. Allocation was not masked to investigators or patients. For 12 cycles of 3 weeks, patients in the VRd group received 1·3 mg/m2 of bortezomib subcutaneously or intravenously on days 1, 4, 8, and 11 of cycles 1–8, and day 1 and day 8 of cycles nine to twelve, 25 mg of oral lenalidomide on days 1–14, and 20 mg of oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. For nine cycles of 4 weeks, patients in the KRd group received 36 mg/m2 of intravenous carfilzomib on days 1, 2, 8, 9, 15, and 16, 25 mg of oral lenalidomide on days 1–21, and 40 mg of oral dexamethasone on days 1, 8, 15, and 22. The coprimary endpoints were progression-free survival in the induction phase, and overall survival in the maintenance phase. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of their assigned treatment. The trial is registered with ClinicalTrials.gov, NCT01863550. Study recruitment is complete, and follow-up of the maintenance phase is ongoing. Between Dec 6, 2013, and Feb 6, 2019, 1087 patients were enrolled and randomly assigned to either the VRd regimen (n=542) or the KRd regimen (n=545). At a median follow-up of 9 months (IQR 5–23), at a second planned interim analysis, the median progression-free survival was 34·6 months (95% CI 28·8–37·8) in the KRd group and 34·4 months (30·1–not estimable) in the VRd group (hazard ratio [HR] 1·04, 95% CI 0·83–1·31; p=0·74). Median overall survival has not been reached in either group. The most common grade 3–4 treatment-related non-haematological adverse events included fatigue (34 [6%] of 527 patients in the VRd group vs 29 [6%] of 526 in the KRd group), hyperglycaemia (23 [4%] vs 34 [6%]), diarrhoea (23 [5%] vs 16 [3%]), peripheral neuropathy (44 [8%] vs four [<1%]), dyspnoea (nine [2%] vs 38 [7%]), and thromboembolic events (11 [2%] vs 26 [5%]). Treatment-related deaths occurred in two patients (<1%) in the VRd group (one cardiotoxicity and one secondary cancer) and 11 (2%) in the KRd group (four cardiotoxicity, two acute kidney failure, one liver toxicity, two respiratory failure, one thromboembolic event, and one sudden death). The KRd regimen did not improve progression-free survival compared with the VRd regimen in patients with newly diagnosed multiple myeloma, and had more toxicity. The VRd triplet regimen remains the standard of care for induction therapy for patients with standard-risk and intermediate-risk newly diagnosed multiple myeloma, and is a suitable treatment backbone for the development of combinations of four drugs. US National Institutes of Health, National Cancer Institute, and Amgen.

The XPO1 inhibitor selinexor was recently approved in relapsed/refractory DLBCL patients but only demonstrated modest anti-DLBCL efficacy, prompting us to investigate the prognostic effect of XPO1 in DLBCL patients and the rational combination therapies in high-risk DLBCL. High XPO1 expression (XPO1 high ) showed significant adverse prognostic impact in 544 studied DLBCL patients, especially in those with BCL2 overexpression. Therapeutic study in 30 DLBCL cell lines with various molecular and genetic background found robust cytotoxicity of selinexor, especially in cells with BCL2- rearranged ( BCL2 -R + ) DLBCL or high-grade B-cell lymphoma with MYC / BCL2 double-hit (HGBCL-DH). However, expression of mutant (Mut) p53 significantly reduced the cytotoxicity of selinexor in overall cell lines and the BCL2 -R and HGBCL-DH subsets, consistent with the favorable impact of XPO1 high observed in Mut-p53-expressing patients. The therapeutic effect of selinexor in HGBCL-DH cells was significantly enhanced when combined with a BET inhibitor INCB057643, overcoming the drug resistance in Mut-p53-expressing cells. Collectively, these data suggest that XPO1 worsens the survival of DLBCL patients with unfavorable prognostic factors such as BCL2 overexpression and double-hit, in line with the higher efficacy of selinexor demonstrated in BCL2 -R + DLBCL and HGBCL-DH cell lines. Expression of Mut-p53 confers resistance to selinexor treatment, which can be overcome by combined INCB057643 treatment in HGBCL-DH cells. This study provides insight into the XPO1 significance and selinexor efficacy in DLBCL, important for developing combination therapy for relapsed/refractory DLBCL and HGBCL-DH.

Background Reoperations occur frequently after initial lumpectomy for breast cancer. The authors hypothesized that the receipt of neoadjuvant chemotherapy (NAC) is associated with fewer reoperations. Methods The association between timing of chemotherapy and reoperation rates (ROR) after lumpectomy was investigated for patients with stages 1–3 breast cancer in the National Cancer Database (NCDB) from 2010 to 2013 by multivariable logistic regression modeling. Then propensity score-matching was performed. Results The unadjusted ROR for 71,627 stages 1–3 patients was 11.4% for those who had NAC compared with 20.3% for those who had postoperative chemotherapy ( p < 0.001) (odds ratio [OR] 0.53; 95% confidence interval [CI] 0.49–0.57; p < 0.001). The ORs for the reoperations performed for patients with stages 1, 2, and 3 cancers who received NAC were respectively 0.65 (95% CI 0.56–0.75), 0.50 (95% CI 0.45–0.56), and 0.27 (95% CI 0.19–0.38) The p values for all were lower than 0.001. Conclusion For a population of patients receiving chemotherapy, the receipt of chemotherapy before instead of after surgery was associated with fewer reoperations after initial lumpectomy for breast cancer.

Multiple studies have demonstrated that diffuse large B-cell lymphoma (DLBCL) can be divided into subgroups based on their biology; however, these biological subgroups overlap clinically. Using machine learning, we developed an approach to stratify patients with DLBCL into four subgroups based on survival characteristics. This approach uses data from the targeted transcriptome to predict these survival subgroups. Using the expression levels of 180 genes, our model reliably predicted the four survival subgroups and was validated using independent groups of patients. Multivariate analysis showed that this patient stratification strategy encompasses various biological characteristics of DLBCL, and only TP53 mutations remained an independent prognostic biomarker. This novel approach for stratifying patients with DLBCL, based on the clinical outcome of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone therapy, can be used to identify patients who may not respond well to these types of therapy, but would otherwise benefit from alternative therapy and clinical trials.

The purpose of this study was to determine if receipt of chemotherapy was associated with utilization of the 21-gene recurrence score assay (RS assay) or with recurrence score (RS) in eligible patients. Using the National Cancer Data Base (NCDB), we identified female patients eligible for RS assay based on National Comprehensive Cancer Network (NCCN) guidelines: age 18–70, ER-positive and HER2-negative early-stage breast cancer diagnosed during 2010–2013. We excluded patients not meeting testing guidelines. Inclusion required result of RS in patients who underwent RS assay and status for receipt of chemotherapy. Multivariable logistic regression models and propensity matched analysis were used to determine associations between RS assay and RS with receipt of chemotherapy. Among 129,765 patients who were eligible, 74,778 underwent RS assay and had results available. Of these, 59.5 % (44,505) had low-risk, 32.0 % (23,920) had intermediate-risk, and 8.5 % (6353) had high-risk RS. Patients with intermediate- and high-risk RS were more likely to receive chemotherapy [OR 12.9 (CI 12.2–13.6), p  <0.001 and OR 87.2 (CI 79.6–95.6), p  <0.0001], respectively. In both low- and intermediate-risk groups, increasing RS score was significantly associated with increasing odds of receiving chemotherapy [OR 1.10 (CI 1.09–1.12), p <0.0001 and OR 1.26 (CI 1.25–1.27), p <0.0001, respectively, for each point increase in RS]. Receipt of chemotherapy was more likely in patients who did not undergo RS assay compared to those who did, OR 1.21 (CI 1.175–1.249) p  <0.0001. The utilization of RS assay and the RS were both strongly associated with chemotherapy receipt. Patients eligible for chemotherapy, based on NCCN criteria, were more likely to receive chemotherapy if they did not undergo RS assay or they had a high RS.

Background Anti-PD-1 and PD-L1 (collectively PD-[L]1) therapies are approved for many advanced solid tumors. Biomarkers beyond PD-L1 immunohistochemistry, microsatellite instability, and tumor mutation burden (TMB) may improve benefit prediction. Methods Using treatment data and genomic and transcriptomic tumor tissue profiling from an observational trial (NCT03061305), we developed Immunotherapy Response Score (IRS), a pan-tumor predictive model of PD-(L)1 benefit. IRS real-world progression free survival (rwPFS) and overall survival (OS) prediction was validated in an independent cohort of trial patients. Results Here, by Cox modeling, we develop IRS—which combines TMB with CD274 , PDCD1 , ADAM12 and TOP2A quantitative expression—to predict pembrolizumab rwPFS (648 patients; 26 tumor types; IRS-High or -Low groups). In the 248 patient validation cohort (248 patients; 24 tumor types; non-pembrolizumab PD-[L]1 monotherapy treatment), median rwPFS and OS are significantly longer in IRS-High vs. IRS-Low patients (rwPFS adjusted hazard ratio [aHR] 0.52, p = 0.003; OS aHR 0.49, p = 0.005); TMB alone does not significantly predict PD-(L)1 rwPFS nor OS. In 146 patients treated with systemic therapy prior to pembrolizumab monotherapy, pembrolizumab rwPFS is only significantly longer than immediately preceding therapy rwPFS in IRS-High patients (interaction test p = 0.001). In propensity matched lung cancer patients treated with first-line pembrolizumab monotherapy or pembrolizumab+chemotherapy, monotherapy rwPFS is significantly shorter in IRS-Low patients, but is not significantly different in IRS-High patients. Across 24,463 molecularly-evaluable trial patients, 7.6% of patients outside of monotherapy PD-(L)1 approved tumor types are IRS-High/TMB-Low. Conclusions The validated, predictive, pan-tumor IRS model can expand PD-(L)1 monotherapy benefit outside currently approved indications. Plain language summary Therapies activating the immune system (checkpoint inhibitors) have revolutionized the treatment of patients with advanced cancer, however new molecular tests may better identify patients who could benefit. Using treatment data and clinical molecular test results, we report the development and validation of Immunotherapy Response Score (IRS) to predict checkpoint inhibitor benefit. Across patients with more than 20 advanced cancer types, IRS better predicted checkpoint inhibitor benefit than currently available tests. Data from >20,000 patients showed that IRS identifies ~8% of patients with advanced cancer who may dramatically benefit from checkpoint inhibitors but would not receive them today based on currently available tests. Our approach may help clinicians to decide which patients should receive checkpoint inhibitors to treat their disease. Tomlins et al. develop an Immunotherapy Response Score (IRS) to predict clinical benefit from checkpoint inhibition across solid tumors. IRS integrates TMB and gene expression, is evaluable from FFPE material, and is predictive for real-world progression-free survival and overall survival in patients receiving PD-1/PD-L1 blockade therapy.

Primary testicular (PT) diffuse large B-cell lymphoma (DLBCL) is a rare and aggressive lymphoma with distinct clinical and molecular characteristics. To identify prognostic biomarkers in PT-DLBCL, in this study we analyzed DNA and RNA samples of PT-DLBCL tumors from 206 patients using next-generation sequencing platforms and assays. Genetic alteration analysis found that multiple chromosomal copy number variations (CNVs), TP53 transcript mutations with high variant allele frequency, and MCD subtype had significantly adverse prognostic effects, whereas elevated microsatellite instability had a significantly favorable prognostic effect in PT-DLBCL. Targeted RNA-seq analysis identified a PTL gene expression signature by comparing PT-DLBCL with systemic DLBCL and revealed the heterogeneity within PT-DLBCL by unsupervised clustering, which classified PT-DLBCLs into a testicular lymphoma tumor (TLT) subtype and a microenvironment (ME) subtype. The TLT subtype featured upregulation of genes functioning in DNA damage response, DNA repair, chromatin remodeling, the cell cycle, and the nucleus, and was associated with significantly poorer patient survival and higher frequencies of MYD88 mutations, multiple CNVs, MCD subtype, bulk tumors, and elderly patients in the PT-DLBCL cohort. In contrast, the ME subtype distinctively featured upregulation of various signaling pathway genes involving the tumor microenvironment and downregulation of BTK and B-cell receptor signaling genes, and was associated with significantly better clinical outcome than the TLT subtype of PT-DLBCL independently of CNVs, MCD and MYD88 mutation and than systemic DLBCL. Moreover, genomic microRNA profiling analysis identified a PTL microRNA signature significantly differentially expressed between PT-DLBCL and systemic DLBCL patients and within the PT-DLBCL cohort, and PT-DLBCL patients with higher expression of 16 PTL microRNAs (14 are testicular tissue-specific) had significantly better survival. In summary, this study revealed the molecular heterogeneity in genetic abnormalities and expression profiles of coding genes and microRNAs within the PT-DLBCL entity, and identified significant prognostic biomarkers and PTL signatures.

Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population. KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0–1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with ClinicalTrials.gov number NCT02702414. Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11–26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares. Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma. Merck & Co, Inc.

The availability of P in feedstuffs and the effect of feedstuffs, feed additives, and anti-nutritional factors on secretory IgA (sIgA) production in chickens were evaluated. A rapid method was developed using the precision-fed rooster assay to evaluate phytic acid disappearance, P digestibility, and phytase efficacy. Further, exogenous phytase was found to be effective at degrading myo-inositol 1,2,3,4,5,6-hexakis, however, the enzyme was less efficient at P release from lower inositol phosphates. The availability of P in feedstuffs was found to be affected by dietary Ca content, where increasing Ca linearly reduced (P < 0.05) both phytic acid hydrolysis and P digestibility. For example, the standardized ileal digestibility of P was reduced from 73 to 47% in soybean meal when the dietary Ca content was increased from 0.30 to 0.75%. The digestibility of P in distillers dried grains with solubles (DDGS) and corn fermented protein (CFP), however, was high across all Ca levels (71 to 80%). Relative P bioavailability based on tibia bone ash was also found to be high for DDGS and CFP, being 81 and 78%, respectively. Upon further evaluation, it was observed that utilizing low dietary Ca levels (0.30%) when P digestibility in individual plant-based feedstuffs was determined overestimated the P digestibility in practical grower diets by up to 16 percentage units. Utilization of higher Ca levels (0.75%) when P digestibility in individual plant-based feedstuffs was determined, however, resulted in calculated P digestibility values that were within 1 to 3 percentage units of the measured digestibility in practical grower diets. Aside from P, feedstuffs were also evaluated to determine their effect on sIgA production in the intestine. Roosters excreted approximately 6 to 30 mg of sIgA / 24 h. Further, the proportional contribution of sIgA to total endogenous amino acid (AA) losses ranged from 1 to 13%, with the greatest contribution being observed for Trp. The addition of casein to a protein-free diet increased (P < 0.05) sIgA production in both roosters and broiler chickens. There was no change (P > 0.05) in sIgA production compared with the protein-free diet when the same amino acids (AA) were added in purified form; therefore, this effect was unique to the intact protein source. A variety of feedstuffs, feed additives, and anti-nutritional factors were also evaluated to determine their effect on sIgA production. Raw soybeans reduced (P < 0.05) ileal and excreta sIgA concentrations and total sIgA excretion (mg / 24 h). Feeding DDGS and CFP were also found to result in lower (P < 0.05) sIgA concentrations in excreta. Results from these studies demonstrate that 1) phytic acid disappearance in precision-fed roosters can provide preliminary estimates of P digestibility in plant-based feedstuffs, 2) utilization of low dietary Ca levels in when determining P digestibility in individual plant-based feedstuffs overestimates P digestibility in commercially relevant diets due to reduced hydrolysis of phytic acid as Ca content increases, and 3) feedstuffs and other dietary components can regulate sIgA production in the gastrointestinal tract through host-diet interactions.