Hypercholesterolemia, the driving force of atherosclerosis, accelerates the expansion and mobilization of hematopoietic stem and progenitor cells (HSPCs). The molecular determinants connecting ...hypercholesterolemia with hematopoiesis are unclear. Here, we report that a somite-derived prohematopoietic cue, AIBP, orchestrates HSPC emergence from the hemogenic endothelium, a type of specialized endothelium manifesting hematopoietic potential. Mechanistically, AIBP-mediated cholesterol efflux activates endothelial Srebp2, the master transcription factor for cholesterol biosynthesis, which in turn transactivates Notch and promotes HSPC emergence. Srebp2 inhibition impairs hypercholesterolemia-induced HSPC expansion. Srebp2 activation and Notch up-regulation are associated with HSPC expansion in hypercholesterolemic human subjects. Genome-wide chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing (RNA-seq), and assay for transposase-accessible chromatin using sequencing (ATAC-seq) indicate that Srebp2 transregulates Notch pathway genes required for hematopoiesis. Our studies outline an AIBP-regulated Srebp2-dependent paradigm for HSPC emergence in development and HPSC expansion in atherosclerotic cardiovascular disease.
Four US National Clinical Trials Network components (Southwest Oncology Group, Cancer and Leukemia Group B/Alliance, Eastern Cooperative Oncology Group, and the AIDS Malignancy Consortium) conducted ...a phase II Intergroup clinical trial that used early interim fluorodeoxyglucose positron emission tomography (FDG-PET) imaging to determine the utility of response-adapted therapy for stage III to IV classic Hodgkin lymphoma.
The Southwest Oncology Group S0816 (Fludeoxyglucose F 18-PET/CT Imaging and Combination Chemotherapy With or Without Additional Chemotherapy and G-CSF in Treating Patients With Stage III or Stage IV Hodgkin Lymphoma) trial enrolled 358 HIV-negative patients between July 1, 2009, and December 2, 2012. A PET scan was performed after two initial cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and was labeled PET2. PET2-negative patients (Deauville score 1 to 3) received an additional four cycles of ABVD, whereas PET2-positive patients (Deauville score 4 to 5) were switched to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for six cycles. Among 336 eligible and evaluable patients, the median age was 32 years (range, 18 to 60 years), with 52% stage III, 48% stage IV, 49% International Prognostic Score 0 to 2, and 51% score 3 to 7.
Three hundred thirty-six of the enrolled patients were evaluable. Central review of the interim PET2 scan was performed in 331 evaluable patients, with 271 (82%) PET2-negative and 60 (18%) PET2-positive. Of 60 eligible PET2-positive patients, 49 switched to eBEACOPP as planned and 11 declined. With a median follow-up of 39.7 months, the Kaplan-Meier estimate for 2-year overall survival was 98% (95% CI, 95% to 99%), and the 2-year estimate for progression-free survival (PFS) was 79% (95% CI, 74% to 83%). The 2-year estimate for PFS in the subset of patients who were PET2-positive after two cycles of ABVD was 64% (95% CI, 50% to 75%). Both nonhematologic and hematologic toxicities were greater in the eBEACOPP arm than in the continued ABVD arm.
Response-adapted therapy based on interim PET imaging after two cycles of ABVD seems promising with a 2-year PFS of 64% for PET2-positive patients, which is much higher than the expected 2-year PFS of 15% to 30%.
Background
Diabetes places patients with cancer at an increased risk of infections, hospitalizations, and mortality. The objective of the current study was to characterize diabetes care management ...patterns among patients with cancer in the year before and, separately, after cancer diagnosis. The authors hypothesized that diabetes care declines after a diagnosis of cancer.
Methods
The Surveillance, Epidemiology, and End Results (SEER) cancer registry linked to Medicare claims data was used. The authors included diabetic beneficiaries aged ≥65 years who were diagnosed with incident, nonmetastatic breast, prostate, or colorectal cancer between 2008 and 2013. Controls were diabetic Medicare beneficiaries in SEER regions who did not have cancer. Cases were matched to controls based on age, sex, Charlson Comorbidity Index, and diabetes severity. Primary outcomes were diabetes care received over 12 months: 1) hemoglobin A1c testing; 2) eye examination; and 3) low‐density lipoprotein testing. Using a difference‐in‐difference (DID) approach, the authors examined use differences 12 months before to after diagnosis for patients with cancer and controls. To avoid capturing testing related to diagnosis and not diabetes management, the authors implemented a 90‐day washout period (45 days before and/or after diagnosis).
Results
A total of 32,728 diabetic patients with cancer and 32,728 matched noncancer controls were included. After diagnosis, patients with cancer were found to have modest, but significantly lower, rates of diabetes care use compared with controls. Patients with cancer had greater declines in hemoglobin A1c testing (DID, 2.4%; 95% CI, 1.7%‐3.0%), low‐density lipoprotein testing (DID, 4.3%; 95% CI, 3.6%‐5.0%), and receipt of all diabetes indicators (DID, 2.7%; 95% CI, 1.8%‐3.5%) 12 months before to after diagnosis.
Conclusions
Compared with controls, less diabetes care use was observed among patients with cancer in the year after diagnosis. Understanding and addressing the reasons for this may improve outcomes in this population.
Herein, the authors report less use of diabetes care among patients with cancer in the year after their cancer diagnosis compared with noncancer controls. Understanding and addressing the reasons for this may improve cancer and diabetes outcomes in this population.
TP53 is the most frequently mutated tumor suppressor gene in human cancer, with nearly 50% of all tumors exhibiting a loss-of-function mutation. To further elucidate the genetic pathways involving ...TP53 and cancer, we have exploited the zebrafish, a powerful vertebrate model system that is amenable to whole-genome forward-genetic analysis and synthetic-lethal screens. Zebrafish lines harboring missense mutations in the tp53 DNA-binding domain were identified by using a target-selected mutagenesis strategy. Homozygous mutant fish from two of these lines were viable and exhibited mutations similar to those found in human cancers (tp53N168 Kand tp53M214 K). Although homozygous tp53N168 Kmutants were temperature-sensitive and suppressed radiation-induced apoptosis only at 37°C, cells in the tp53M214 Kembryos failed to undergo apoptosis in response to γ radiation at both 28 and 37°C. Unlike wild-type control embryos, irradiated tp53M214 Kembryos also failed to up-regulate p21 and did not arrest at the G1/ S checkpoint. Beginning at 8.5 months of age, 28% of tp53M214 Kmutant fish developed malignant peripheral nerve sheath tumors. In addition to providing a model for studying the molecular pathogenic pathways of malignant peripheral nerve sheath tumors, these mutant zebrafish lines provide a unique platform for modifier screens to identify genetic mutations or small molecules that affect tp53-related pathways, including apoptosis, cell-cycle delay, and tumor suppression.
A negative interim positron emission tomography/computerized tomography (PET/CT) after 1 to 3 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with newly diagnosed, ...nonbulky stage I or II Hodgkin lymphoma (HL) predicts a low relapse rate. This phase 2 trial was designed to determine if a population of patients with early-stage disease can be treated with short-course ABVD without radiation therapy (RT) on the basis of a negative interim PET/CT, thereby limiting the risks of treatment. Between 15 May 2010 and 21 February 2013, 164 previously untreated patients with nonbulky stage I/II HL were enrolled, and 149 were included in the final analysis. Patients received 2 cycles of ABVD followed by PET. Deauville scores 1 to 3 were negative (≤ liver uptake) based on central review. PET− patients received 2 more cycles of ABVD, and PET+ patients received 2 cycles of dose-intense bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escalated BEACOPP) plus 3060-cGy involved-field RT. The primary objective was to determine 3-year progression-free survival (PFS) for the PET− group. One hundred thirty-five patients (91%) were interim PET−, and 14 patients (9%) were PET+. With median follow-up time of 3.8 years, the estimated 3-year PFS was 91% for the PET− group and 66% for the PET+ group (hazard ratio, 3.84; 95% confidence interval, 1.50-9.84; P = .011). There was 1 death as a result of suicide. Four cycles of ABVD resulted in durable remissions for a majority of patients with early-stage nonbulky HL and a negative interim PET. This trial was registered at www.clinicaltrials.gov as #NCT01132807.
•Interim PET− nonbulky stage I/II patients had 3-year PFS of 91% with 4 ABVD cycles and no RT.•Too few patients were interim PET+ to draw firm conclusions about efficacy of escalated BEACOPP plus involved-field RT.
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Lenalidomide combined with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (R2CHOP) in untreated diffuse large B-cell lymphoma (DLBCL) has shown promising activity, ...particularly in the activated B-cell-like (ABC) subtype. Eastern Cooperative Oncology Group (ECOG)-ACRIN trial E1412 was a randomized phase II study comparing R2CHOP versus R-CHOP in untreated DLBCL.
Patients with newly diagnosed DLBCL, stage II bulky-IV disease, International Prognostic Index (IPI) ≥ 2, and ECOG performance status ≤ 2 were eligible and randomly assigned 1:1 to R2CHOP versus R-CHOP for six cycles. Tumors were analyzed using the NanoString Lymph2Cx for cell of origin. The primary end point was progression-free survival (PFS) in all patients with the co-primary end point of PFS in ABC-DLBCL. Secondary end points included overall response rate (ORR), complete response (CR) rate, and overall survival (OS).
Three hundred forty-nine patients were enrolled; 280 patients (145 R2CHOP and 135 R-CHOP) were evaluable: 94 were ABC-DLBCL, 122 germinal center B-cell-like-DLBCL, 18 unclassifiable, and 46 unknowns. Baseline characteristics were well-balanced between arms, and the median age was 66 (range, 24-92); 70% of patients had stage IV disease; 34%, 43%, and 24% had IPI 2, 3, and 4 or 5, respectively. Myelosuppression was more common in the R2CHOP arm. The ORR and CR rate were 92% and 68% in R-CHOP and 97% (
= .06) and 73% (
= .43) in the R2CHOP arm, respectively. The median follow-up was 3.0 years; R2CHOP was associated with a 34% reduction in risk of progression or death versus R-CHOP (hazard ratio HR, 0.66 95% CI, 0.43 to 1.01) and 3-year PFS of 73% versus 61%, one-sided
= .03, and an improvement in OS (83% and 75% at 3 years; HR, 0.67; one-sided
= .05). The PFS HR for R2CHOP was 0.67 for ABC-DLBCL, one-sided
= .1.
In this signal-seeking study, the addition of lenalidomide to R-CHOP (R2CHOP) improved outcomes in newly diagnosed DLBCL including patients with ABC-DLBCL.
We report 5-year follow-up of a multicenter phase 2 study of lenalidomide plus rituximab (LR) as initial treatment of mantle cell lymphoma (MCL). The regimen includes induction and maintenance with ...the LR doublet. Treatment was continuous until progression, with optional discontinuation after 3 years. The median age of the 38 participants was 65 years, with MCL international prognostic index scores balanced among low, intermediate, and high risk (34%, 34%, and 32%, respectively). Twenty-seven (75%) of the 36 evaluable patients completed ≥3 years of study treatment. At a median follow-up of 64 months (range, 21-78), the 3-year progression-free survival (PFS) and overall survival (OS) were 80% and 90%, respectively, with 5-year estimated PFS and OS of 64% and 77%, respectively. During maintenance, hematologic adverse events (AEs) included asymptomatic grade 3 or 4 cytopenias (42% neutropenia, 5% thrombocytopenia, 3% anemia) and mostly grade 1 or 2 infections managed in the outpatient setting (45% upper respiratory infection, 21% urinary tract infection, 13% sinusitis, 11% cellulitis, 8% pneumonia). Nonhematologic AEs, such as constitutional and inflammatory symptoms, occurred at reduced frequency and intensity compared with induction. A peripheral blood minimal residual disease (MRD) assay (clonoSEQ) showed MRD-negative complete remission in 8 of 10 subjects who had completed ≥3 years of treatment and with available samples for analysis. With longer follow-up, LR continues to demonstrate durable responses and manageable safety as initial induction and maintenance therapy for MCL (ClinicalTrials.gov NCT01472562).
•Lenalidomide plus rituximab as induction and maintenance therapy for MCL can achieve durable MRD-negative complete remissions.•Chronic therapy–associated adverse events are generally nonaccumulative and remain manageable.
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Post-infarction ventricular septal defect (PIVSD) is a mechanical complication of acute myocardial infarction (AMI) with a poor prognosis. Surgical repair is the mainstay of treatment, although ...percutaneous closure is increasingly undertaken.
Patients treated with surgical or percutaneous repair of PIVSD (2010-2021) were identified at 16 UK centres. Case note review was undertaken. The primary outcome was long-term mortality. Patient groups were allocated based upon initial management (percutaneous or surgical). Three-hundred sixty-two patients received 416 procedures (131 percutaneous, 231 surgery). 16.1% of percutaneous patients subsequently had surgery. 7.8% of surgical patients subsequently had percutaneous treatment. Times from AMI to treatment were similar percutaneous 9 (6-14) vs. surgical 9 (4-22) days, P = 0.18. Surgical patients were more likely to have cardiogenic shock (62.8% vs. 51.9%, P = 0.044). Percutaneous patients were substantially older 72 (64-77) vs. 67 (61-73) years, P < 0.001 and more likely to be discussed in a heart team setting. There was no difference in long-term mortality between patients (61.1% vs. 53.7%, P = 0.17). In-hospital mortality was lower in the surgical group (55.0% vs. 44.2%, P = 0.048) with no difference in mortality after hospital discharge (P = 0.65). Cardiogenic shock adjusted hazard ratio (aHR) 1.97 (95% confidence interval 1.37-2.84), P < 0.001), percutaneous approach aHR 1.44 (1.01-2.05), P = 0.042, and number of vessels with coronary artery disease aHR 1.22 (1.01-1.47), P = 0.043 were independently associated with long-term mortality.
Surgical and percutaneous repair are viable options for management of PIVSD. There was no difference in post-discharge long-term mortality between patients, although in-hospital mortality was lower for surgery.
PURPOSE Romidepsin (depsipeptide or FK228) is a member of a new class of antineoplastic agents active in T-cell lymphoma, the histone deacetylase inhibitors. On the basis of observed responses in a ...phase I trial, a phase II trial of romidepsin in patients with T-cell lymphoma was initiated. PATIENTS AND METHODS The initial cohort was limited to patients with cutaneous T-cell lymphoma (CTCL), or subtypes mycosis fungoides or Sézary syndrome, who had received no more than two prior cytotoxic regimens. There were no limits on other types of therapy. Subsequently, the protocol was expanded to enroll patients who had received more than two prior cytotoxic regimens. Results Twenty-seven patients were enrolled onto the first cohort, and a total of 71 patients are included in this analysis. These patients had undergone a median of four prior treatments, and 62 patients (87%) had advanced-stage disease (stage IIB, n = 15; stage III, n= 6; or stage IV, n = 41). Toxicities included nausea, vomiting, fatigue, and transient thrombocytopenia and granulocytopenia. Pharmacokinetics were evaluated with the first administration of romidepsin. Complete responses were observed in four patients, and partial responses were observed in 20 patients for an overall response rate of 34% (95% CI, 23% to 46%). The median duration of response was 13.7 months. CONCLUSION The histone deacetylase inhibitor romidepsin has single-agent clinical activity with significant and durable responses in patients with CTCL.
Brentuximab vedotin is a drug immunoconjugate with an antibody targeting CD30, an antigen expressed mainly on Hodgkin's and anaplastic large-cell lymphomas, linked to a potent microtubule inhibitor. ...In a study involving 45 patients after relapse, 11 complete remissions were observed.
Approximately 15 to 30% of patients with Hodgkin's lymphoma do not have a long-term remission with conventional therapy,
1
resulting in an estimated 1300 deaths annually in the United States alone.
2
Autologous hematopoietic stem-cell transplantation (ASCT) represents a potentially curative treatment for some patients with recurrent or progressive Hodgkin's lymphoma after failure of initial combination chemotherapy. Unfortunately, ASCT is only effective in approximately 50% of such patients.
3
,
4
Among those who have a relapse after ASCT, overall survival is 55% at 2 years and 32% at 5 years.
5
Because the incidence of Hodgkin's lymphoma peaks during young adulthood, these premature deaths . . .
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