Impaired cell death program has been noted as one of the hallmarks of chronic lymphocytic leukemia (CLL) and contributes to its accumulation of malignant monoclonal B cells as well as to chemotherapy resistance. A cell can die through the apoptosis or necrosis pathway. Recent investigations suggest that in apoptotic-deficient conditions, such as most types of cancer, a process of programmed necrosis, called necroptosis, prevails. However, the detailed molecular mechanisms underlying this alternative cell death pathway are still not fully understood. Here we demonstrate that CLL cells failed to undergo necroptosis upon stimulation of TNFa combined with pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD). Two core components of necroptotic machine, RIP3 and deubiquitinase cylindromatosis (CYLD), are markedly downregulated in CLL. Moreover, we identified lymphoid enhancer-binding factor 1 (LEF1), a downstream effector of the Wnt/b-catenin pathway, as a transcription repressor of CYLD in CLL. Knocking down LEF1 sensitizes CLL cells to TNFa/zVAD-induced necroptosis. The present investigation provides the first evidence that CLL cells have defects not only in apoptotic program but also in necroptotic signaling. Targeting the key regulators of necroptotic machine, such as LEF1, to restore this pathway may represent a novel approach for CLL treatment.

The use of autologous skin cell suspension with hydrocolloid dressings accelerated epithelialization and improved healing quality of the donor site compared with hydrocolloid dressings alone. Registration number: UMIN000015000 ( http://www.umin.ac.jp/ctr).

Optimal treatment strategies for natural killer/T‐cell lymphoma (NKTCL) patients with stage IV disease have not been well defined. In this prospective phase 2 study, we evaluated the treatment using MEDA (methotrexate, etoposide, dexamethasone and pegaspargase) as induction chemotherapy and autologous hematopoietic stem cell transplantation (Auto‐HSCT) for consolidation. Patients with stage IV disease without prior L‐asparaginase‐based chemotherapy were eligible. Four cycles of MEDA were administered as induction treatment. Patients with complete response (CR, necessary to have complete metabolic remission of PET/CT, negative plasma EBV‐DNA and negative EBER staining of bone marrow biopsy tissue) were consolidated by Auto‐HSCT. A total of 53 patients were enrolled. The overall response (OR) rate and CR rate after four cycles of MEDA chemotherapy were 75.5% and 56.6%, respectively. Among them, 25 patients underwent Auto‐HSCT. The 4‐year overall survival (OS) rate and progression‐free survival (PFS) rate were 58.0% (95% CI, 43.4%‐70.0%) and 43.4% (95% CI, 29.9%‐56.1%), respectively. Patients who underwent Auto‐HSCT had a 4‐year OS rate of 92.0% (95% CI, 71.6%‐97.9%) and a 4‐year PFS rate of 80.0% (95% CI, 58.4%‐91.1%). Grade 3/4 neutropenia and thrombocytopenia occurred in 28.3% and 17.0% of the patients, respectively. MEDA chemotherapy is an effective induction regimen with reduced grade 3/4 hematological toxicities for stage IV NKTCL. Consolidation with Auto‐HSCT can be considered as a potential approach to improve the long‐term survival of CR patients after induction treatment.

Background:The prognostic value of additional copies of chromosome 1q (1q gain/ amplification [amp]) in multiple myeloma (MM) remains controversial. In the meantime, the kinetics of the response to MM therapy has long been an area of debate. Few studies have pointed out the relationship of response kinetics with cytogenetic abnormalities (CAs) in MM. Methods:The authors retrospectively analyzed the data of 1068 real-world newly diagnosed MM patients from a Chinese national medical center. Results: Overall, 405 (51.9%) patients had 1q gain/amp, with aggressive clinical characteristics and significant inferior survival. The variation in copy number (CN) of 1q (CN = 3 or CN >3) had no significant impact on the survival of MM patients with 1q abnormalities. No difference was found in the outcome of 1q gain/amp patients treated with doublet or triplet regimens. Upfront autologous stem cell transplantation could eliminate the adverse prognostic effect of 1q gain but not 1q amp. The duration from diagnosis to the first time achieving very good partial response (VGPR) or better was significantly shorter in patients with 1q gain/amp (77 days vs. 100 days, p = .001). Finally, multifactor regression analysis was performed to construct a new risk stratification model in MM patients with 1q gain/amp, which was validated in the Multiple Myeloma Research Foundation CoMMpass study cohort and worked better than the Revised International Staging System and Second Revision of the International Staging System (Harrell's concordance index: 0.631 vs. 0.598 and 0.537). Conclusions:In the setting of novel therapy, 1q gain/amp still acts as an independent adverse prognostic factor. Patients with 1q gain/amp achieved VGPR rapidly but had inferior survival.

Background Inflammatory breast cancer (IBC) is the most aggressive type of breast cancer. HMG-CoA reductase inhibitors (statins) are cholesterol reducing agents with pleiotropic effects, including antitumorigenic and anti-inflammatory properties. We hypothesized that statins reduce the metastatic potential in primary IBC. Methods We retrospectively reviewed 724 patients diagnosed with and treated for primary IBC at The University of Texas MD Anderson Cancer Center between Jan. 12, 1995 and Jan. 27, 2011. Patients with records indicating statin use at the time of IBC diagnosis on the electronic medical record were compared with those without. We further compared outcomes stratified by statin type (hydrophilic [H] versus lipophilic [L]). We used the Kaplan-Meier method to estimate the median disease-free survival (DFS) after surgery, overall survival (OS), and disease specific survival (DSS), followed by Cox proportional hazards regression model to test statistical significance of several potential prognostic factors. Results For primary IBC patients who had information on their statin use status at IBC diagnosis, the median DFS time were 4.88 years, 2.47 years and 1.76 years (P= 0.04); the median OS time 5.05 years, 3.79 years and 4.32 years (P= 0.35); and the median DSS time 5.10 years, 3.79 years and 4.52 years (P= 0.37), for patients who took “ H”, “L” and no statin, respectively. In multivariable Cox model stratified by radiation therapy, ER/PR status and HER2 status, statin “H” use was associated with significantly improved DFS compared to no statin use (HR=0.49; 95% CI: 0.28–0.84; p<0.01), adjusted for lymphatic/vascular invasion. Although there is a trend that patients who used statin “H” had a longer time to death compared to patients who did not take statin, it did not reach statistical significance for OS (HR=0.80; 95% CI: 0.43–1.49; p=0.49) and DSS (HR=0.85; 95% CI: 0.46–1.57, p=0.59) after adjustment for lymphatic/vascular invasion, nuclear grade and surgery status within one year. Conclusions Hydrophilic statin use was associated with improved DFS. There was a trend for reduced HR in OS and DSS among primary IBC patient who used hydrophilic statins. A prospective randomized study to evaluate the potential survival benefits of statins in primary IBC population is warranted. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-08.

Background Significant advances in multiple myeloma (MM) over the past 15 years led to exciting changes in the management of MM patients in China, which in turn brought about the early diagnoses, precise risk stratifications, and improved prognoses. Methods We summarized the dynamic changes in the management of newly diagnosed (ND) MM in a national medical center, crossing the old and novel drug era. Demographics, clinical characteristics, first‐line treatment, response rate, and survival were retrospectively collected among NDMMs diagnosed in Zhongshan Hospital Fudan University from January 2007 to October 2021. Results Of the 1256 individuals, median age was 64 (range 31–89) with 45.1% patients >65 years. About 63.5% were male, 43.1% were at ISS stage III and 9.9% had light‐chain amyloidosis. Patients with abnormal ratio of free light chain (80.4%), extramedullary disease (EMD, 22.0%), and high‐risk cytogenetic abnormalities (HRCA, 26.8%) were detected by novel detection techniques. The best confirmed ORR was 86.5%, including 39.4% with CR. Short‐ and long‐term PFS and OS rates persistently increased each year along with increasing novel drug applications. Median PFS and OS were 30.9 and 64.7 months. Advanced ISS stage, HRCA, light‐chain amyloidosis and EMD independently predicted an inferior PFS. First‐line ASCT indicated a superior PFS. Advanced ISS stage, elevated serum LDH, HRCA, light‐chain amyloidosis, and receiving PI/IMiD‐based regimen versus PI+IMiD‐based regimen independently indicated a poorer OS. Conclusions In brief, we illustrated a dynamic landscape of MM patients in a national medical center. Chinese MM patients evidently benefited from newly introduced techniques and drugs in this field.

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