Some 'watch and wait' (W&W) FL patients suffer from rapid progression in a short term. Herein, we sought to identify these patients and also develop a risk score to screen them at diagnosis. Between 2008 and 2022, a total of 411 FL patients managed by the W&W strategy from 16 cancer centres were retrospectively enrolled in this study, and their time to lymphoma treatment (TLT) and progression-free survival (PFS) were evaluated. Thirty-five percent of W&W FL patients experienced TLT within 24 months (TLT24) after diagnosis. Their 5-year PFS rate was significantly lower than those without treatment at 24 months (62.3% vs. 89.5%). In multivariable analysis, five factors were identified as independent predictors of TLT24: stages III-IV, beta 2 microglobulin >= 3 mg/L, lymphocyte-to-monocyte ratio <3.8, bone marrow involvement and spleen enlargement (above umbilical line). Their AUCs for TLT24 were 0.76 (95% CI, 0.70-0.82) in the training cohort and 0.76 (95% CI, 0.67-0.85) in the validation cohort respectively. Risk groups were also associated with PFS (p < 0.001). In FL patients initially managed by W&W, TLT24 was associated with poor outcomes. This multivariable model helps screening for predicting TLT24, which may be useful to identify candidates for early interventional treatment.

Introduction: In recent years, chemo-free regimens have become one of the hot spots for the exploration of first-line therapy for mantle cell lymphoma (MCL). Orelabrutinib (O), a novel highly selective bruton tyrosine kinase inhibitor, has shown high activity and good tolerability in MCL. Orelabrutinib combined with rituximab could preserve NK cell-mediated ADCC induced by rituximab and enhance the apoptosis of tumor. We aimed to explore the efficacy and safety of O plus lenalidomide (L) and rituximab (R) in untreated MCL. Methods: This multicenter, phase 2 study (NCT05076097) enrolled patients (pts; ≥18 y) with untreated MCL. Pts received OLR-induction therapy on a 28-day cycle for 6 cycles (O, 150 mg/d; L, 15 mg on days 1-21, then 20 mg of cycles 2-6 if tolerated or 10 mg if not tolerated; R, 375 mg/m2 on days 1, 8, 15, 22, then day 1 of cycles 3, 5), followed by OLR-maintenance therapy for up to 18 cycles. Peripheral blood MRD (PB-MRD) and bone marrow MRD (BM-MRD) were evaluated using qPCR (<10−6). The gene mutation profile and circulating tumor DNA (ctDNA) were assessed by next-generation sequencing (NGS). The primary endpoint was complete response rate (CRR) after 6 cycles of induction therapy. Secondary endpoints were objective response rate (ORR), duration of response (DOR), time to response (TTR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of March 8, 2023, 24 pts with MCL were enrolled (male, 87.5%; median age, 57.5 y [range, 51.5-63.5]; median follow-up, 7.4 months). The 24 pts were characterized with 79.2% stage III-IV disease, 95.8% ECOG PS of 0-1, 79.2% low- and 20.8% intermediate-risk MIPI scores, 41.7% Ki67 index (<30%), 33.3% bone marrow involvement, and 58.3% maximum lesion diameter of ≥5 cm. Eighteen pts have completed induction therapy. Among the evaluable pts (n = 18), the ORR was 100%, including 14 (77.8%) CR (Figure 1). Meanwhile, 16 of 18 pts were available for MRD analysis, and PB-MRD and BM-MRD of these 16 pts were negative. The results in CRR were observed in several specific subgroups as classified by MIPI scores (low vs. intermediate, 84.6% and 60.0%) and maximum lesion diameter (<5 cm vs. ≥5 cm, 85.7% and 72.7%). Throughout the treatment, the median TTR was 3.0 months (range, 2.8–3.2). The median DOR and median PFS were not reached. One pt had disease progression at cycle 12. The most common adverse events (AEs; any grades, ≥3 grades) were neutropenia (45.8%, 33.3%), leukopenia (41.7%, 8.3%), COVID-19 infection (29.2%, 4.2%), lymphopenia (25.0%, 4.2%), and thrombocytopenia (25.0%, 4.2%). At the data cutoff, 23 pts remained on study (Figure 1). No deaths were reported. Conclusions: The preliminary data indicated that the OLR exerted synergistic antitumor activity, with manageable toxicity in MCL. More updated data will be presented in this ongoing study. Keywords: aggressive B-cell non-Hodgkin lymphoma, indolent non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

The Global Consortium for the Classification of Fungi and fungus-like taxa is an international initiative of more than 550 mycologists to develop an electronic structure for the classification of these organisms. The members of the Consortium originate from 55 countries/regions worldwide, from a wide range of disciplines, and include senior, mid-career and early-career mycologists and plant pathologists. The Consortium will publish a biannual update of the Outline of Fungi and fungus-like taxa, to act as an international scheme for other scientists. Notes on all newly published taxa at or above the level of species will be prepared and published online on the Outline of Fungi website (https://www.outlineoffungi.org/), and these will be finally published in the biannual edition of the Outline of Fungi and fungus-like taxa. Comments on recent important taxonomic opinions on controversial topics will be included in the biannual outline. For example, 'to promote a more stable taxonomy in Fusarium given the divergences over its generic delimitation', or 'are there too many genera in the Boletales?' and even more importantly, 'what should be done with the tremendously diverse 'dark fungal taxa?' There are undeniable differences in mycologists' perceptions and opinions regarding species classification as well as the establishment of new species. Given the pluralistic nature of fungal taxonomy and its implications for species concepts and the nature of species, this consortium aims to provide a platform to better refine and stabilise fungal classification, taking into consideration views from different parties. In the future, a confidential voting system will be set up to gauge the opinions of all mycologists in the Consortium on important topics. The results of such surveys will be presented to the International Commission on the Taxonomy of Fungi (ICTF) and the Nomenclature Committee for Fungi (NCF) with opinions and percentages of votes for and against. Criticisms based on scientific evidence with regards to nomenclature, classifications, and taxonomic concepts will be welcomed, and any recommendations on specific taxonomic issues will also be encouraged; however, we will encourage professionally and ethically responsible criticisms of others' work. This biannual ongoing project will provide an outlet for advances in various topics of fungal classification, nomenclature, and taxonomic concepts and lead to a community-agreed classification scheme for the fungi and fungus-like taxa. Interested parties should contact the lead author if they would like to be involved in future outlines.

Mixed-metal metal-organic frameworks (MM-MOFs) contain more than one type of metal node, which can improve or even introduce new features compared with the single metal frameworks. Traditionally, most of the MM-MOFs are synthesized by solution method which requires all the metal ions to form stable coordination with the ligand in a single framework and therefore limits the choice of the metal ions. In this work, Pt-doped Zn-MOF-74 (PtZn-MOF-74) has been prepared through a mechanochemical conversion approach from Pt-doped ZnO (Pt–ZnO) directly. The absence of a large quantity of solvent limits the solvation and diffusion of growth species during the mechanochemical conversion and therefore prevented the agglomeration of Pt dopants in PtZn-MOF-74. CO oxidation was used to evaluate the catalytic performance of the prepared MM-MOFs. Compared with inert Zn-MOF-74, PtZn-MOF-74 with unsaturated coordinated Pt at elevated temperature can act as the active sites to catalyze CO oxidation reaction. This study provides a novel design strategy for the synthesis of MM-MOFs with extended functionalities.

Neutropenia is a common complication of chemotherapy, which will lead to the delay or reduction of chemotherapy and affect the therapeutic effect. Mecapegfilgramtim (code name HHPG-19K), the novel long-acting rhG-CSF, has been developed. This study was evaluated the efficacy and safety of HHPG-19K for reducing neutropenia compared with un-prevention. This was a randomized, controlled non-inferiority study. A total of 151 lymphoma patients who were eligible for chemotherapy were randomly assigned into two groups, which received HHPG-19K fixed dosage of 6 mg or un-prevention in the first cycle of chemotherapy. The primary endpoint was the duration of grade≥3 neutropenia in cycle 1, incidence of grade≥3 neutropenia, and febrile neutropenia (FN). The safety profile was also evaluated. The adjusted mean duration of grade>1 neutropenia was 5 days in HHPG-19K fixed dosage of 6 mg group and 7 days in the un-prevention group (P<0.01). There was difference between the two groups in the incidence of grade≥3 neutropenia (P<0.01). There were 10 patients (12.82%) in HHPG-19K fixed dosage of 6 mg/kg group, 15 patients (20.55%) in un-prevention group experienced grade≥3 neutropenia. Compared with un-prevention group, the incidence of grade 4 neutropenia was significantly lower in patients treated with HHPG-19K fixed dosage of 6 mg/kg (7.69% vs 15.07%). For the incidence of FN, there were 5 patients (6.41%) in HHPG-19K fixed dosage of 6 mg/kg group, 11 patients (15.07%) in un-prevention group experienced FN (P<0.05). For safety profile, HHPG-19K group were all well-tolerated. The frequent AEs were ostalgia (13.70 vs 6.41%), fever (24.66% vs 11.54%), nausea (21.92% vs 1.28%), emesis (16.44% vs 1.28%), weakness (9.59% vs 2.56%) and others (19.18% vs 10.26%) during the chemotherapy, which were inferior to the un-prevention group (P<0.01). The frequent AEs were ostalgia (6.41 vs 13.70%), fever (11.54% vs 24.66%), nausea (1.28% vs 21.92%), emesis (1.28% vs 16.44%), weakness (2.56% vs 9.59%) and others (10.26% vs 19.18%) during the chemotherapy, which were inferior to the un-prevention group (P<0.01). No unexpected AE was observed. This study provided new evidence for HHPG-19K, which would be a new alternative clinical practice for prophylaxis of chemotherapy induced neutropenia.

Intruduction Extranodal natural killer/T-cell lymphoma (ENKTL) is an uncommon, aggressive form of non-Hodgkin's lymphoma. Optimal therapeutic strategies have not been fully defined yet. Nasal NK/T-cell lymphomas present mostly with stage I/II disease. For stage I/II nasal lymphoma, a combination of chemotherapy and radiotherapy yields optimal results. Concomitant chemoradiotherapy and sequential chemotherapy and radiotherapy give similar response rates and survivals. For stage III/IV nasal, nonnasal, and disseminated ENKTL, systemic chemotherapy is indicated. Conventional anthracycline-based regimens are ineffective. Regimens containing L-asparaginase are most effective. Both AspaMetDex and P-Gemox is recommended as major effective combined chemotherapy regimen by NCCN guideline. Therefore, we try to evaluate the efficacy and toxicity for P-Gemox plus thalidomide and AspaMetDex followed by extensive involved field radiotherapy (EIFRT) as first-line treatment for newly diagnosed stage I/II patients and as salvage regimen for newly diagnosed stage III/IV or relapsed/refractory ENKTL in this clinical study. Methods We initiated a prospective, multicentre, randomized, phase II clinical trial at 12 centers in China at March 2014. Patients were randomly assigned to receive either P-Gemox+thalidomide regimen (Group A: Pegaspargase 2000U/m2; im d1, Gemcitabine 1000mg/m2; ivdrip , d1, d8. Oxaliplatin 130mg/m2; ivdrip, d1, thalidomide 100mg/d po, for one year.) or AspaMetDex regimen ( Group B: Pegaspargase 2000U/m2; im, d1, Methotrexate 3000mg/ m2; civ 6-hour, d1, calcium folinate 30mg iv, q6h, until reach safe serum MTX concentration, Dexamethasone 40mg/d ivdrip, d1-4.). For newly diagnosed stage I/II patients, both regimens were repeated every three weeks for a maximum four cycles as induction chemotherapy and followed by EIFRT at the dosage of 56Gy in 28 fractions over 4 weeks. Primary EIFRT was delivered using 6-MeV linear accelerator using 3-dimensional conformal treatment planning. For newly diagnosed stage III/IV or relapsed/refractory ENKTL, the regimens were repeated every three weeks for a maximum six cycles. Patients underwent autologous hematopoietic stem cell transplantation (ASCT) as consolidation if they achieved response (complete remission,CR or partial remission,PR). The primary endpoint was progression-free survival(PFS). Results Between March 2014 and March 2018, 165 patients were randomly assigned. 85 patients to Group A, 80 patients to Group B. 156 patients were evaluable for response. Investigator-assessed overall response at the end of induction was 88.2% in the Group A and 75.0% in the Group B. Complete remission (CR) rate were 60.0% and 55.0%. Among 107 newly diagnosed stage I/II patients, 54 patients were assigned to Group A (52 assessed), and 53 to Group B (47 assessed). Overall response during induction in Group A and B was similar in both groups, were 64.8% and 64.2%. 58 newly diagnosed stage III/IV or relapsed refractory patients were enrolled. 31 patients were assigned to Group A (30 assessed), and 27 to Group B. The efficacy rate of Group A was higher than that of Group B. Overall response rate were 87.1% and 66.6%, respectively. At median follow-up of 24.6 (1.0-60.9)months, 3-year progression-free survival (PFS) and overall survival (OS) of whole cohort were 61.4% and 63.4%. PFS and OS rate of Group A were similar to Group B(Figure 1). Group B was better tolerated than Group A, with lower rates of agranulocytosis, thrombocytopenia and infections. While anemia,hyperbilirubinemia, edema, and increased BUN/Cr were more common in Group B. Three patients died of treatment related toxicity only in Group B . Two patients died of severe acute renal failure and sepsis at the first cycle, and one patient died of sepsis at the third cycle. CONCLUSION: Induction chemotherapy of both P-Gemox+Thalidomide and AspaMetDex regimen followed by EIFRT yielded promising efficacy for patients with stage I/II ENKTL. There is little difference therapeutic effect between the two regimens. For advanced or relapsed patients, both regimen showed unsatisfied survival outcome. Meanwhile, P-Gemox+ Thalidomide was less toxic with more convenient administration in outpatients clinics in comparison to AspaMetDex. ( ClinicalTrials.gov, NCT 2085655 ). Disclosures Li: Guangdong Province Hospital: Employment.

Introduction: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous subtype of non-Hodgkin lymphoma varied with clinical, immunophenotypic and genetic features. Anthracycline is considered as the key cytotoxic agent of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). However, whether anthracycline dose intensification can improve the prognosis needs to be addressed. Methods: In this phase III randomized trial, we assigned 400 patients with untreated DLBCL between the age of 16 and 60 years to receive six courses of regimen on a 21-day basis, at either the standard dose (doxorubicin 50 mg/m2, R-CHOP50 or epirubucin 70 mg/m2, R-CEOP70) or a high dose (epirubucin 90 mg/m2, R-CEOP90), followed by additional two cycles of rituximab consolidation. The primary end point was progression-free survival. Moreover, whole genomic sequencing (WGS) and whole exome sequencing (WES) were performed on tumor samples of 28 and 63 patients, respectively. Results: In the intention-to-treat analysis, R-CEOP90 resulted in higher 2-year progression-free survival rate than R-CHOP50/R-CEOP70 (90.3% vs 82.2%, P = 0.016). The rates of serious adverse events were similar among the three groups. Median follow-up was 24.2 months. In subgroup analysis, good R-IPI and germinal center B-cell origin benefited from intensified anthracycline dose. As revealed by WGS/WES, frequent mutated genes (>5%) were enriched in pathways as previously reported by Western population (ASH abstract, Blood 2016 128:152): NOTCH (CTBP2, MAML2, DTX1, NOTCH2, SGK1, NCOR2), TP53 (TP53, FAS, TP73), JAK-STAT (PIM1, SOCS1, STAT3), epigenetic (KMT2D, ARID1A, TET2, CREBBP/EP300, TAF1), BCR (CD79B/CD79A, NFKBIE, CARD11, LYN), toll-like/TNF receptor (MYD88, TNFAIP3, TRAF2), PI3K (KLF2, MTOR, RAG1, FOXO1, BCL2L11, GNA13), MAPK (FGFR3, DUSP2, ETS1), B-cell differentiation (PRDM1 and IRF4), immune surveillance (B2M, HLA-B, CIITA, CD58) and cell cycle (ATM, MYC, CCND3). Two novel pathways were identified: TCR/NK-mediated cytotoxicity (NFATC1 and KIR2DL1) and EBV/HBV infection (DDX3X and HSPG2). Pathway-specific genes less frequently observed than Western population (<5%) were NOTCH (NOTCH1, NOTCH3, FBXW7), JAK-STAT (STAT6), epigenetic (EZH2 and MEF2B), BCR (BCL10, PRKCB, MALT1), PI3K (ID3, TCF3, PTEN, PIK3CD, PIK3R1, PIK3CA), MAPK (BRAF, MAP4K1, KRAS, MAP3K7), B-cell differentiation (BCL6 and IRF8) and cell cycle (CDKN2A, CDK6, RB1). Clinical relevance study on gene mutations was ongoing. Conclusions: This is the first prospective study on anthracycline dose intensification in Chinese DLBCL cohort. High-dose epirubucin improved progression-free survival in young adults with DLBCL. Significant difference in gene mutation pattern was observed between Chinese and Western population. (ClinicalTrials.gov number: NCT00049517). Keywords: anthracycline; diffuse large B-cell lymphoma (DLBCL)

Recently, two genome-wide association studies (GWASs) of schizophrenia (SCZ) in Han Chinese identified several susceptibility loci. Replication efforts aiming to validate the GWAS findings were made and focused on the top hits. We conducted a more extensive follow-up study in an independent sample of 1471 cases and 1528 matched controls to verify 26 genetic variants by including nine top single-nucleotide polymorphisms (SNPs) that reached genome-wide significance and 17 promising SNPs nominated in the initial discovery phase. rs8073471 in an intron of tubulin-folding cofactor D (TBCD) obtained nominal significance ( P <0.01) in single SNP analysis. Logistic regression identified significant interaction between rs3744165 (5’-untranslated region variant of exon 2 of zinc finger protein 750 (ZNF750), and in an intron of TBCD) and rs8073471 (Deviance test P -value=2.77 × 10 −34 ). Both SNPs are located at 17q25, an interesting region that has been implicated in SCZ. By using the Genotype-Tissue Expression (GTEx) data set, we implemented an expression quantitative trait loci epistasis analysis to explore the association between the genotype combinations of the two SNPs and gene expression levels in 13 areas of human central nervous system. We observed that rs3744165 × rs8073471 interaction modulated the expression profile of TEAD3 ( P =1.87 × 10 −8 ), SH3TC2 ( P =2.00 × 10 −8 ), KCNK9 ( P =5.20 × 10 −7 ) and PPDPF ( P =1.13 × 10 −6 ) in postmortem cortex tissue; EFNA1 ( P =7.26 × 10 −9 ), RNU4ATAC ( P =2.32 × 10 −8 ) and NUPL2 ( P =6.79 × 10 −8 ) in cerebellum tissue. To the best of our knowledge, our study is the first one that links TBCD and ZNF750 mutations to SCZ susceptibility and to the transcript levels in human brain tissues. Further efforts are needed to understand the role of those variants in the pathogenesis of SCZ.

Survivin, a key member of the inhibitor of apoptosis protein family, has been reported to be capable of regulating both cellular proliferation and apoptotic cell death. This protein is found to be overexpressed in many human cancers. The aim of this study was to evaluate the prognostic significance of survivin mRNA expression in oral squamous cell carcinoma (OSCC) and to analyze its correlation with chemoresistance. Reverse-transcription polymerase chain reaction assay was performed to detect the expression of survivin mRNA in OSCC cell lines or tissue samples. Immunohistochemistry was performed to detect the expression of survivin protein in OSCC tissues or corresponding nontumor tissues. Then the correlation between survivin mRNA expression and clinicopathologic features or prognosis of OSCC patients was analyzed. Small interfering RNA technology was used to down-regulate the expression of the survivin gene in the OSCC cell line. Methylthiazol tetrazolium and flow cytometric assays were performed to detect proliferation and apoptosis of the OSCC cell line (HSC-3). Furthermore, the effect of small interfering RNA (siRNA) targeting survivin on the sensitivity of OSCC cells to chemotherapeutic agents (cisplatin and 5-fluorouracil [5-FU]) was determined. Results showed that the levels of survivin mRNA expression were significantly higher in OSCC cells or tissues than those in normal human oral keratinocyte or corresponding noncancerous tissues. The immunostaining of survivin protein was significantly stronger in OSCC tissues than in corresponding nontumor tissues. Moreover, high survivin mRNA expression was correlated with poorer tumor differentiation, higher clinical stage, and the presence of lymph node metastasis (P < .05). Multivariate analysis showed that the status of survivin mRNA could be an independent prognostic factor for OSCC patients (hazard ratio 2.71, 95% confidence interval 1.46-5.10; P = .012). In addition, siRNA-mediated survivin down-regulation could significantly inhibit proliferation and induce apoptosis of OSCC cells. Suvivin down-regulation could also significantly enhance chemosensitivity of OSCC cells, which was associated with apoptosis enhancement. Thus, the status of survivin mRNA expression was a potential prognostic factor for OSCC patients, and siRNA-mediated survivin down-regulation could become a novel strategy for chemosensitization of human OSCCs.