[Efficacy and safety of daratumumab in patients with relapsed/refractory multiple myeloma].

Objective: To investigate the efficacy and safety of daratumumab in relapsed/refractory multiple myeloma (RRMM) patients. Methods: Fifty-two RRMM patients treated with daratumumab from September 2019 to November 2021 in West China Hospital were retrospectively enrolled, including 31 males and 21 females. The mean age of these patients at the first diagnosis of multiple myeloma was (58±10) years. According to the dosage of daratumumab, patients were divided into low dosage group (n=10) and high dosage group (n=42). Overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse event rates were investigated. Univariate and multivariate analysis of potential factors were conducted. Results: Of the 52 patients, 8 received daratumumab monotherapy, 27 received daratumumab plus immuno-modulatory drug (IMiD) treatment, 4 received daratumumab plus proteosome inhibitor (PI) treatment, and 11 received daratumumab plus dexamethasone treatment. The diagnosis age of high dosage group patients was (57±9) years, which was significantly younger than that of low dosage group [(66±10) years] (P=0.009). The baseline creatinine level of high dosage group patients [M (Q1, Q3)] was 91 (68, 196) µmol/L, which was significantly higher than that of low dosage group [66 (51, 76) µmol/L] (P=0.021). There was no significant difference in other baseline clinical characteristics, previous treatment regimens, previous lines of treatment, and regimen and cycles of daratumumab between the high dosage group and low dosage group (all P>0.05). The ORR for the 52 patients was 71.2% (37/52). The ORR for daratumumab plus IMiD group was 81.5% (22/27), which was significantly higher than that in monotherapy or dexamethasone group [ORR: 52.6% (10/19), P=0.036). With a median follow-up [M (Q1, Q3)] of 7 (5, 26) months, the median PFS for overall cohort was 17 (95%CI: 9.6-24.4) months. The median PFS for daratumumab plus IMiD group was 26 (95%CI: 6.0-46.0) months, which was significantly better than that in monotherapy or dexamethasone group [12 (95%CI: 3.5-20.5) months] (HR=0.231, 95%CI: 0.075-0.715, P=0.011). Higher diagnosis age was the risk factor of progression (HR=1.085, 95%CI: 1.016-1.158, P=0.014), while more cycles of daratumumab treatment was the protective factor of progression (HR=0.669, 95%CI: 0.495-0.904, P=0.009). There was no significant influence of daratumumab dosage on progression (high dosage vs low dosage, HR=1.016, 95%CI: 0.221-4.668, P=0.984). The median OS for overall cohort was 26 (95%CI: 13.1-38.9) months. Higher serum calcium was the independent risk factor of death (HR=12.190, 95%CI: 1.170-127.048, P=0.037). There was no significant influence of daratumumab dosage on death (high dosage vs low dosage, HR=0.818, 95%CI: 0.171-3.917, P=0.802). Adverse events included infections (43.2%, 16/37), infusion-associated reactions (29.7%, 11/37), and thrombocytopenia (27.0%, 10/37). Conclusions: Daratumumab is effective to treat RRMM. The dosage of daratumumab has no significant influence on prognosis when used in combined treatment. The incidence of adverse events is relatively low, with a favorable safety profile.

[Clinical characteristics and prognosis of lymphoma-associated hemophagocytic syndrome].

Subjective To investigate clinical characteristics, treatment, and prognosis of lymphoma-associated hemophagocytic syndrome (LAHS) patients. Methods: The clinical data of patients diagnosed with LAHS from January 2010 to October 2021 in West China Hospital were retrospectively analyzed. Clinical characteristics, treatment, overall response rate (ORR), and overall survival (OS) were investigated. Univariate and multivariate analysis of potential factors were conducted. Results: Of all 94 patients included, 59 were male and 35 were female. The age at hemophagocytic lymphohistiocytosis (HLH) diagnosis was (40.5±17.3) years. Seventy-four cases were T/NK cell lymphoma; 15 were B cell lymphoma; 5 were Hodgkin lymphoma. The age at HLH diagnosis of T/NK cell LAHS patients was (37.9±16.2) years, while that of B cell LAHS patients was (55.9±14.0) years. T/NK cell LAHS patients were significantly younger than B cell LAHS patients (P<0.001). Baseline fibrinogen of T/NK cell LAHS patients was 1.34 (0.86, 2.44) g/L, while that of B cell LAHS patients was 2.20 (1.75, 4.25) g/L. T/NK cell LAHS patients showed significantly lower fibrinogen levels than B cell LAHS patients (P=0.008). Combined treatment of anti-HLH and anti-lymphoma treatment was conducted in 35 patients; anti-HLH treatment was conducted in 31 patients; anti-lymphoma treatment was conducted in 8 patients; glucocorticoid treatment was conducted in 7 patients. ORR was 49.4%, and the median OS was 61 days for overall patients. Patients who received anti-HLH treatment and turned to anti-lymphoma treatment early displayed the best ORR and OS, significantly higher than those of anti-HLH patients (69.0 vs 38.7%, P=0.019, and 192.0 vs 24.5 days, P=0.028, respectively), which were also insignificantly higher than those of anti-lymphoma patients. Extranodal NK/T-cell lymphoma or aggressive natural killer cell leukemia was the risk factor of LAHS prognosis (HR=0.113, 95%CI: 0.018-0.728, P=0.022). Conclusions: Prognosis of LAHS patients is poor. Anti-lymphoma treatment should be initiated as soon as HLH is rapidly controlled.

[In vitro pharmacodynamic studies of novel class â and â ¡b selective histone deacetylase inhibitor purinostat mesylate in the treatment of diffuse large B-cell lymphoma and its mechanism].

Objective: To investigate the in vitro inhibitory activity of a novel class Ⅰ and Ⅱb selective histone deacetylase (HDAC) inhibitor, purinostat mesylate (PM) , in diffuse large B-cell lymphoma and its mechanism. Methods: The 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide method was used to detect the effect of PM on cell proliferation. The effects of PM on cell cycle and apoptosis were detected by flow cytometry. The acetylation levels of HDAC substrate, cell cycle protein, apoptosis-related protein, and oncogene protein expression were detected by Western blot. Results: PM significantly inhibited the proliferation of lymphoma SUDHL-4 and SUDHL-6 cells and increased the acetylation levels of HDAC substrates H3, H4, and α-tubulin. In cell cycle experiments, PM induced G(0)/G(1) phase arrest in SUDHL-4 and SUDHL-6 cells. Western blot experiment showed that PM could significantly downregulate the expression of cyclin-dependent kinases Cdk2, Cdk4, Cdk6, cyclin D1, and cyclin E and upregulate the expression of CDK inhibitor protein p21. In the apoptosis experiment, PM could induce the apoptosis of SUDHL-4 and SUDHL-6 cells. Western blot experiment demonstrated that PM promoted endogenous apoptosis by activating caspase-3 kinase and affecting antiapoptotic protein Bcl-2. In addition, PM could downregulate the expression of oncogene marker proteins MYC, IKZF1, and IKZF3. Conclusion: PM has an efficient biological activity in vitro for diffuse large B-cell lymphoma, including double-hit lymphoma, and provides valuable experimental evidence for PM in clinical treatment.

[A novel compound heterozygous mutation in MYSM1 gene in a 1-month-old girl: a bone marrow failure syndrome 4 family survey and literature review].

Objective: To report the clinical manifestations and total exon detection results of one case of MYSM1 gene complex heterozygosity mutation of bone marrow failure syndrome 4 and the results of total exon detection of her family to provide a case phenotype for the early diagnosis of bone marrow failure syndrome 4. Methods: A 1-month-old girl with severe anemia was sequenced with trio-WES. Similarly, the family was also sequenced with tribe-WES to confirm the molecular diagnosis. BWA, GATK, and other software were used for annotation analysis of sequencing results. After polymerase chain reaction, Sanger sequencing was performed by ABI3730 sequencer to verify the target sequence. Moreover, the verification results were obtained by the sequence analysis software. The clinical diagnosis of this girl was reported and the relevant pieces of literature were reviewed. Results: The girl presented with pancytopenia, polydactylism, nonspecific white matter changes, and cysts. However, CD3(-)CD19(+) B decreased. The child was identified with MYSM1 complex heterozygous mutation by whole-exome sequencing, NM_001085487.2:c.1607_c.1611delAAGAG and c.1432C>T, which was respectively inherited from his parents. Genealogy verification confirmed that the c.1432C>T mutation carried by the father was from the grandfather (father's father) , whereas the c.1607_c.1611delAAGAG mutation carried by the mother was from the grandfather (mother's father) , whereas the grandmothers, aunts, and uncle did not carry the mutation. The child was diagnosed with BMFS4 combined with clinical phenotypic and molecular genetic findings. Conclusion: This case provides a case phenotype for the early diagnosis of BMFS4 and extends the pathogenicity variation and phenotype spectrum of the MYSM1 gene. The newly discovered pathogenic variant of MYSM1 c. 1607_c.1611delAAGAG has not been reported at home or abroad.

Hyperoxia induces the apoptosis of alveolar epithelial cells and changes of pulmonary surfactant proteins.

OBJECTIVE: To explore the changes of surfactant protein C, D (SP-C, SP-D) and apoptosis of alveolar epithelial cells (AEC) in the lung injury of neonatal rats induced by hyperoxia. MATERIALS AND METHODS: We divided neonatal rats within 24 hours into two groups randomly: the air group (n = 50) and the hyperoxia group (n = 50). Rats in the air group and hyperoxia group were bred conventionally and in tanks with normal pressure and 90% concentration of oxygen, respectively. On the 1st, 3rd, 7th, 10th, and 14th day after exposure, lung tissue of 8 rats in each group was collected and stained with hematoxylin and eosin (HE). We observed and recorded pathologic changes of lung tissue and detected apoptosis rate of alveolar epithelial cells by TUNEL (TdT-mediated dUTP nick end labeling). We detected the content of SP-C, SP-D in bronchoalveolar lavage fluid (BALF) by ELISA (enzyme-linked immunosorbent assay). RESULTS: In the air group, the alveolar formed gradually with equable size and regular shape during growth. While the amount of alveolar decreased gradually and we observed small vessels dilation and increasing hemorrhage as well as increasing interstitial cells and swollen lung tissue in the hyperoxia group. In the air group, the content of SP-C in the BALF reduced during growth. However, the content of SP-C in the hyperoxia group was lower than that in the air group on the first day, higher on the third day, reached the peak on the seventh day and began to decrease on the tenth day and more obviously on the fourteenth day. The level of SP-D in the air group declined gradually with growing. On the first day, the content of SP-D in the hyperoxia group was similar to that in the air group. It began to increase on the third day, reached its peak on the seventh day, and began to decrease on the tenth day, more obviously on the fourteenth day. CONCLUSIONS: Long-term exposure to hyperoxia inhibits the development of alveolar. The apoptosis of alveolar epithelial cells increased and the content of SP-C, SP-D in the lung tissue first increased and then decreased with the increase of exposure time.

Comparison of carcinoembryonic antigen prognostic value in serum and tumour tissue of patients with colorectal cancer.

OBJECTIVE: Carcinoembryonic antigen (CEA) in the serum and the tumour tissue of colorectal cancer (CRC) patients is the most commonly used tumour marker for the diagnosis and evaluation of prognosis or recurrence after treatment, but the role remains controversial. The objective of this study was to compare the prognostic value of CEA both in serum and tumour tissue in CRC. METHOD: A total of 173 patients with CRC in stages I-III were retrospectively assessed with the endpoint of recurrence or metastasis after curative operation. CEA was assessed both in serum and tumour tissue. RESULTS: 37.0% (64/173) patients had a high level of CEA in serum (S-CEA) while 39.3% (68/173) had high CEA in tumour tissue (T-CEA). There were no significant differences in clinico-pathological features between the low and high S-CEA or T-CEA groups. The high S-CEA group had a worse prognosis than the low S-CEA group but the difference was not significant. The high T-CEA group had a significantly poorer prognosis than the low T-CEA group (P = 0.028) in the univariate analysis. The multivariate analysis demonstrated that the T-CEA was an independent prognosis factor in CRC. Because many factors would affect the concentration of S-CEA, there was no correlation between S-CEA and T-CEA directly. CONCLUSION: Our study suggests that a high T-CEA concentration may be a useful and independent predictor for poor outcome after surgery in CRC patients. It may be stronger than a high preoperative serum CEA level.

First Report of Hainesia lythri Causing Leaf Spots of Paeonia suffruticosa in China.

Tree peony (Paeonia suffruticosa) is known as "the king of flowers" for its beautiful and showy flowers. It is regarded as the symbol flower of China and is cultivated throughout the country. During the summer of 2006, a leaf spot was observed on tree peony cultivated in the Zhengzhou area of Henan Province, and in 2007, the leaf spot was observed in the Luoyang area. In some gardens, the leaf spot affected more than 50% of the plants. Early symptoms appeared as small, round, water-soaked lesions on the leaves. Lesions expanded into 5 to 35-mm-diameter spots that were circular or irregular, brown to dark brown, with pale brown margins. Later, the center of some lesions dropped out. Signs of the suspected pathogen were usually seen on the leaf spots after an abundant rainfall. Lesions contained numerous, pale brown, cupulate conidiomata with salmon-colored spore masses. Conidiophores (70 × 1 to 2 µm) were hyaline, branched, septate, and filiform. Conidia (5.5 to 7.5 × 1.5 to 2 µm) were hyaline, aseptate, and cymbiform to allantoid. The pathogen was identified as Hainesia lythri on the basis of the morphology. This fungus infects a wide variety of hosts including P. suffruticosa, Acer pseudoplatanus, Calluna sp., Dissotis paucistellata, Epilobium angustifolium, and Eucalyptus saligna (3). The fungus was isolated on potato dextrose agar (PDA) medium using conidia from conidiomata found on symptomatic leaf tissue; the fungus produced gray-to-brown colonies. Pathogenicity was tested by inoculating 10 leaves on one 5-year-old tree with a mycelia plug from the colony (0.5 cm in diameter); leaves inoculated with plugs of PDA medium served as controls. Inoculated leaves were covered with plastic for 24 h to maintain high relative humidity and incubated at 25 to 28°C. After 5 days, 100% of the inoculated leaves showed symptoms identical to those observed on leaves from P. suffruticosa infected in the field while controls remained symptom free. Reisolation of the fungus from lesions on inoculated leaves confirmed that the causal agent was H. lythri. Thus, we concluded that H. lythri is the causal agent of leaf spots of P. suffruticosa. To our knowledge, this is the first report of H. lythri infecting P. suffruticosa in China. H. lythri has been previously reported on Paeonia in Japan and Korea (1,2). References: (1) W. D. Cho and H. D. Shin, eds. List of Plant Diseases in Korea. 4th ed. Korean Society of Plant Pathology, 2004. (2) M. E. Palm. Mycologia 83:787, 1991. (3) B. C. Sutton. The Coelomycetes. CAB International Publishing, New York, 1980.

Colorectal cancer or colon and rectal cancer? Clinicopathological comparison between colonic and rectal carcinomas.

AIMS: The aim of this study was to compare features of colon and rectal cancers such as prognosis, clinicopathological features and tumor markers, namely carcinoembryonic antigen (CEA), matrix metalloproteinase (MMP)-2 and p27(kip1). METHODS: Two hundred and thirty patients with stage I-III colon or rectal cancer were retrospectively assessed with the endpoint of recurrence or metastasis after curative operation. CEA, MMP-2 and p27(kip1) were studied by immunohistochemistry in cancer tissues of all patients. RESULTS: The disease-free 3-year survival rate after operation of the total 230 patients was 63.0%. The prognosis of colon cancer was significantly better than that of rectal cancer (70.6 vs. 57.0%; p = 0.017), especially for stage III (p = 0.0059). Multivariate analysis also demonstrated that tumor location in the colon or rectum, differentiation, venous invasion and the expression of CEA were independent factors for prognosis. The hazard of recurrence and metastasis in rectal cancer was 1.564 times that in colon cancer. In both groups, there were no statistical differences in age, gender, tumor size, tumor gross type, mucin production, tumor differentiation, venous invasion, MMP-2 and p27(kip1). CONCLUSION: We investigated prognosis, clinicopathological factors, oncogenes and tumor suppressor gene production in colon and rectal cancers. The prognosis of colon cancer is better than that of rectal cancer, especially for stage III. This study shows some differences between colon and rectal cancer.