Volume 104 · Issue 07 · 2024

Paying attention to the diagnosis and classification of acquired aplastic anemia (AA) is the basis for improving the efficacy and the guarantee for the correct exploration of the pathological mechanism, which is of great clinical and academic significance. At present, AA classification is still based on clinical characteristics, which is a historical product of academic development.It is beneficial to guide symptomatic treatment and for the onset of curative treatment. However, the clinical classification of AA cannot replace the pathological mechanism classification to guide the treatment of the root cause. The classification of the pathological mechanism of AA determines the choice of treatment strategy, and can provide a basis for the study of etiology and prevention, and is also the future research direction. Paying attention to the classification of the pathological mechanism of AA is the basis for improving the efficacy and the guarantee for the correct exploration of the pathological mechanism. Modern medicine has entered the era of "molecular targets" and "precision", and how to treat clinical classification based on clinical characteristics is an important issue faced by clinicians. When many different mechanisms of bone marrow failure isolated from AA patients can be accurately identified, that is, when the clinically diagnosed AA has been truly purified into a disease with a clear pathological mechanism, the clinical classification of AA can help to choose the root cause strategy. This article mainly focuses on how to view the clinical classification of AA for the reference of colleagues.

Multiple myeloma (MM) is the second most common hematologic malignancy and the incidence of MM in mainland China in 2016 was 1.15/100 000.With the development of China′s aging society, the incidence of MM is expected to increase year by year. Immunotherapy for MM has become the fourth pillar of therapy after autologous hematopoietic stem cell transplantation, immunomodulators, and proteasome inhibitors, and is the most active area of MM treatment. Nine new drugs have been approved for multiple myeloma treatment in China, and three are expected to be approved in 2024, which will focus on immunotherapy. There are many ambiguities about the current status of research and utilization in this emerging field in China. Determining the optimal integration of these therapies into the treatment regimen for Chinese MM patients constitutes a critical challenge for clinicians. Immunotherapy for MM primarily encompasses two major categories: antibody-based drug therapy and cellular immunotherapy. Antibody-based medications primarily include monoclonal antibodies, T-cell engagers, IgG-like bispecific antibodies, and trispecific antibodies. Cellular immunotherapy mainly consists of chimeric antigen receptor T (CAR-T) cells, as well as other immune cells such as chimeric antigen receptor natural killer (CAR-NK) cells, dendritic cells, T cell receptor-engineered T cells, and peptide vaccines.This article mainly focuses on the current research status and existing issues of the aforementioned immunotherapy methods, with the aim of providing references for the treatment of MM.

Anaplastic lymphoma kinase (ALK) fusion represents one of pivotal driver genes within the realm of non-small cell lung cancer (NSCLC). ALK-tyrosine kinase inhibitors (ALK-TKI) have demonstrated remarkable therapeutic efficacy for patients afflicted with ALK-positive NSCLC. As of June 27, 2023, seven ALK-TKI, including crizotinib, ceritinib, alectinib, ensartinib, brigatinib, lorlatinib, and iruplinalkib, have garnered approval from the China National Medical Products Administration (NMPA)(ranking according to the approval time for marketing by NMPA), providing individualized treatment modalities for ALK-positive NSCLC patients. To standardize the application of ALK-TKI, the Chinese Association for Clinical Oncologists and the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care has organized experts to compile the " China expert recommendations on anaplastic lymphoma kinase-tyrosine kinase inhibitors treatment for advanced non-small cell lung cancer (2024 edition)". This treatment expert recommendation provides recommendations in four aspects, encompassing ALK fusion testing, ALK-TKI targeted therapy, ALK-TKI adverse events management, and patient post-treatment follow-up, thus serving as a valuable reference for the standardized treatment of Chinese advanced ALK fusion-positive NSCLC.

Yttrium-90 microsphere selective internal radiation therapy (⁹⁰Y-SIRT) has been used clinically for more than 50 years for liver malignancies, with confirmed safety and efficacy. Although it has been widely used for more than 20 years abroad, ⁹⁰Y-SIRT is just getting started in China. The procedure of ⁹⁰Y-SIRT is relatively complex, which need multidisciplinary teamwork and higher requirements for operators. Once the ectopic distribution of ⁹⁰Y microspheres occurs, it may lead to relatively serious complications. Therefore, it does need to standardize the procedure of ⁹⁰Y-SIRT to ensure its efficacy, reduce the incidence of complications, and promote the popularization and application in China. It is for these reasons that experts from Chinese College of Interventionalists and Society for Hepato-pancreato-biliary Surgery of Chinese Research Hospital Association formulate the Expert consensus based on the literature evidence and clinical practice, which including patient selection, preoperative imaging examination, aim of ⁹⁰Y-SIRT, prescription dose calculation, ⁹⁰Y-SIRT protocol, postoperative management, common adverse reactions and complications, etc.

To analyze the efficacy and safety of first-line treatment with an anti-CD38 monoclonal antibody regimen for primary plasma cell leukemia (pPCL).

Patients diagnosed with pPCL from December 1^st, 2018 to July 26^th, 2023, receiving first-line treatment of anti-CD38 monoclonal antibody-based regimens across multiple centers including Peking University People′s Hospital, Fuxing Hospital of Capital Medical University, Qingdao Municipal Hospital, Shengjing Hospital of China Medical University, Handan Central Hospital, the First Affiliated Hospital of Harbin Medical University, the Fourth Hospital of Hebei Medical University and General Hospital of Ningxia Medical University were consecutively included. A total of 24 pPCL patients were included with thirteen being male and eleven being female. The median age [M(Q₁, Q₃)] was 60 (57, 70) years. Patients were grouped according to peripheral blood plasma cell (PBPC) percentage [5%-19% (n=14) vs ≥20% (n=10)]. Last follow-up date was September 26^th, 2023. The median follow-up period was 9.1 (4.2, 15.5) months. Patients′ data related with clinical baseline characteristics, efficacy, survival and safety were retrospectively collected. Cox proportional hazards regression model was used to analyze risk factors associated with survival.

Among 24 pPCL patients, 16 (66.7%) patients had anemia at diagnosis, 13(54.2%) patients had thrombocytopenia, 8 (33.3%) patients had a baseline estimated glomerular filtration rate (eGFR)<40 ml·min^-1·(1.73m²)^-1, 13 (54.2%) patients had elevated lactate dehydrogenase (LDH) levels. The median PBPC percentage was 16% (8%, 26%) . Fluorescence in situ hybridization testing indicated that patients harboring 17p deletion, t(4;14) or t(14;16) were 6 (25.0%), 4 (16.7%) and 4 (16.7%), respectively. The overall response rate was 83.3% (20/24). The median progression-free survival (PFS) was 20.5 (95%CI: 15.8-25.2) months, and the median overall survival (OS) was not reached. Estimated 1-year and 2-year PFS and OS rates were 75.0% and 89.1%, 37.5% and 53.4%, respectively. The median PFS and OS for patients with PBPC percentages 5%-19% and≥20% were not reached and 20.5 (95%CI:15.7-25.3) months, 17.8 months and not reached, respectively. There was no significant statistical difference of PFS and OS between two groups (all P>0.05). Multivariate Cox regression analysis showed that 1p32 deletion was the risk factor associated with PFS (HR=7.7, 95%CI: 1.1-54.9, P=0.043). Seventeen patients (70.8%) developed grade 3-4 hematologic toxicities. Twelve patients (50.0%) developed grade 3-4 thrombocytopenia. Sixteen patients (66.7%) developed infection. All hematologic toxicities and infections were improved after supportive treatment.

First-line treatment with anti-CD38 monoclonal antibody-based therapy for pPCL is effective and safe.

To investigate the characteristics of cytopenia and its impact on prognosis in patients with relapsed and refractory multiple myeloma (RRMM) after B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) immunotherapy therapy.

Clinical data of 36 RRMM patients received BCMA CAR-T therapy at the First Affiliated Hospital of Nanjing Medical University from April 2017 to March 2023 were retrospectively collected. Among them, there were 17 males and 19 females, with an age [M (Q₁, Q₃)] of 62 (53, 67) years. The follow-up deadline was August 31, 2023, and the follow-up time [M (Q₁, Q₃)] was 33 (10, 30) months. The characteristics of cytopenia at different time points before lymphodepleting chemotherapy and after CAR-T cell infusion in all patients were analyzed. Kaplan-Meier method was used to compare the differences in progression-free survival (PFS) and overall survival (OS) in patients with different clinical characteristics. Single-cell sequencing analysis was used to analyze the changes in hematopoietic stem cells in three patients after CAR-T cell therapy.

The incidence of cytopenia after BCMA CAR-T cell therapy in 36 RRMM patients reached 100%. The incidence of neutropenia peaked on the 7th and 28th day after cell infusion with a biphasic pattern of change.Patients with all grade neutropenia reached 61.1% (22/36) and grade 3 or higher reached 33.3% (12/36) on the 7th day, while patients with all grade neutropenia reached 67.9% (19/28) and grade 3 or higher reached 28.6% (8/28) on the 28th day (P<0.001),respectively. The occurrence rate of lymphopenia reached a peak on the day of CAR-T cell infusion [97.2% (35/36) patients showed lymphopenia, while 80.6% (29/36) patients showed grade 3 or higher lymphopenia] (P<0.001).The incidence of all grade of thrombocytopenia and severe thrombocytopenia (grade 3 or higher) peaked on the 14th day after cell infusion, with the rates of 69.4% (25/36) and 30.6% (11/36) respectively, which had a prolonged duration(P<0.001). Even after 12 months, 40% (8/20) of patients still experienced thrombocytopenia.The incidence of anemia peaked on the 7th and 14th day after cell infusion, with a rate of 100% (36/36) (P<0.001). 50% (10/20) of patients still had anemia even 12 months after cell infusion. Kaplan-Meier survival analysis showed that patients with thrombocytopenia < grade 3 had undefined OS, while patients with thrombocytopenia ≥grade 3 had shorter OS [17 (95%CI: 2-32) months, χ²=4.154, P=0.042], indicating a poorer prognosis. However, there was no statistically significant difference in the relationship between other cytopenia and survival (all P>0.05). Single-cell sequencing analysis of bone marrow cells revealed decreased proliferation, increased apoptosis, and cell cycle arrest of hematopoietic stem cells after CAR-T cell infusion.

All patients experienced varying degrees of cytopenia after receiving BCMA CAR-T cell infusion, and patients with thrombocytopenia ≥grade 3 had shorter OS and poorer prognosis.

To investigate the therapeutic effect and prognostic value of oligoclonal bands (OB) in multiple myeloma (MM) patients after autologous stem cell transplant (ASCT).

The data of 156 patients with MM who underwent ASCT after inductive treatment in the Department of Hematology, Jiangsu Provincial People′s Hospital from December 2013 to February 2022 were retrospectively analyzed, including 91 males and 65 females. The median age was 56 (26, 71) years. Patients were divided into two groups according to OB formation after ASCT treatment, including OB group (n=60) and non-OB group (n=96). The last follow-up date was August 31, 2023, and the follow-up period was 42 (18, 117) months. The clinical baseline characteristics and efficacy of the two groups were compared. Progression-free survival (PFS) and overall survival (OS) were compared between the two groups by Kaplan-Meier method. Cox risk regression modal was used to analyze the risk factors associated with prognosis.

There were no significant differences in age, type, stage, risk stratification, extramedullary disease (EMD), proportion of circulating plasma cells and induction therapy regimen between OB and non-OB groups (all P>0.05). The proportion of patients in OB group who achieved complete response (CR) or above after ASCT treatment was 93.3% (56/60), which was higher than that in non-OB group (80.2%, 77/96) (P=0.024). The negative rate of minimal residual disease (MRD) in OB group was 66.7% (40/60), which was higher than that in non-OB group (34.4%, 33/96) (P=0.001). The median PFS and OS in the OB group were not reached, and the median PFS and OS in the non-OB group were 28 (2, 80) months and 86 (2, 100) months, respectively. The PFS (P<0.001) and OS (P=0.017) of patients with OB were considerably longer. In the Cox multivariate analysis, OB was an independent prognostic factor for PFS in MM patients (HR=0.314, 95%CI: 0.153-0.644, P=0.002). Subgroup analysis showed that among high-risk patients with mSMART, the OS of patients in OB group was not reached, which was significantly better than that of non-OB group [71 (2, 90) months, P=0.046]. However, no significant difference was observed in the OS of patients with OB and those with non-OB in standard risk group (not reached vs not reached, P=0.103). In those with EMD at diagnosis, patients with OB had significantly better OS than those with non-OB [not reached vs 47 (6, 74) months, P=0.037]. However, no significant difference was observed in the OS of patients with OB and those with non-OB in those without EMD at diagnosis [not reached vs 86 (2, 100) months, P=0.130].

OB formation after ASCT treatment in MM patients is related to the efficacy and prognosis. OB formation can increase the negative MRD rate, prolong the OS and improve the prognosis, especially for newly diagnosed patients with extramedullary disease or patients with high-risk genetic characteristics.

To investigate the efficacy and safety in relapsed and refractory multiple myeloma (RRMM) patients with combination regimen of daratumumab.

The clinical data of 42 RRMM patients admitted to Qingdao Municipal Hospital from December 2020 to November 2023 were retrospectively analyzed, which included 26 males and 16 females, with a median age of 59 (47, 82) years old. According to the number of courses of treatment with Daratumumab, patients were divided into three groups: long course group (≥9 courses, n=21), medium course group (7-8 courses, n=12), and short course group (≤6 courses, n=9). The deadline for follow-up was November 10, 2023, and the follow-up period was 15.6 (6.0, 34.0) months. After completing at least 2 courses of treatment, patients were evaluated for efficacy, including stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), stable disease (SD), and progressive disease (PD). Basic clinical characteristics of patients, overall response rate of treatment, and adverse reactions were statistically analyzed. Kaplan-Meier method was used to compare the differences of progression-free survival (PFS) in patients with different courses of treatment.

Among the 42 patients, 15 (35.7%) had extramedullary disease or plasmacytic leukemia, 7 (16.6%) had amyloidosis, and 18 (42.9%) had renal insufficiency. In Mayo stage, 25 patients (59.5%) were at high risk of myeloma cytogenetic stratification, 8 patients (19%) were standard risk, 9 patients (21.4%) had no cytogenetic data. There were 16 patients with second-line treatment (38.0%), 13 patients with third-line treatment (31%), and 13 patients with more than fourth-line treatment (31%). All patients received at least 2 courses of treatment, achieving the best degree of disease response in 4 cases of sCR (9.5%), 3 cases of CR (7.1%), 10 cases of VGPR (23.8%), 11 cases of PR (26.2%), and 6 cases of MR (14.2%). The overall response rate (ORR) was 80.9% (34/42). The overall response rate was 100% (21/21) in the long course group, 91.6% (11/12) in the medium course group and 22.2% (2/9) in the short course group. Kaplan-Meier survival analysis showed that the duration of PFS was 5.0 (95%CI: 3.1-6.9) months in the short course group,>8.0 months in the medium course group, and>38.0 months in the long course group, the difference was statistically significant (P<0.05). Grade≥3 adverse reactions were mainly neutropenia (3 cases) and thrombocytopenia (1 case). None of the patients discontinued treatment due to adverse reactions.

Treatment of RRMM with a regimen containing Daratumumab requires a longer course of treatment to achieve maximum efficacy and the adverse reactions can be controlled.

To observe the clinical efficacy of a 3D printed self-stable zero-profile artificial vertebral body for anterior cervical corpectomy decompression and fusion in the treatment of ossification of the posterior longitudinal ligament (OPLL) of the cervical spine.

In this prospective randomized controlled trial, patients diagnosed with OPLL in Luohe Central Hospital from January to July 2022 were divided into a zero-profile group (3D printed self-stable zero-profile artificial vertebral body was used for internal fixation and fusion after anterior cervical subtotal decompression,) and titanium-mesh group (titanium-mesh and titanium plate were used for internal fixation and fusion after anterior cervical subtotal decompression) according to envelope random method. Operation time, intraoperative blood loss, Japanese Orthopaedic Association (JOA) score and improvement rate, incidence of postoperative prosthesis subsidence, and bone graft fusion were recorded and compared between the two groups.

Finally, 21 patients in the zero notch group and 20 patients in the titanium mesh group were included in the study and were followed-up. In the zero-profile group, there were 16 males and 5 females, aged (48.0±12.7) years. In the titanium-mesh group, there were 14 males and 6 females, aged (49.8±10.2) years. All the 41 patients successfully completed the operation. In the zero-profile group, the surgical time was (50.04±8.45) minutes, the blood loss was (95.38±26.07) ml and the hospitalization cost was (42.32±6.12) thousand yuan. In the titanium-mesh group, the surgical time was (59.20±11.95) minutes, the blood loss was (93.10±27.86) ml and the hospitalization cost was (42.10±6.71) thousand yuan. The surgical time in the zero-profile group was shorter than that in the titanium-mesh group (P=0.007), and there was no statistically significant difference in blood loss and hospitalization costs between the two groups (both P>0.05). The 41 patients were followed-up for (14.29±1.45) months. Four cases (20.0%) in the titanium mesh group experienced swallowing difficulties and 0 cases in the zero incision group, the difference between the two groups was statistically significant (P=0.048). No intraoperative hematoma, spinal cord nerve recompression, airway crisis, incision infection complications, and no steel plate or screw breakage or displacement occurred after surgery. At the last follow-up, all cases had bone fusion. At the follow-up of 12 months after surgery, the JOA score of the zero incision group increased from preoperative (10.33±1.71) points to (15.47±0.81) points, with an improvement rate of 76.1%±15.7%; the JOA score of the titanium mesh group increased from (10.30±1.75) points to (15.30±0.92) points, with an improvement rate of 73.2%±16.7%; there was no statistically significant difference in improvement rate between the two groups (P=0.580). At the follow-up of 12 months after surgery, 1 case (4.8%) in the zero incision group and 8 cases (40.0%) in the titanium mesh group experienced implant sinking, and the difference between the two groups was statistically significant (P=0.009).

Compared with titanium-mesh, 3D printed self-stable zero-profile artificial vertebral body for the treatment of OPLL of the cervical spine can achieve good surgical efficacy, shorter surgical time, lower incidence of postoperative chronic swallowing discomfort, and can provide a better bone material bonding interface and be less prone to prosthesis settlement.

To evaluate the value of virtual non-calcium (VNCa) technique of dual-energy CT (DECT) for detecting bone marrow edema (BME) around nontraumatic osteonecrosis of the femoral head (ONFH) using MRI as reference standard.

Nontraumatic ONFH patients were prospectively studied in the Fourth Medical Center of Chinese PLA General Hospital from October 2022 to May 2023, and their MRI and DECT images were analyzed. The diagnostic efficiency of the subjective assessment of BME around ONFH by two radiologists in VNCa color-coded images were calculated using the MRI results as the reference standard. The BME ranges were compared between VNCa images and MRI. Traditional CT values and VNCa CT values were compared between normal bone marrow and BME. The receiver operator characteristic (ROC) curve was established based on the statistically different CT values, and the area under the curve (AUC) was calculated to find the threshold to distinguish normal bone marrow from BME and evaluate the diagnostic efficacy.

Thirty patients with ONFH were included, including 24 males and 6 females, aged (39±12) years. There were 18 bilateral hips and 12 unilateral hips, with a total of 48 hips, 34 hips of which showed BME on MRI. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of subjective detection of BME on VNCa color coded maps by two physicians were 97.1% (33/34) and 97.1% (33/34), 92.9% (13/14) and 71.4% (10/14), 97.1% (33/34) and 89.2% (33/37), 92.9% (13/14) and 90.9% (10/11), 95.8% (46/48) and 89.6% (43/48), respectively, with no statistical difference (all P>0.05).There was no statistical difference between VNCa color-coded images and MRI in the BME range (P=1.160). The traditional CT values measured by the two radiologists were in good agreement with VNCa CT values, with intraclass correlation coefficient (ICC) of 0.948 (95%CI: 0.908-0.971) and 0.982 (95%CI: 0.969-0.990), respectively. The traditional CT value of normal bone marrow was (400.7±82.8) HU, and that of BME was (443.7±65.7) HU, with no statistical difference (P=0.062). The VNCa CT value of normal bone marrow was (-103.1±27.8) HU, and that of BME was (-32.9±25.7) HU, with statistical difference (P<0.001). The AUC of distinguishing normal bone marrow from BME based on VNCa CT value was 0.958 (95%CI: 0.857-0.995). The best cut-off value was -74.5 HU, and when the VNCa CT value was higher than -74.5 HU, the sensitivity, specificity, PPV, NPV and accuracy of diagnosing BME were 97.1%, 92.9%, 97.1%, 92.9% and 95.8 %, respectively.

The VNCa technique of DECT has high efficiency in detecting BME around ONFH, and can accurately demonstrate the range of BME.

To establish an acute graft-versus-host disease (aGVHD) model in aged mice after non-myeloablative haploidentical peripheral blood stem cell transplantation (haplo-PSCT).

C57BL/6 (H-2^b) male mice aged 6-8 weeks were used as donor mice, and CB6F1 (H-2^b×d) female mice aged 14-16 months were used as recipient mice. The donor mice were injected subcutaneously with rehuman granulocyte-colony stimulating factor (rhG-CSF) 5 days before transplantation for hematopoietic stem cell mobilization.The recipient mice were divided into control group (CG), spleen cell low-dose group (SL), spleen cell medium-dose group (SM) and spleen cell high-dose group (SH) according to random number table method, with 16 rats in each group, all of which received total linear accelerator X-ray irradiation (TBI) with a total dose of 6 Gy. Peripheral blood mononuclear cells (PBMC) and spleen cells of different doses (0.5×10⁷/each, 1.0×10⁷/each and 2.0×10⁷/each in SL group, SM group and SH group, respectively) were transfused through the tail vein within 4 hours after TBI, and only the same amount of normal saline was transfused in CG group. After transplantation, the survival and weight changes of mice in each group were observed for 30 days, and the changes of blood routine were monitored regularly. Mice peripheral blood was collected 21 days after transplantation to detect the chimerism rate of the donor. Hematoxylin-eosin staining was performed on the skin, liver and colon of mice 21 days after transplantation to analyze the histopathological changes of aGVHD target organs.

All the mice in each group were successfully transplanted. After TBI, the weight and activity of mice in all groups decreased, and the phenomenon of bone marrow suppression appeared. During the observation period, all mice in CG group and SL group survived, 3 mice in SM group died with survival time of (26.0±5.8) days, and 6 mice in SH group died with survival time of (20.9±7.3) days. The body weight of mice in SH group was lower than that in CG group, SL group and SM group 21days after transplantation [(25.0±0.7), (25.5±0.4), (25.0±1.4) vs (20.8±0.8) g, all P<0.05]. Compared with CG group, SL group and SM group, the levels of leukocyte, erythrocyte, hemoglobin and platelet in SH group decreased 21 days after transplantation (all P<0.05). There was no significant difference in donor chimerism rate among SL group, SM group and SH group [(95.8%±0.8%), (95.5%±1.4%) and (95.1%±1.3%), respectively, all P>0.05]. Compared with CG group, SL group and SM group, the tissue structure of aGVHD target organs in SH group was severely damaged, with a large number of inflammatory cells infiltratedand higher histopathological scores than SL group and SM group (all P<0.05).

For aging CB6F1 mice, after 6 Gy TBI pretreatment with linear accelerator X-ray, PBMC (1×10⁷/each) and spleen cells (2.0×10⁷/each) were injected to successfully induce aGVHD model after non-myelablative haplo-PSCT.

In this study, a case of Lynch syndrome (LS) family line with a novel mutation site in the MLH1 c.463dupC gene was reported and the clinical and pathogenic genetic features of this family were analyzed. A 40-year-old female patient with colon cancer diagnosed at the First Affiliated Hospital of Kunming Medical University on October 2, 2020 was retrospectively included. The clinical data of the family were collected and the family lineage was drawn. The family tumor history met the Amsterdam Criteria Ⅱ and the diagnostic criteria of LS in Chinese, which was a typical LS family lineage. A germline code-shift missense mutation c.463dupC in the MLH1 gene located in exon 6, a possible pathogenic variant, was detected by second-generation sequencing (NGS) in the patient. Subsequently, Sanger sequencing was performed on a total of 20 direct lineage members of the family of the MLH1 gene, 7 cases were found to harbor the mutation and included in the LS high-risk control. Follow-up to October 2023 showed that the patient had endometrial and cervical polyps, one case had colorectal cancer, and two cases had intestinal polyps, all were treated with early intervention and therapy; two cases did not show any clinical symptoms. This study is the first to report a new mutation site for the potentially pathogenic MLH1 c.463dupC, providing a rationale for the pathogenicity of the mutation and standardized health management for familial carriers.

The incidence of Hodgkin's lymphoma (HL) accounts for 5% to 10% of all lymphomas. Although the standard first-line chemotherapy combined with ABVD regimen (doxorubicin + bleomycin + vinblastine + dacarbazine) has a high cure rate for HL patients, there are still about 20% patients in my country who progress or relapse after first-line treatment. Autologous hematopoietic stem cell transplantation in relapsed patients after rescue chemotherapy can slightly improve the progression-free survival time, but the overall cure rate is only about 50%. Whether complete remission can be achieved by pre-transplantation treatment is crucial to whether long-term progression-free survival can be achieved after transplantation. Therefore, patients who have failed first-line chemotherapy and are difficult to tolerate chemotherapy need effective rescue treatment and pre-transplantation bridging scheme. In recent years, programmed cell death receptor 1 (PD-1) monoclonal antibodies have made great progress in the treatment of relapsed and refractory HL, but monotherapy has exposed many shortcomings. This paper summarizes the results of clinical trials of combination therapy containing PD-1 monoclonal antibody in recent years, and introduces some potential combination therapy regimens based on molecular immunology and preclinical studies, including PD-1 monoclonal antibody combined with cytotoxic drug regimen, PD-1 monoclonal antibody combined with epigenetic drug regimen, PD-1 monoclonal antibody combined with cell adaptor protein regimen, PD-1 monoclonal antibody combined with other immunomodulator regimen, PD-1 monoclonal antibody combined with adoptive cellular immunotherapy regimen, PD-1 monoclonal antibody combined with hematopoietic stem cell transplantation regimen, and explains the advantages and disadvantages of different combination therapy regimens from the aspects of clinical effect and mechanism of action, in order to provide reference for clinical diagnosis and treatment.

Treatment-resistant depression (TRD) refers to depression in which patients have not improved significantly after at least two antidepressants with different mechanisms of action, sufficient treatment, and standardized treatment. It has the characteristics of low remission rate and high relapse rate. According to statistics, 10% ~30% of patients with severe depression suffer from TRD, which is significantly associated with the occurrence of complications, increased mortality and suicide rates, and increased economic burden. At present, the primary goal of initial treatment for major depression is to alleviate the condition, and the goal of maintenance treatment is to prevent recurrence. Clinical guidelines recommend esketamine nasal spray or quetiapine sustained-release therapy in combination with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) for TRD. The study conducted an open-label, single-blind (raters do not know the grouping), multicenter, randomized, active drug-controlled clinical phase 3b trial (ESCAPE-TRD) to compare the efficacy and safety of the two therapies.

Benzodiazepines that act on gamma-aminobutyric acid (GABA) A receptor are often used as preoperative medications and anesthesia because of their good sedative, hypnotic and anxiolytic effects. While its anterograde amnestic effect may prevent intraoperative knowledge, the increased risk of delirium caused by the use of such drugs in the intensive care unit (ICU) is no longer in line with medical standards. Therefore, the 2018 Perioperative Brain Health Initiative avoids benzodiazepines for patients at risk of postoperative neurocognitive impairment and delirium. However, without weighting the risks and benefits of perioperative benzodiazepine use, there remains uncertainty about its perioperative safety. The study evaluated the safety and efficacy of perioperative benzodiazepine medication through a systematic review and meta-analysis.