[Systemic therapeutic strategies for hepatocellular carcinoma: current status and prospects].

Hepatocellular carcinoma (HCC) is a common type of poorly prognosticated malignant tumor. Surgical resection is the preferred treatment method for early-stage HCC. However, at the time of the initial diagnosis, fewer than 30% of patients with liver cancer are suitable for radical therapy. Systemic therapy plays an important role in the treatment process of patients with intermediate- to advanced-stage HCC, as it can effectively extend patients' survival time. With an emphasis on the status and role of systemic therapy for comprehensive management of HCC, this article summarizes the latest progress at home and abroad in the past five years, including first-line combined immunotherapy for advanced-stage HCC, second-line therapy selection, perioperative systemic therapy application, and combined therapy of systemic and local. Currently, the treatment model combined with local therapy has already become a new research hotspot in the treatment of advanced-stage HCC. Nevertheless, in the future, individualized and precise systemic therapeutic strategies will need further exploration.

Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers.

How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal-regulated kinase (ERK)-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome (APC/C) and other components of the cell cycle machinery as key processes that drive pancreatic ductal adenocarcinoma (PDAC) growth. Our findings elucidate mechanistically the critical role of ERK in driving KRAS-mutant tumor growth and in resistance to KRAS-ERK MAPK targeted therapies.

[Efficacy and safety analysis of the zanubrutinib-based bridging regimen in chimeric antigen receptor T-cell therapy for relapsed/refractory diffuse large B-cell lymphoma].

Objective: To further elucidate the clinical efficacy and safety of a combination regimen based on the BTK inhibitor zebutanil bridging CD19 Chimeric antigen receptor T cells (CAR-T cells) in the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) . Methods: Twenty-one patients with high-risk r/r DLBCL were treated with a zanubrutinib-based regimen bridging CAR-T between June 2020 and June 2023 at the Department of Hematology, Tongji Hospital, Tongji University and the Second Affiliated Hospital of Zhejiang University, and the efficacy and safety were retrospectively analyzed. Results: All 21 patients were enrolled, and the median age was 57 years (range: 38-76). Fourteen patients (66.7%) had an eastern cooperative oncology group performance status score (ECOG score) of ≥2. Eighteen patients (85.7%) had an international prognostic index (IPI) score of ≥3. Three patients (14.3%) had an IPI score of 2 but had extranodal infiltration. Fourteen patients (66.7%) had double-expression of DLBCL and seven (33.3%) had TP53 mutations. With a median follow-up of 24.8 (95% CI 17.0-31.6) months, the objective response rate was 81.0%, and 11 patients (52.4%) achieved complete remission. The median progression-free survival (PFS) was 12.8 months, and the median overall survival (OS) was not reached. The 1-year PFS rate was 52.4% (95% CI 29.8% -74.3%), and the 1-year OS rate was 80.1% (95% CI 58.1% -94.6%). Moreover, 18 patients (85.7%) had grade 1-2 cytokine-release syndrome, and two patients (9.5%) had grade 1 immune effector cell-associated neurotoxicity syndrome. Conclusion: Zanubrutinib-based combination bridging regimen of CAR-T therapy for r/r DLBCL has high efficacy and demonstrated a good safety profile.

[Clinicopathological and molecular features of metaplastic thymoma].

Objective: To investigate the clinicopathological features, and molecular genetic alterations of metaplastic thymoma (MT). Methods: A total of ten MT cases, diagnosed from 2011 to 2021, were selected from the Department of Pathology of Jinling Hospital, Nanjing University Medical School, Nanjing, China for clinicopathological and immunohistochemical (IHC) examination and clinical follow-up. Fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), and YAP1 C-terminus (YAP1-CT) IHC were performed to detect YAP1::MAML2 fusions. Results: There were four males and six females, ranging in age from 29 to 60 years (mean 50 years, median 54 years). Microscopically, all tumors showed a typical biphasic morphology consisting of epithelial components and gradually or abruptly transitioning spindle cell components. The two components were present in varying proportions in different cases. Immunophenotypically, the epithelial cells were diffusely positive for CKpan, CK5/6 and p63. The spindle cells were diffusely positive for vimentin and focally positive for EMA. TdT was negative in the background lymphocytes. Ki-67 proliferation index was less than 5%. YAP1 and MAML2 break-apart FISH analyses showed that all ten cases had narrow split signals with a distance of nearly 2 signal diameters and may be considered false-negative. Using YAP1::MAML2 fusion FISH assays, abnormal fusion signals were observed in all the ten cases. NGS demonstrated YAP1::MAML2 fusions in all eight cases with adequate nucleic acids; in two cases the fusions were detected by DNA sequencing and in eight cases by RNA sequencing. All ten cases of MT demonstrated loss of YAP1 C-terminal expression in epithelioid cells. Conclusions: MT is a rare and low-grade thymic tumor characterized by a biphasic pattern and YAP1::MAML2 fusions. Break-apart FISH assays may sometimes show false-negative results due to the proximity of YAP1 and MAML2, while YAP1 C-terminal IHC is a highly sensitive and specific marker for MT. Loss of YAP1 C-terminal expression can also be used to screen YAP1::MAML2 fusions for possible MT cases.

[Incidence and prognosis of olfactory and gustatory dysfunctions related to infection of SARS-CoV-2 Omicron strain: a national multi-center survey of 35 566 population].

Objective: This cross-sectional investigation aimed to determine the incidence, clinical characteristics, prognosis, and related risk factors of olfactory and gustatory dysfunctions related to infection with the SARS-CoV-2 Omicron strain in mainland China. Methods: Data of patients with SARS-CoV-2 from December 28, 2022, to February 21, 2023, were collected through online and offline questionnaires from 45 tertiary hospitals and one center for disease control and prevention in mainland China. The questionnaire included demographic information, previous health history, smoking and alcohol drinking, SARS-CoV-2 vaccination, olfactory and gustatory function before and after infection, other symptoms after infection, as well as the duration and improvement of olfactory and gustatory dysfunction. The self-reported olfactory and gustatory functions of patients were evaluated using the Olfactory VAS scale and Gustatory VAS scale. Results: A total of 35 566 valid questionnaires were obtained, revealing a high incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain (67.75%). Females(χ2=367.013, P<0.001) and young people(χ2=120.210, P<0.001) were more likely to develop these dysfunctions. Gender(OR=1.564, 95%CI: 1.487-1.645), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), oral health status (OR=0.881, 95%CI: 0.839-0.926), smoking history (OR=1.152, 95%CI=1.080-1.229), and drinking history (OR=0.854, 95%CI: 0.785-0.928) were correlated with the occurrence of olfactory and taste dysfunctions related to SARS-CoV-2(above P<0.001). 44.62% (4 391/9 840) of the patients who had not recovered their sense of smell and taste also suffered from nasal congestion, runny nose, and 32.62% (3 210/9 840) suffered from dry mouth and sore throat. The improvement of olfactory and taste functions was correlated with the persistence of accompanying symptoms(χ2=10.873, P=0.001). The average score of olfactory and taste VAS scale was 8.41 and 8.51 respectively before SARS-CoV-2 infection, but decreased to3.69 and 4.29 respectively after SARS-CoV-2 infection, and recovered to 5.83and 6.55 respectively at the time of the survey. The median duration of olfactory and gustatory dysfunctions was 15 days and 12 days, respectively, with 0.5% (121/24 096) of patients experiencing these dysfunctions for more than 28 days. The overall self-reported improvement rate of smell and taste dysfunctions was 59.16% (14 256/24 096). Gender(OR=0.893, 95%CI: 0.839-0.951), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), history of head and facial trauma(OR=1.180, 95%CI: 1.036-1.344, P=0.013), nose (OR=1.104, 95%CI: 1.042-1.171, P=0.001) and oral (OR=1.162, 95%CI: 1.096-1.233) health status, smoking history(OR=0.765, 95%CI: 0.709-0.825), and the persistence of accompanying symptoms (OR=0.359, 95%CI: 0.332-0.388) were correlated with the recovery of olfactory and taste dysfunctions related to SARS-CoV-2 (above P<0.001 except for the indicated values). Conclusion: The incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain is high in mainland China, with females and young people more likely to develop these dysfunctions. Active and effective intervention measures may be required for cases that persist for a long time. The recovery of olfactory and taste functions is influenced by several factors, including gender, SARS-CoV-2 vaccination status, history of head and facial trauma, nasal and oral health status, smoking history, and persistence of accompanying symptoms.

[Clinical value of nomogram model in evaluating the prognosis of cholangiocarcinoma after interventional therapy].

Objective: To investigate the clinical value and efficacy of the nomogram model in evaluating the prognosis of cholangiocarcinoma after interventional therapy. Methods: The clinical data of 259 patients with cholangiocarcinoma who received interventional therapy at the First Affiliated Hospital of zhengzhou University from January 2014 to June 2021 were retrospectively analyzed, including 148 males and 111 females, aged from 26 to 91 (65±12) years. They were randomly divided into a training group (181 cases) and a validation group (78 cases) in a ratio of 7∶3. Cox regression analysis was performed in the training group, independent risk factors affecting the prognosis of patients were screened, and a nomogram for 6-month, 1-year, and 2-year survival was constructed. The performance of the nomogram was analyzed by calculating the area under the receiver operating characteristic curve (AUC) value, calibration curve, and decision curve, and the predictive efficacy of the model was evaluated in the validation group. Results: There was no significant difference in baseline data between the training group and the validation group, which was comparable. Regression analysis showed that T stage (T2: HR=0.147,95%CI: 0.077-0.281;T3: HR=0.207,95%CI: 0.122-0.351;T4: HR=0.864,95%CI: 0.537-1.393), tumor diameter (17-33 mm: HR=0.201,95%CI: 0.119-0.341;≥33 mm: HR=0.795,95%CI: 0.521-1.211) and differentiation degree(middle differentiation: HR=3.318,95%CI: 2.082-5.289;highly differentiation: HR=1.842,95%CI: 1.184-2.867) were risk factors affecting the prognosis of interventional therapy for cholangiocarcinoma. The AUC values of the survival curve prediction models were generally consistent between the training and validation groups, and the AUC values of the training group at 6 months, 1 year, and 2 years were 0.925 (95%CI: 0.888-0.963), 0.921 (95%CI: 0.877-0.964) and 0.974 (95%CI: 0.957-0.993), respectively. In the validation group, the 6-month, 1-year, and 2-year AUC values were 0.951 (95%CI: 0.911-0.991), 0.917 (95%CI: 0.857-0.977) and 0.848 (95%CI: 0.737-0.959), respectively, and the AUC values were all greater than 0.8, suggesting that the nomogram had better discrimination ability. The calibration curves of the prediction models of the two groups were basically consistent, and the shape of the calibration curves at 6 months and 1 year fitted the ideal curve, while the fitting degree of the calibration curves at 2 years was relatively poor. The decision curve showed the high clinical utility of this nomogram in predicting the 6-month, 1-year survival of patients with cholangiocarcinoma. Conclusions: T stage, tumor diameter, and differentiation are independent risk factors affecting the prognosis of patients with interventional cholangiocarcinoma, and the nomogram model proposed in this study has good distinguishing ability and exact clinical value for prognosis evaluation.

VCP/p97, a pleiotropic protein regulator of the DNA damage response and proteostasis, is a potential therapeutic target in KRAS-mutant pancreatic cancer.

We and others have recently shown that proteins involved in the DNA damage response (DDR) are critical for KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) cell growth in vitro. However, the CRISPR-Cas9 library that enabled us to identify these key proteins had limited representation of DDR-related genes. To further investigate the DDR in this context, we performed a comprehensive, DDR-focused CRISPR-Cas9 loss-of-function screen. This screen identified valosin-containing protein (VCP) as an essential gene in KRAS-mutant PDAC cell lines. We observed that genetic and pharmacologic inhibition of VCP limited cell growth and induced apoptotic death. Addressing the basis for VCP-dependent growth, we first evaluated the contribution of VCP to the DDR and found that loss of VCP resulted in accumulation of DNA double-strand breaks. We next addressed its role in proteostasis and found that loss of VCP caused accumulation of polyubiquitinated proteins. We also found that loss of VCP increased autophagy. Therefore, we reasoned that inhibiting both VCP and autophagy could be an effective combination. Accordingly, we found that VCP inhibition synergized with the autophagy inhibitor chloroquine. We conclude that concurrent targeting of autophagy can enhance the efficacy of VCP inhibitors in KRAS-mutant PDAC.

[Effect of early tocilizumab intervention on patients with cytokine release syndrome following chimeric antigen receptor T cell therapy].

Objective: This study aimed to evaluate the effect of early tocilizumab intervention to relieve cytokine release syndrome (CRS) following chimeric antigen receptor T cell (CAR-T) therapy. Methods: Twenty-two patients with acute lymphoblastic leukemia who received tocilizumab to relieve CRS response after CAR-T cell infusion in our research center from October 2015 to July 2021 were retrospectively analyzed. According to the timing of tocilizumab intervention, patients were divided into the conventional and early intervention groups. Patients who received tocilizumab treatment after sustained high fever for 4 h were included in the early intervention group. The clinical data, CRS grade, and event-free survival (EFS) between the two groups were evaluated. Results: Compared with patients who used tocilizumab after severe CRS, no patients in the early intervention group died from CRS, and there was no increased risk of neurotoxicity. Eleven patients (84.62%) achieved complete remission with minimal residual lesions. The median EFS of patients in the early intervention and conventional groups was 2 (95% CI 0-5) and 7 (95% CI 3-11) months, respectively. Conclusion: Early tocilizumab intervention in patients with CRS reduces severe CRS and provides a more optimized therapeutic strategy for CRS caused by CAR-T cell therapy.

Sortilin 1 regulates hepatocellular carcinoma progression by activating the PI3K/AKT signaling.

BACKGROUND: Sortilin 1 (SORT1) has been reported as an oncogene in several human tumors. Nonetheless, the biological functions of SORT1 in hepatocellular carcinoma (HCC) remain poorly understood. METHODS: Western blotting was employed for the determination of protein expression. Hepatocellular carcinoma cell viability, apoptosis, migration, and invasion were measured via CCK-8, flow cytometry, wound healing, and Transwell assays. RESULTS: Sortilin 1 was upregulated in HCC and closely associated with unsatisfactory outcomes of HCC patients. Furthermore, in vitro and in vivo assays revealed that SORT1 knockdown significantly diminished HCC cell proliferation and metastasis but accelerated HCC cell apoptosis; moreover, SORT1 depletion also restrained the growth of xenografted HCC tumors. Mechanistically, SORT1 activated PI3K/AKT signaling in HCC cells, thereby promoting the malignant behaviors of HCC cells. CONCLUSION: This study demonstrated that SORT1 might promote HCC progression by activating PI3K/AKT signaling, indicating that SORT1 might be a promising target and biomarker for HCC treatment and prognosis.

Saturn Anomalous Myriametric Radiation, a New Type of Saturn Radio Emission Revealed by Cassini.

A new radio component namely Saturn Anomalous Myriametric Radiation (SAM) is reported. A total of 193 SAM events have been identified by using all the Cassini Saturn orbital data. SAM emissions are L-O mode radio emission and occasionally accompanied by a first harmonic in R-X mode. SAM's intensities decrease with increasing distance from Saturn, suggesting a source near Saturn. SAM has a typical central frequency near 13 kHz, a bandwidth greater than 8 kHz and usually drifts in frequency over time. SAM's duration can extend to near 11 hr and even longer. These features distinguish SAM from the regular narrowband emissions observed in the nearby frequency range, hence the name anomalous. The high occurrence rate of SAM after low frequency extensions of Saturn Kilometric Radiation and the SAM cases observed during compressions of Saturn's magnetosphere suggest a special connection to solar wind dynamics and magnetospheric conditions at Saturn.

[Efficacy of in-situ full-left/full-right split liver transplantation for adult recipients using the living donor liver transplantation technique:a single-center report of 25 cases].

Objective: To evaluate the efficacy of in-situ full size split liver transplantation(fSLT) for adult recipients using the living donor liver transplantation(LDLT) technique and to compare the characteristics of the left hemiliver graft (LHG) and the right hemiliver graft(RHG)transplantation. Methods: Deceased donor and recipient data of 25 consecutive cases of fSLT at Department of Hepatopancreatobiliary Surgery, Ningbo Medical Center Lihuili Hospital from March to December 2021 was retrieved and the patients divided into two groups:LHG group and RHG group. Among the 13 donors,11 were male and 2 were female,aged (M(IQR))38(19) years(range: 25 to 56 years),with height of 168(5) cm(range:160 to 175 cm) and weight of 65(9) kg(range: 50 to 75 kg). The median age of the 25 recipients was 52(14) years(range:35 to 71 years),17 were male and 8 were female,15 had primary liver cancer and 10 had benign end-stage liver disease,model for end-stage liver disease score was 10(9) points(range:7 to 23 points). Of the 25 recipients,10 recipients had previously undergone hepatobiliary surgery. The follow-up period was to January 2022. Demographic,clinicopathological,surgical outcomes and postoperative complications were evaluated and compared between the two groups. Continuous quantitative data were compared using Mann-Whitney U test. Classification data were expressed as frequencies,and were compared between groups using χ2 test or Fisher exact probability method. Results: Using LDLT technique,in-situ full-left/full-right liver splitting was performed and 13 viable pairs of hemiliver grafts were harvested with acquisition time of 230(53) minutes(range:125 to 352 minutes) and blood loss of 250(100) ml(range:150 to 1 000 ml). A total of 25 hemiliver grafts(13 LHG and 12 RHG) were allocated to patients listed for liver transplantation in our center by China Organ Transplant Response System. In the LHG group(13 cases),there were more females and more patients with benign end-stage liver disease than in the RHG group(12 cases)(P<0.05). The body weight and graft weight of recipients in the LHG group were lower than that in RHG group(both P<0.05). There were no significant differences in other baseline data between the two groups(all P>0.05). The graft to recipient weight ratio(GRWR) was 1.2(0.4)%(range:0.7% to 1.9%) for 25 recipients,1.1(0.5)%(range:0.7% to 1.6%)for the LHG group and 1.3(0.5)%(range:0.9% to 1.9%)for the RHG group. There was no significant difference between the two groups (P>0.05). Sharing patterns of hepatic vessels and the common bile duct are as follows:all the trunk of middle hepatic vein were allocated to the LHG group. The proportion of celiac trunk,main portal vein and common bile duct assigned to LHG and RHG was 10∶3 (P=0.009), 9∶4 (P>0.05) and 4∶9 (P=0.027),respectively. The vena cava of 12 donors in early stage retained in LHG and that of last one was shared between LHG and RHG (P<0.01). The median cold ischemia time of 25 hemiliver grafts was 240(90) minutes(range:138 to 420 minutes). For the total of 25 fSLT,the median anhepatic phase was 50(16) minutes(range:31 to 98 minutes) and the operation time was 474(138)minutes(range:294 to 680 minutes) with blood loss of 800(640) ml(range:200 to 5 000 ml). There were no significant differences in all of operation data between two groups. In the LHG group,3 patients with GRWR≤0.8% had postoperative small-for-size syndrome which improved after treatment. Postoperative Clavien-Dindo grade≥Ⅲ complications were observed in 6 cases(24.0%),4 cases(4/13) in the LHG group and 2 cases(2/12) in the RHG group,respectively. The difference was not statistically significant. Among them,5 cases improved after re-operation and intervention,1 case in LHG group died of secondary infection 2 weeks after operation,and the mortality was 4.0%. Analysis of serious postoperative complications and death has suggested that conventional caval interposition should not be used for LHG transplantation. Conclusion: Relying on accurate donor-recipient evaluation and the apply of LDLT technique,the morbidity and mortality of in-situ fSLT in adults is acceptable.

[Papillary renal neoplasm with reverse polarity: a clinicopathological analysis].

Objective: To study the clinical pathological characteristics, immunophenotype, molecular changes and prognosis of the papillary renal neoplasm with reverse polarity (PRNRP). Methods: Nine cases of PRNRP, diagnosed from 2013 to 2019, were retrieved from the Department of Pathology of Nanjing Jinling Hospital, Nanjing University School of Medicine. Histomorphology, immunophenotype and molecular genetics were analyzed with review of the literatures. Results: There were five male and four female patients, aged from 49 to 70 years, with an average age of 60.1 years. During a mean follow-up of 29 months, one patient died for other cause, and the others survived without disease. Microscopically, the tumor cells arranged in papillary structure with a fibrovascular core, the surface of which was covered with a single layer of cuboidal or columnar cells. The most prominent feature was that the tumor nuclei located at the top of the cytoplasm far from the basement membrane, and they were monotonous in size and arranged neatly with no or few nucleoli. Immunohistochemically, all nine cases of PRNRP showed diffuse positive expression of CK7 and E-cadherin, various degrees of P504s expression, and no expression of CD10 and CD117, with a Ki-67 index of 1%-3%. Unlike other papillary renal cell carcinoma, the nine cases of PRNRP all showed characteristic positive expression of GATA3. The fluorescence in situ hybridization assay showed that the majority of PRNRPs (8/9) did not have triploids on chromosomes 7 and 17. The sequencing of the KRAS gene confirmed the presence of a nonsense KRAS mutation in 8 of the 9 cases. Conclusions: PRNRP is a subtype of papillary renal cell carcinoma with characteristic morphological, immunophenotypic and molecular features, and indolent behaviors. More data are needed to define PRNRP as "carcinoma", and a definitive diagnosis of PRNRP is of great significance for proper treatment choice and accurate prognostication.

Adamts18 Deficiency Causes Spontaneous SMG Fibrogenesis in Adult Mice.

Chronic sclerosing sialadenitis of the submandibular gland (also known as Küttner tumor) is characterized by concomitant swelling of the submandibular glands secondary to strong lymphocytic infiltration and fibrosis. The pathogenesis of this disease has been unclear, but it is associated with immune disorders. ADAMTS18 is a member of the ADAMTS superfamily of extracellular proteinases. In this study, we showed that Adamts18 is highly expressed in submandibular salivary gland (SMG) during embryonic development and decreases but is retained in adult SMG tissue in mice. Adamts18 deficiency led to reduced cleft formation and epithelial branching in embryonic SMG before embryonic day 15.5 in mice. No significant histologic changes in the later stages of branching or the morphology of SMG were detected in Adamts18-/- mice. However, Adamts18 deficiency causes spontaneous SMG fibrogenesis and fibrosis in adult mice. At 8 wk of age, Adamts18-/- mice began to manifest the first signs of pathologic changes of mild fibrosis and CD11b+ cell infiltration in SMG tissues. At ≥8 mo, all male and female Adamts18-/- mice developed unilateral or bilateral SMG scleroma that is similar to patients with chronic sclerosing sialadenitis of the submandibular gland. Adamts18-/- mice also showed secretory dysfunction and severe dental caries. Histologically, SMG scleroma is characterized by progressive periductal fibrosis, acinar atrophy, irregular duct ectasis, and dense infiltration of IgG-positive plasma cells. A significant infiltration of CD4+ T lymphocytes and CD11b+ monocytes and macrophages was also detected in the SMG scleroma of Adamts18-/- mice. The levels of TGF-ß1, IL-6, and IL-33 were significantly increased in Adamts18-/- SMGs, which induces chronic inflammation and myofibroblast activation, ultimately leading to fibrosis. This study indicates that Adamts18 regulates the early branching morphogenesis of embryonic SMG and plays a role in protecting from spontaneous SMG fibrogenesis via modulating local inflammation, autoimmune reaction, and myofibroblast activation in adult mice.

[Efficacy of venetoclax combined azacitidine in newly diagnosed acute myeloid leukemia unfit for standard chemotherapy: a single center experience].

Objective: To investigate the effectiveness and safety of the VA regimen, which combines venetoclax with azacitidine in the treatment of patients with newly diagnosed acute myeloid leukemia (AML) who are not suitable candidates for conventional chemotherapy. Methods: In the Department of Hematology at the Second Hospital of Hebei Medical University, 66 AML patients who received venetoclax and azacitidine treatment from May 2020 to March 2022 were the subject of a retrospective study. The complete remission (CR) rate, cCR rate, ORR rate, MRD negative rate, the incidence of adverse events,1-year EFS, and OS were retrospectively analyzed. Patients subgroups with varying ages, ECOG scores, primary and secondary, risk stratifications, and gene mutation were compared for differences in efficacy and survival. Results: The median follow-up was 4.25 (0.9-19.9) months, and the median number of treatment courses was 2 (1-8) cycles. After the first cycle, the cCR rate was 78.8% , and the MRD negative rate was 51.9% . After prolonged treatment, the cCR rate was 81.8% and MRD negative rate was 66.7% . The median EFS and OS, respectively, were13.2 and 15.3 months. Secondary AML showed inferior efficacy and prognosis. IDH1/2 or NPM1 mutation groups had a significantly higher rate of CR than the control group (P<0.05) . The CR rate and MRD negative rate of patients with rebound thrombocytosis were significantly higher than those without rebound thrombocytosis (P<0.05) . Those who had epigenetic modification mutations (DNMT3, ASXL1, TET2) were more likely to benefit from ongoing therapy. The most common grade 3 and 4 adverse reactions were neutropenia, thrombocytopenia, and anemia. Conclusions: In real-world patients with newly diagnosed AML who are not candidates for standard chemotherapy, the VA regimen produces rapid deep remission. Primary AML patients, rebound thrombocytosis, IDH1/2, and NPM1 gene mutations are favorable factors for treatment benefit, and adverse reactions were tolerable.

CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment.

We apply genetic screens to delineate modulators of KRAS mutant pancreatic ductal adenocarcinoma (PDAC) sensitivity to ERK inhibitor treatment, and we identify components of the ATR-CHK1 DNA damage repair (DDR) pathway. Pharmacologic inhibition of CHK1 alone causes apoptotic growth suppression of both PDAC cell lines and organoids, which correlates with loss of MYC expression. CHK1 inhibition also activates ERK and AMPK and increases autophagy, providing a mechanistic basis for increased efficacy of concurrent CHK1 and ERK inhibition and/or autophagy inhibition with chloroquine. To assess how CHK1 inhibition-induced ERK activation promotes PDAC survival, we perform a CRISPR-Cas9 loss-of-function screen targeting direct/indirect ERK substrates and identify RIF1. A key component of non-homologous end joining repair, RIF1 suppression sensitizes PDAC cells to CHK1 inhibition-mediated apoptotic growth suppression. Furthermore, ERK inhibition alone decreases RIF1 expression and phenocopies RIF1 depletion. We conclude that concurrent DDR suppression enhances the efficacy of ERK and/or autophagy inhibitors in KRAS mutant PDAC.

Differences in tumour heterogeneity based on dynamic contrast-enhanced MRI between tumour and peritumoural stroma for predicting Ki-67 status of invasive ductal carcinoma.

AIM: To evaluate and compare the heterogeneity of intratumour and peritumour areas in the prediction of Ki-67 of invasive ductal carcinoma (IDC) and the predictive accuracy of different contrast frames based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). MATERIALS AND METHODS: This study included 88 patients with histologically confirmed IDC with 57 patients with high Ki-67 status and 31 patients with low Ki-67 status. All patients underwent DCE-MRI before surgery. A grey-level co-occurrence matrix (GLCM) was performed on slice-matched images from six frames by drawing the region of the interest (ROI) on the inner and outer regions of the tumours. The correlations between texture characteristics and Ki-67 status of lesions were analysed, using the Mann-Whitney test and receiver operating characteristic curve analysis. RESULTS: In the high-Ki-67 group, the entropy was significantly higher than that of the low-Ki-67 group (p<0.001). The entropy obtained, based on the tumour boundary as a band-like area inside and outside at the first post-contrast series, revealed the highest receiver operating characteristic (AUC = 0.765). In the multivariate analysis, a higher entropy value (>4.305; p<0.001) remained independently associated with a high-Ki-67 status after adjustment for menopausal status, tumour size, histologic grade, oestrogen receptor (ER) status, and progesterone receptor (PR) status. The other parameters did not show significant differences between the high- and low-Ki-67 groups. CONCLUSION: Heterogeneity analysis based on DCE-MRI could discriminate between high- and low-Ki-67 status. Texture characteristics from the band-like region inside and outside the tumour boundary could predict the Ki-67 status and showed higher accuracy.