[Clinical analysis of cytomegalovirus infection-associated hemophagocytic lymphohistiocytosis in five patients without underlying diseases].

The clinical data of five patients [one male and four female; median age: 31 (21-65) years] with cytomegalovirus (CMV)-induced hemophagocytic lymphohistiocytosis (HLH) diagnosed and treated in the First Affiliated Hospital of Nanjing Medical University were retrospectively analyzed from January 2011 to December 2020. None of the patients had any underlying disease, and all were immunocompetent. The main clinical presentations were fever in all five patients, splenomegaly in four, enlarged lymph nodes in two, liver enlargement in one, and rash in three. Pulmonary infection was found in three patients, two of whom developed respiratory failure. Two patients had jaundice. Central nervous system symptoms and gastrointestinal bleeding were observed in one case. All patients received glucocorticoids and antiviral therapy. One patient was treated with the COP (cyclophosphamide+vincristine+prednisone) chemotherapy regimen after antiviral therapy failed and he developed central nervous system symptoms. After treatment, four patients achieved remission, but the fifth pregnant patient eventually died of disease progression after delivery. CMV-associated HLH in an immunocompetent individual without underlying diseases is extremely rare, and most patients have favorable prognosis. Antiviral therapy is the cornerstone of CMV-HLH treatment.

[Clinicopathological analysis of benign mammary ductal cystic papillomatosis with loss of myoepithelial cells].

Objective: To investigate the histopathological and immunohistochemical characteristics of benign apocrine cystic papillary hyperplasia of the breast with loss of myoepithelial cell layer. Methods: The clinical data, histopathological features and immunohistochemical profile of patients with benign apocrine cystic papillary hyperplasia of breast with loss of myoepithelial cell layer from January 2016 to December 2021 were examined, in which six patients were identified. Results: All six patients were female, aged 36-61 years (median 46 years), who presented with a breast mass; three cases were from the left breast and three cases were from the right breast. Microscopic examination of all cases showed breast hyperplasia with apocrine cysts, accompanied by different degrees of micropapillary and papillary hyperplasia of apocrine cells. One case was associated with lobular carcinoma in situ, and one case was associated with apocrine ductal carcinoma in situ with intraductal dissemination in adenosis. Immunohistochemical staining of CK5/6, p63, SMA, SMMHC, Calponin and CD10 showed complete absence of myoepithelial cell layer surrounding ducts in apocrine cystic papillary hyperplasia. Conclusions: The myoepithelial cells of apocrine cystic papillary hyperplasia of the breast may undergo abnormal changes and may even be completely lost. The diagnosis should be comprehensively considered along with cytomorphological and histological features to avoid overdiagnosis.

[Effect of Friday surgery on clinical outcome of elderly patients with hip fracture under multidisciplinary treatment].

Objective: To assess the impact of Friday surgery on clinical outcomes in elderly patients with hip fracture under multidisciplinary treatment. Methods: A retrospective cohort study. The clinical data of 414 geriatric patients with hip fractures admitted to Zhongda Hospital Affiliated with Southeast University from January 2018 to March 2021 were analyzed retrospectively, including 126 males and 288 females with a mean age of (81.3±7.6) years. The patients were divided into two groups based on whether they underwent surgery on Friday or not. The Friday group(n=69) and the non-Friday group(n=345) were compared in terms of general information, American Society of Anesthesiologists(ASA) classification, fracture type, injury to admission time, preoperative waiting time, surgical method, anesthesia type and use of intensive care unit (ICU) fast track. Propensity score matching (PSM) was performed based on age, ASA grade, time from injury to admission, preoperative waiting time, hemoglobin and albumin levels at admission. Clinical outcomes were collected and compared between the two groups, including length of hospital stay, total hospitalization cost and 30-day, 90-day and 1-year mortality rates, and postoperative complications. Multivariate logistic regression analyses were conducted to identify influencing factors for 1-year mortality in geriatric patients with hip fracture. Results: Baseline data showed statistically significant differences in hemoglobin, albumin and preoperative waiting time between the two groups (all P<0.05). After PSM matching, 69 patients were included in each group, and no significant differences were observed in baseline data between the two groups (all P>0.05). There was no significant differences in 30-day mortality rate (4.3% vs 0, P=0.080), 90-day mortality rate (7.2% vs 1.4%, P=0.095), length of hospital stay [(10.85±4.45)d vs (10.92±3.68)d, P=0.919], total hospitalization cost [(60.9±15.4) thousands yuan vs (59.1±15.4) thousands yuan, P=0.489], postoperative complications [pneumonia (11.6% vs 13.0%, P=0.796), cardio-cerebrovascular complications (11.6% vs 8.7%, P=0.573) and delirium (5.7% vs 2.9%, P=0.245)] between the Friday group and the non-Friday group (all P>0.05). However, the 1-year mortality rate was higher in the Friday group than that in the non-Friday group(18.8% vs 4.3%, P=0.008). Multivariate analysis revealed that surgery on Friday (OR=11.222, 95%CI: 2.198-57.291, P=0.004), low hemoglobin levels at admission (OR=0.920, 95%CI: 0.875-0.967, P=0.001), hemiarthroplasty treatment (OR=5.127, 95%CI: 1.308-20.095, P=0.019) and longer surgery duration (OR=0.958, 95%CI: 0.927-0.989, P=0.009) were influencing factors for 1-year mortality in geriatric patients with hip fracture. Conclusions: In the context of multidisciplinary treatment, Friday surgery does not increase short-term mortality, length of hospital stay, total hospitalization cost or incidence of complications in geriatric patients with hip fracture. However, it remains a influencing factor for 1-year mortality in those patients.

[Clinical and molecular biological characterization of patients with accelerated chronic lymphocytic leukemia].

Objective: To investigate the clinical and molecular biological characteristics of patients with accelerated chronic lymphocytic leukemia (aCLL) . Methods: From January 2020 to October 2022, the data of 13 patients diagnosed with aCLL at The First Affiliated Hospital of Nanjing Medical University were retrospectively analyzed to explore the clinical and molecular biological characteristics of aCLL. Results: The median age of the patients was 54 (35-72) years. Prior to aCLL, five patients received no treatment for CLL/small lymphocytic lymphoma (SLL), while the other patients received treatment, predominantly with BTK inhibitors. The patients were diagnosed with aCLL through pathological confirmation upon disease progression. Six patients exhibited bulky disease (lesions with a maximum diameter ≥5 cm). Positron emission tomography (PET) -computed tomography (CT) images revealed metabolic heterogeneity, both between and within lesions, and the median maximum standardized uptake value (SUVmax) of the lesion with the most elevated metabolic activity was 6.96 (2.51-11.90). Patients with unmutated IGHV CLL accounted for 76.9% (10/13), and the most frequent genetic and molecular aberrations included +12 [3/7 (42.9% ) ], ATM mutation [6/12 (50% ) ], and NOTCH1 mutation [6/12 (50% ) ]. Twelve patients received subsequent treatment. The overall response rate was 91.7%, and the complete response rate was 58.3%. Five patients experienced disease progression, among which two patients developed Richter transformation. Patients with aCLL with KRAS mutation had worse progression-free survival (7.0 month vs 26.3 months, P=0.015) . Conclusion: Patients with aCLL exhibited a clinically aggressive course, often accompanied by unfavorable prognostic factors, including unmutated IGHV, +12, ATM mutation, and NOTCH1 mutation. Patients with CLL/SLL with clinical suspicion of disease progression, especially those with bulky disease and PET-CT SUVmax ≥5, should undergo biopsy at the site of highest metabolic uptake to establish a definitive pathological diagnosis.

[Expression of PD-L1 and tumor infiltrating lymphocyte markers in uterine cervical carcinoma].

Objective: To investigate the expression of PD-L1, CD4, CD8 and CXCL-13 in cervical carcinoma, and their clinicopathological significance was analyzed. Methods: A total of 77 patients with cervical carcinoma in the Seventh Medical Center, PLA General Hospital from January 2019 to December 2021 were included. All patients received radical surgical resection in the Seventh Medical Center of Chinese PLA General Hospital. The expression of PD-L1, CD4, CD8 and CXCL-13 was detected by immunohistochemical (IHC) method. The correlation between IHC markers and patients' clinicopathological parameters was analyzed. Results: There were 59 cases of squamous cell carcinoma and 18 cases of adenocarcinoma (ranging from 29 to 69 years) with an average of (49.4±9.8) years. PD-L1 was expressed in different degrees in cervical squamous cell carcinoma and adenocarcinoma (χ²=4.975, P=0.026); CD4+, CD8+and CXCL-13+tumor infiltrating lymphocytes (TIL) were observed in the carcinoma cell nests and peritumoral stroma. PD-L1 expression in cervical carcinoma was moderately correlated with the number of CD4+TIL in the carcinoma nests, and the number of CD8+, CXCL-13+TIL infiltration in the carcinoma nests and stroma, but not to the patient's age, histologic differentiation, presence or absence of vascular invasion, presence or absence of lymph node metastasis and FIGO stage (P>0.05). Conclusions: The high expression of PD-L1 in cervical carcinoma tissues is closely related to the number of TIL in the carcinoma nests and peritumor stroma, suggesting that they may have important reference value for predicting the response to immunotherapy in patients with cervical carcinoma.

[Clonality relatedness and molecular characteristics of Richter transformation].

Objective: To investigate the clinical, genetic, and clonality related aspects of individuals with Richter transformation (RT) . Methods: From January 2019 to December 2021, 18 RT patients with diagnoses at the First Affiliated Hospital of Nanjing Medical University (Pukou CLL center) were retrospectively examined. The immunoglobin heavy variable (IGHV) gene usage and IGHV-D-J rearrangement pattern of diagnosed CLL/SLL and transformed diffuse large B-cell lymphoma (DLBCL) were compared to determine the clonality relatedness. To investigate the risk factors of RT, Clinical and laboratory data from patients with newly diagnosed CLL/SLL and transformed DLBCL were gathered. Results: The median age of RT was 56.5 (41-75) years old. 17 patients transformed to DLBCL and 1 transformed to Hodgkin lymphoma (HL) . Of 17 individuals who had DLBCL transformation, 15 had CLL/SLL-related clonality and 2 had unrelated clonality. Next-generation sequencing (NGS) analysis of 11 paired initially diagnosed treatment-naive CLL/SLL and RT DLBCL found that EGR2、TP53 and NOTCH1 were among the most frequently mutated genes both in treatment-naive CLL/SLL and in RT DLBCL. In several cases, specific mutations were gained or lost throughout RT, indicating clonal evolution. Among 10 patients before exposure to BTK inhibitors before RT, four patients acquired BTK mutation. The aforementioned mutations should be considered high-risk variables for transformation; in addition, TP53 and EGR2 mutations could be linked to a poor prognosis following RT in patients receiving a cocktail of new medicines. Conclusion: Most RT DLBCL patients in our center are clonality related (15/17, 88.2% ) and we recommend all qualified centers to evaluate clonality relatedness of RT DLBCL patients. There was some variability in the mutational landscape between DLBCL that had undergone a transformation and initially diagnosed, treatment-naive CLL/SLL. The underlying molecular mechanism of RT needs more research.

[The risk prediction models for occurrence of cervical cancer: a systematic review].

Objective: To systematically summarize and assess risk prediction models for occurrence of cervical cancer and to provide evidence for selecting the most reliable model for practice, and guide cervical cancer screening. Methods: Two groups of keywords related to cervical cancer and risk prediction model were searched on Chinese databases (CNKI, and Wanfang) and English databases (PubMed, Embase, and Cochrane Library). Original articles that developed or validated risk prediction models and published before November 21, 2019, were selected. Information form was created based on the CHARMS checklist. The PROBAST was used to assess the risk of bias. Results: 12 eligible articles were identified, describing 15 prediction models, of which five were established in China. The predicted outcomes included multiple stages from cervical precancerous lesions to cancer occurrence, i.e., abnormal Pap smear (1), occurrence or recurrence of CIN (9), and occurrence of cervical cancer (5), etc. The most frequently used predictors were HPV infection (12), age (7), smoking (5), and education (5). There were two models using machine learning to develop models. In terms of model performance, the discrimination ranged from 0.53 to 0.87, while only two models assessed the calibration correctly. Only two models were externally validated in Taiwan of China, using people in different periods. All of the models were at high risk of bias, especially in the analysis domain. The problems were concentrated in the improper handling of missing data (13), preliminary evaluation of model performance (13), improper use of internal validation (12), and insufficient sample size (11). In addition, the problems of inconsistency measurements of predictors and outcomes (8) and the flawed report of the use of blindness for outcome measures (8) were also severe. Compared with the other models, the Rothberg (2018) model had relatively high quality. Conclusions: There are a certain number of cervical cancer risk prediction models, but the quality is poor. It is urgent to improve the measurement of predictors and outcomes, the statistical analysis details such as handling missing data and evaluation of model performance and externally validate existing models to better guide screening.

[Comparison of four prognostic scoring system in patients with early asymptomatic chronic lymphocytic leukemia patients].

Objective: To compare the prognostic value of four prognostic models in predicting time to first treatment (TTFT) in patients with Binet A Chinese chronic lymphocytic leukemia (CLL) . Methods: This retrospective analysis included one hundred and ten patients with Binet A CLL, initially diagnosed in the First Affiliated Hospital of Nanjing Medical University (Pukou CLL center) from June 2009 to January 2020. Risk stratification was conducted according to IPS-E, CLL-IPI, CLL1-PM, and Barcelona-Brno prognostic models. Results: Among 110 patients with Binet A CLL patients, the median age was 58 (25-84) years. The median follow-up time was 35 (4-189) months, and 57 (51.8%) patients met the indication for treatment due to symptomatic disease progression during follow-up. Log-rank analysis of nine variables was conducted involving age, Rai stage, absolute lymphocyte count (ALC) , lymph node size, lymphocyte doubling time (LDT) , ß(2)-Microglobulin, IGHV status, TP53, and Del (11q) . Additionally, Rai Ⅰ-Ⅲ, ALC>15×10(9)/L, palpable lymph node size ≥1cm, ß(2)-Microglobulin>3.5 mg/L, unmutated IGHV, TP53 mutation or deletion, and 11q deletion were independent risk factors of TTFT. Predictive value of each model was assessed by Harrel C-index and Akaike information criterion (AIC) with CLL1-PM (C-index=0.736, AIC=777) , followed by CLL-IPI (C-index=0.722, AIC=933) , IPS-E (C-index=0.683, AIC=1004) , and Barcelona-Brno prognostic model (C-index=0.663, AIC=986) . Conclusion: All four prognostic models effectively predicted TTFT. IPS-E might be an ideal model to guide clinical surveillance because of its easy accessibility and low expenses in routine clinical practice. Therefore, for patients receiving fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) examination at diagnosis, CLL-IPI or CLL1-PM could be applied to evaluate their prognosis more comprehensively.

Combination therapy with interleukin-15 and metformin as a synergistic treatment for pancreatic cancer.

OBJECTIVE: To investigate the efficacies and mechanisms of combination therapy with interleukin-15 (IL-15) and metformin (Met) on suppressing pancreatic cell proliferation and protecting Panc02-bearing mice. MATERIALS AND METHODS: MTT assays were applied to assess the inhibitory effects of IL-15 combined Met or Met and IL-15 alone on proliferation of normal HPDE6-C7 and Panc02 cells. After tumor grew up to 150 mm3, the Panc02-bearing xenograft model mice were randomly divided into saline group, IL-15 and Met alone group and combined treatment group (n=8) with the administration of each agent every other day for three weeks, and survival rates were recorded. The changes in tumor size, expression levels of the apoptosis, autophagy as well as Akt/mTOR/STAT3-related factors in tumor tissues were all measured. RESULTS: MTT assays demonstrated significantly inhibiting efficacy of combination therapy with IL-15 and Met on Panc02 cell proliferation compared to other groups (all p<0.05) with combination index<1 showing evident synergistic effect. Moreover, the apoptosis rate of Panc02 cell under combined treatment were 95.5±3.2% and significantly higher than those of others (all p<0.01). In addition, combined administration remarkably inhibited the growth of pancreatic carcinoma, and improved survival rate of Panc02-bearing model with less body weight loss. Furthermore, combined treatment significantly downregulated anti-apoptotic proteins as well as Akt/mTOR/STAT3 signaling pathway and upregulated autophagy related factors, respectively, compared with those of monotherapy groups in both Panc02 cells and tumor tissues. CONCLUSIONS: Combined treatment of IL-15 with Met showed synergistic anti-tumor efficacies on Panc02 cells attributing to promotion on apoptosis, autophagy and inhibition on Akt/mTOR/STAT3 signaling-transduction in Panc02-bearing model mice.

[Clinical characteristics of T-cell large granular lymphoblastic leukemia with STAT3 gene mutation].

Objective: This study aims to explore the clinical characteristics of T-cell large granular lymphocyte leukemia (T-LGLL) patients with STAT3 mutation status and provide a reference for clinical management of such patients. Methods: The clinical data of T-LGLL patients between 2009 and 2019 in Jiangsu Province Hospital were retrospectively analyzed. Differences in baseline clinical data, treatment responses, and survival outcomes in patients with STAT3 mutations or with no mutations were compared. Results: A total of 80 patients were included, including 66 patients without STAT3 mutation and 14 patients (17.5%) with STAT3 mutation. The frequency of Y640F mutation was the highest (42.9%) . Compared with non STAT3 mutation group, STAT3 mutation group had lower HGB (67.5 g/L vs 82.5 g/L, P=0.018) , lower neutrophil count (0.665×10(9)/L vs 1.465×10(9)/L, P<0.001) , higher LDH (229 U/L vs 198 U/L, P=0.041) , higher ferritin (402.5 g/L vs 236.0 g/L, P=0.029) , higher expression rate of TCR Vß subfamily (89.2% vs 65.4%, P=0.014) and higher proportion of patients with treatment indications (100% vs 74%, P=0.033) . The complete remission rates of STAT3 mutation group and non mutation group were 38.5% and 32.7%, respectively, with no significant difference (P=0.748) . The overall response rate of first-line immunosuppressive therapy in STAT3 mutation group and non mutation group were 69.2% and 69.4%, respectively, with no significant difference (P=1.000) . The median follow-up time was 63 (2-121) months. There was no significant difference in the overall survival time between the two groups (P=0.170) . Conclusions: T-LGLL patients with STAT3 mutations seems to be correlated with an increased tumor burden and high treatment demand, and had a good response to first-line immunotherapies. The prognostic significance of STAT3 mutation in T-LGLL patients requires further validation.

Analysis of the clinicopathological characteristics and prognosis of adenoid cystic carcinoma of the intraoral minor salivary glands: a retrospective study of 40 cases.

The clinicopathological aspects and prognostic factors of 40 patients with adenoid cystic carcinoma (ACC) of the intraoral minor salivary glands, treated between 2007 and 2017 at a single institution, were evaluated retrospectively. Twenty-six were female and 14 were male, and they ranged in age from 26 to 81 years (median 55 years). ACC occurred mainly in the palate, with 54.8% of cases presenting T3-T4 lesions. Curative surgery was performed in all patients, and 62.5% of patients were treated with postoperative adjuvant radiotherapy. In the final analysis, positive surgical margins were noted in 57.5% of cases and perineural invasion in 70%. Follow-up was at least 13 months (range 13-141 months, median 59 months). Nineteen patients (47.5%) developed recurrent disease after initial surgery and nine patients had died at the end of follow-up. The 5- and 10-year overall survival rates were 88.3% and 25.6%, respectively. The 5- and 10-year disease-free survival rates were 75.6% and 34.0%, respectively. Patients with a tumour size >4cm and those with positive surgical margins showed a significantly higher risk of local recurrence. Elective neck dissection is suggested for patients with clinically positive lymph nodes or a locally advanced tumour, especially those undergoing microvascular reconstruction. The survival analysis results are similar to those reported previously in the literature.

[The value of conventional magnetic resonance imaging based radiomic model in predicting the texture of pituitary macroadenoma].

Objective: To investigate the value of conventional magnetic resonance imaging (MRI) based radiomic model in predicting the texture of pituitary macroadenoma. Methods: The complete data of 101 patients with pituitary macroadenoma confirmed by surgery and pathology in Yijishan Hospital of Wannan Medical College from December 2014 to December 2019 were retrospectively analyzed. According to the texture of the intraoperative pituitary tumor, patients were divided into soft group (n=58) and hard group (n=43). They were randomly divided into training group (n=72) and validation group (n=29) at a ratio of 7∶3. All patients underwent conventional MRI scan of the pituitary gland. Itk-snap software was used to manually outline the T(1)-weighted image (T(1)WI), T(2)-weighted image (T(2)WI) and enhanced T(1)WI image section by section on tumor area of interest (ROI) and perform three-dimensional fusion. Then AK software was imported to extract texture features. The regression analysis methods of minimum redundancy maximum relevance (mRMR) and least absolute shrinkage and selection operator (LASSO) were used for feature selection and radiomic signature establishment. The reliability of the model was verified by 100 leave-group-out cross validation (LGOCV), and the predictive ability of the model was evaluated by drawing the receiver operating characteristic (ROC) curve. The decision curve analysis (DCA) was used to evaluate the clinical application value of the model. Results: The AUC (Area Under the ROC Curve) (95%CI) values of T1WI, T2WI, enhanced T1WI, and the combined sequence model to predict the texture of pituitary macroadenomas in the training and validation groups were 0.91 (0.84-0.98) and 0.90 (0.78-1.00), 0.86 (0.78-0.95) and 0.83 (0.64-1.00), 0.90 (0.83-0.97) and 0.89 (0.77-1.00),0.92 (0.85-0.98) and 0.91 (0.79-1.00), respectively. DCA demonstrated that T(1)WI, T(2)WI, enhanced T(1)WI, and combined sequence model all had good net benefits in clinical practice. Conclusions: T(1)WI, T(2)WI, enhanced T(1)WI, and combined sequence model of conventional MRI all had high efficacy in predicting the texture of pituitary macroadenoma, which provided a new quantitative method for predicting the texture of pituitary macroadenoma.