Could ceftriaxone be a viable alternative to penicillin for the treatment of ocular syphilis?

This study was conducted to compare the effectiveness of ceftriaxone with that of aqueous crystalline penicillin G in treating ocular syphilis. We conducted a retrospective study from 2010 to 2021. Syphilis patients were administered either ceftriaxone (2 g intravenously daily for 14 days) or aqueous crystalline penicillin G [4 million units (MU) intravenously every 4 h for 14 days] as therapeutic interventions. Subsequently, we utilized these two groups to assess the serological results, cerebrospinal fluid analysis, and visual acuity at time intervals spanning 3 to 6 months post-treatment. A total of 205 patients were included, with 34 assigned to the ceftriaxone group and 171 to the penicillin group. The median age of patients was 56 years, with an interquartile range of 49-62 years, and 137 of them (66.8%) were male. Between 3 and 6 months after treatment, 13 patients (38.2%) in the ceftriaxone group and 82 patients (48.0%) in the penicillin group demonstrated effective treatment based on the clinical and laboratory parameters. The crude odds ratio (OR) was 0.672 (95% confidence interval [CI]: 0.316-1.428, P = 0.301), indicating no significant difference in effectiveness between the two groups. Thirty patients (17.5%) in the penicillin group and six patients (17.6%) in the ceftriaxone group did not experience successful outcomes. Notably, no serious adverse effects were reported in both the groups. There was no significant difference in the effectiveness of ceftriaxone and aqueous crystalline penicillin G in treating ocular syphilis. The administration of ceftriaxone without requiring hospitalization presents a convenient and safe alternative treatment option for ocular syphilis.

Clinical spectrum of late symptomatic neurosyphilis in China: an 11-year retrospective study.

OBJECTIVES: This study aimed to describe the clinical features of neurosyphilis in Chinese patients in an attempt to find clinical features that are helpful for the early identification of neurosyphilis. METHODS: This retrospective study included people with syphilis who visited Shanghai Skin Disease Hospital between January 2010 and December 2020. Lumbar puncture was performed on those who met the inclusion and exclusion criteria. The diagnosis of neurosyphilis was based on clinical and laboratory findings. The parameters were analysed statistically. RESULTS: Of the 3524 patients with neurosyphilis, 2111 (59.9%) and 1413 (40.1%) were asymptomatic and symptomatic neurosyphilis, respectively. General paresis was the most common type of symptomatic neurosyphilis (46.8%). The clinical manifestations of symptomatic neurosyphilis include psychiatric and neurotic symptoms, among which general paresis predominantly presented as psychiatric symptoms such as affective (66.7%) and memory disorder (72.9%). Tabes dorsalis is often presented as neurotic symptoms. One hundred fifty patients (10.6%) with symptomatic neurosyphilis presented candy signs, a rare and specific neurosyphilis symptom that is common in general paresis. Girdle sensation was presented in 13 patients, mainly with tabes dorsalis, which had not been reported in previous studies. CONCLUSIONS: Notably, the candy sign is identified as a specific symptom of general paresis, while girdle sensations are highlighted as a particular symptom of tabes dorsalis. This is the largest study describing the clinical spectrum of neurosyphilis since the onset of the penicillin era and could help doctors learn more about the disease. A comprehensive description of the possible clinical manifestations of late symptomatic neurosyphilis, particularly highlighting rare symptoms, can identify suspicious patients and prevent diagnostic delays.

Clinical parameter-based prediction model for neurosyphilis risk stratification.

Accurately predicting neurosyphilis prior to a lumbar puncture (LP) is critical for the prompt management of neurosyphilis. However, a valid and reliable model for this purpose is still lacking. This study aimed to develop a nomogram for the accurate identification of neurosyphilis in patients with syphilis. The training cohort included 9,504 syphilis patients who underwent initial neurosyphilis evaluation between 2009 and 2020, while the validation cohort comprised 526 patients whose data were prospectively collected from January 2021 to September 2021. Neurosyphilis was observed in 35.8% (3,400/9,504) of the training cohort and 37.6% (198/526) of the validation cohort. The nomogram incorporated factors such as age, male gender, neurological and psychiatric symptoms, serum RPR, a mucous plaque of the larynx and nose, a history of other STD infections, and co-diabetes. The model exhibited good performance with concordance indexes of 0.84 (95% CI, 0.83-0.85) and 0.82 (95% CI, 0.78-0.86) in the training and validation cohorts, respectively, along with well-fitted calibration curves. This study developed a precise nomogram to predict neurosyphilis risk in syphilis patients, with potential implications for early detection prior to an LP.

Plateletcrit is predictive of clinical outcome and prognosis for early-stage breast cancer: A retrospective cohort study based on propensity score matching.

PURPOSE: Breast cancer (BC) is diagnosed as the most common cancer in women in 2022 according to the American Cancer Society. It is essential to detect early and treat early. Several studies have shown that some blood parameters have important predictive value for BC. In this study, we aim to explore whether some immune-associated blood parameters are relevant to disease-free survival (DFS) in early-stage BC. METHODS: A single-center, regression cohort study of 1490 patients with early-stage BC in Shanghai Cancer Center was conducted from January 2008 to December 2016. The patients were matched according to the ratio of 1:1 based on Propensity Score Matching (PSM). All patients who experienced disease progression were matched successfully. Thus, 58 pairs of subjects were obtained. Matched blood parameters were evaluated by paired samples t-test or Wilcoxon signed-rank test. Factors with statistical difference were further evaluated by stratified COX regression model. RESULTS: Univariate analysis showed differences in platelet-related parameters (PLT, PCT, and PLR) and NLR between the two matched groups. However, stratified COX regression analysis, which ruled out the confounding effects of multiple factors, found that only PCT had prognostic value in early BC patients at baseline and study endpoint. Meanwhile, platelet-related parameters (PLT, MPV) and NLR were different in the progressive group by self before and after comparison. However, the multiple-factor analysis showed that only the NLR had prognostic value. ROC curve analysis indicated that the best sensitivity (65.45%) and specificity (78.18%) were obtained when the baseline PCT was 0.225. The optimal sensitivity (70.91%) and specificity (65.45%) were obtained when the PCT of disease progression was 0.215. The Kaplan-Meier curve was used to calculate the DFS rate based on the critical values of the two groups. CONCLUSIONS: Some blood parameters have value to predict DFS in early-stage BC patients, especially platelet-associated parameters.

Outcomes with and without postmastectomy radiotherapy for pT3N0-1M0 breast cancer: An institutional experience.

AIM: The objective of this study is to comprehensively evaluate the therapeutic efficacy of postmastectomy radiotherapy (PMRT) in treating patients with pT3N0-1M0 breast cancer within the context of modern therapeutic strategies. METHODS: Clinical data from patients with pT3N0-1M0 breast cancer who underwent mastectomy from January 2005 to December 2018 at our institution were retrospectively analyzed. RESULTS: The study involved a total of 222 participants, with 112 individuals undergoing PMRT and 110 individuals not receiving it. The median follow-up duration was 77 months (range: 6-171 months). The entire cohort demonstrated 5-year disease-free survival (DFS) and overall survival (OS) rates of 85.1% and 91.0%, respectively, along with a locoregional recurrence (LRR) rate as low as 7.2%. The PMRT group showed significantly better 5-year DFS (90.2% vs. 80.0%, p = 0.02) and OS (95.5% vs. 86.4%, p = 0.012) rates, as well as a lower LRR rate (4.5% vs. 10.0%, p = 0.122), compared to the group without PMRT. Cox regression analysis confirmed the independent prognostic significance of PMRT for both DFS (p = 0.040) and OS (p = 0.047). Following propensity score matching (PSM), the analysis included 100 matched patients, revealing an improved prognosis for those who received PMRT (DFS: p = 0.067; OS: p = 0.043). CONCLUSIONS: Our study reveals favorable prognoses for pT3N0-1M0 breast cancer patients treated within contemporary therapeutic approaches. The pivotal role of PMRT in this context is evident. However, due to the retrospective design of our study and the relatively limited sample size, further investigation is imperative to validate and enhance these initial findings.

Ba-Qi-Rougan formula alleviates hepatic fibrosis by suppressing hepatic stellate cell activation via the MSMP/CCR2/PI3K pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The Ba-Qi-Rougan formula (BQRGF) is a traditional and effective compound prescription from Traditional Chinese Medicine (TCM) utilized in treating hepatic fibrosis (HF). AIM OF THE STUDY: We aimed to evaluate the therapeutic efficacy of BQRGF on HF and explore the underlying mechanisms of action. MATERIALS AND METHODS: UPLC-Q-TOF-MS technology was employed to identify the material basis of BQRGF. Mice with carbon tetrachloride (CCl4)-induced HF received BQRGF at three doses (3.87, 7.74, and 15.48 g/kg per day). We examined serum and liver biochemical indicators and liver histology to assess the therapeutic impact. Primary mouse cells were isolated and utilized for experimental analysis. MSMP expression levels were examined in vitro and in vivo experimental models, including human and mouse tissue. Furthermore, lentivirus and small interfering RNA (siRNA) transfections were employed to manipulate microseminoprotein (MSMP) expression in LO2 cells (human normal liver cells). These manipulated LO2 cells were then co-cultured with LX2 human hepatic stellate cells (HSCs). Through the modulation of MSMP expression in co-cultured cells, administering recombinant MSMP (rMSMP) with or without BQRGF-medicated serum, and using specific pathway inhibitors or agonists in LX2 cells, we elucidated the underlying mechanisms. RESULTS: A total of 48 compounds were identified from BQRGF, with 12 compounds being absorbed into the bloodstream and 9 compounds being absorbed into the liver. Four weeks of BQRGF treatment in the HF mouse model led to significant improvements in biochemical and molecular assays and histopathology, particularly in the medium and high-dose groups. These improvements included a reduction in the level of liver injury and fibrosis-related factors. MSMP levels were elevated in human and mouse fibrotic liver tissues, and this increase was mitigated in HF mice treated with BQRGF. Moreover, primary cells and co-culture studies revealed that BQRGF reduced MSMP expression, decreased the expression of the hepatic stellate cell (HSC) activation markers, and suppressed critical phosphorylated protein levels in the CCR2/PI3K/AKT pathway. These findings were further validated using CCR2/PI3K/AKT signaling inhibitors and agonists in MSMP-activated LX2 cells. CONCLUSIONS: Collectively, our results suggest that BQRGF combats HF by diminishing MSMP levels and inhibiting MSMP-induced HSC activation through the CCR2/PI3K/AKT pathway.

Arachidonic acid enhances hepatocyte bile acid uptake and alleviates cholestatic liver disease by upregulating OATP1 expression.

Cholestatic liver disease is caused by disorders of bile synthesis, secretion, and excretion. Over the long term, progressive liver cell damage from the disease evolves into liver fibrosis and cirrhosis, ultimately leading to liver failure and even cancer. Notably, cholestatic liver disease has a complex pathogenesis that remains relatively unclear. In this study, we generated two mouse models of cholestatic liver disease using a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet and α-naphthyl isothiocyanate (ANIT) gavage. Quantitative proteomics using liquid chromatography-tandem mass spectrometry showed that arachidonic acid metabolism was a common pathway in both models. Additionally, serum arachidonic acid concentrations were lower in both models than in the control group. Arachidonic acid supplementation in the diet of DDC model mice significantly reduced the levels of serum markers of cholestasis (alanine aminotransferase, aspartate transaminase, alkaline phosphatase, total bile acid, and total bilirubin) and decreased the degree of bile duct hyperplasia and cholestasis. To elucidate the mechanisms by which arachidonic acid improved bile stasis, we analyzed gene expression after arachidonic acid administration and found that Oatp1 was upregulated in the liver tissue of cholestatic mice. Arachidonic acid also increased Oatp1 expression in AML12 cells, which promoted bile acid uptake. Conclusively, our research showed that arachidonic acid mitigates cholestatic liver disease by upregulating Oatp1, promoting bile acid uptake by hepatocytes and participating in intestinal-hepatic circulation. Overall, these results suggest that supplementing foods with arachidonic acid in the daily diet may be an effective treatment strategy for cholestatic liver disease.

CXCR6 expression correlates with radiotherapy response and immune context in triple-negative breast cancer-experimental studies.

BACKGROUND: The chemokine receptor CXCR6 is critical for sustained tumor control mediated by CD8+ cytotoxic T cells (CTLs) in tumors. Previous studies have shown that ionizing radiation induces an inflamed immune contexture by upregulating CXCR6. However, the clinical significance of CXCR6 expression in triple-negative breast cancer (TNBC) and its correlation with radiotherapy remains unknown. This study aimed to clarify the prognostic value of CXCR6 and its role in the breast tumor microenvironment (TME). METHODS: The messenger RNA and protein expression of CXCR6 in human TNBC and their association with survival were analyzed. The role of CXCR6 in the immune context was investigated using a combination of single-cell RNA sequencing, bulk transcriptome sequencing data, and fluorescence-based multiplex immunohistochemistry (mIHC) techniques. RESULTS: Elevated CXCR6 expression correlated with better clinical outcomes and superior response to adjuvant radiotherapy and immunotherapy in TNBC. CXCR6 fostered an immunostimulatory microenvironment characterized by upregulated cytotoxic markers. We also found that CXCR6 plays a crucial role in regulating the differentiation of CD8+ T cells and the intercellular communication of immune cell subtypes, thus shaping the TME. CONCLUSIONS: This study highlights the emerging role of CXCR6 in shaping the TME and targeting CXCR6 may be a promising strategy for improving the effectiveness of radiotherapy and immunotherapy in TNBC.

Neurology care and the long-term outcomes of atrial fibrillation-related ischaemic stroke in China: median 3-year outcome from a high volume academic tertiary hospital.

OBJECTIVES: The initial medical contact of patients with atrial fibrillation (AF) and ischaemic stroke is often performed by neurologists. However, when stand care with oral anticoagulants (OACs) adherence and persistence was emphasised by cardiologists, data regarding the gap between current neurology care and standard care from Chinese tertiary hospitals is scarce and the long-term outcome is unknown. This study was to investigate the AF detection rate, the use of anticoagulation therapy and posthospital clinical outcomes associated with neurology care in patients with AF and ischaemic stroke in China. DESIGN: A retrospective cohort study. SETTING: Clinical data of all patients who had an ischaemic stroke discharged from the neurologic department of a high-volume academic hospital from 1 January 2013 to 31 December 2017 were analysed and patients were followed. PARTICIPANTS: Patients diagnosed with ischaemic stroke and AF were included. MAIN OUTCOME MEASURES: The usage of anticoagulation at discharge, the posthospital restroke rate and all-cause mortality. RESULTS: Among 5797 patients who had an ischaemic stroke, 373 (6.43%) patients were diagnosed with AF during hospitalisation. Among them, only 198 (53.66%) patients were on anticoagulation therapy at discharge. A total of 325 (88.08%) patients were accessible and received follow-up. After a median 3-year follow-up, 103 (31.69%) patients died due to all causes. Among them, 53 (16.31%) patients died from recurrent stroke. And 86 (26.46%) patients restroked. In multivariable analysis, patients without anticoagulation therapy, muscle strength

Evaluating efficacy and safety of sub-anesthetic dose esketamine as an adjuvant to propofol/remifentanil analgosedation and spontaneous respiration for children flexible fibreoptic bronchoscopy: a prospective, double-blinded, randomized, and placebo-controlled clinical trial.

Background: Flexible fiberoptic bronchoscopy (FFB) for children is widely performed under sedation. Currently, the optimal sedation regimen remains unclear. Esketamine is an N-methyl-D-aspartic acid (NMDA) receptor antagonist, which has stronger sedative and analgesic effects and exerts less cardiorespiratory depression than other sedatives. The purpose of this study was to evaluate whether a subanesthetic dose of esketamine as an adjuvant to propofol/remifentanil and spontaneous ventilation compared with control reduces the procedural and anesthesia-related complications of FFB in children. Materials and methods: Seventy-two children ≤ 12 years of age who were scheduled for FFB were randomly assigned, in a 1:1 ratio, to the esketamine-propofol/remifentanil (Group S, n = 36) or to the propofol/remifentanil group (Group C, n = 36). All children were retained spontaneous ventilation. The primary outcome was the incidence of oxygen desaturation (respiratory depression). Perioperative hemodynamic variables, blood oxygen saturation (SPO2), end-tidal partial pressure of carbon dioxide (PetCO2), respiratory rate (R), and the Bispectral index (BIS), induction time, procedural time, recovery time, the time to the ward from the recovery room, consumption of propofol and remifentanil during the procedure and the appearance of adverse events, including paradoxical agitation following midazolam administration, injection pain, laryngospasm, bronchospasm, PONV, vertigo, and hallucination were also compared. Results: The incidence of oxygen desaturation was significantly lower in Group S (8.3%) compared to Group C (36.1%, p = 0.005). The perioperative hemodynamic profile including SBP, DBP, and HR were more stable in Group S than that in Group C (p < 0.05). Consumption of propofol and remifentanil was lower in Group S than in Group C (p < 0.05). Furthermore, PAED scores, cough scores and injection pain were lower in the Group S than in Group C (p < 0.05). The recovery time of Group S was slightly longer than that of Group C (p < 0.05). Nobody happened paradoxical agitation following midazolam administration, PONV, vertigo, and hallucinations in both groups (p > 0.05). Conclusion: Our findings indicate that a subanesthetic dose of esketamine as an adjuvant to propofol/remifentanil and spontaneous respiration is an effective regimen for children undergoing FFB. Our findings will provide a reference for clinical sedation practice during these procedures in children. Clinical Trail Registration: Chinese clinicaltrials.gov registry (identifier: ChiCTR2100053302).

Wip1 regulates wound healing by affecting activities of keratinocytes and endothelial cells through ATM-p53 and mTOR signaling.

BACKGROUND: As a p53-regulated gene, Wip1 regulates proliferation, migration, apoptosis, and senescence of several type cells, but its biological functions in keratinocytes and endothelial cells which are involved wound healing are not fully understood. This study aims to reveal the function and underlying mechanism of Wip1 in wound healing using models of transgenic animal, keratinocytes, and endothelial cells. METHODS: Using Wip1 knockout C57 BL/6 mice, we investigated effect of Wip1 deficiency on wound healing and angiogenesis; And using HaCaT and HUVEC as keratinocytes and endothelial cells, combined using primary keratinocytes from Wip1 knockout mice, we studied the effects of Wip1 knockdown/knockout or overexpression on proliferation, migration, and protein expressions of signaling components in ATM-p53 and mTOR pathway. RESULTS: Wip1 deficiency in mice impaired the wound repair and endothelial angiogenesis, reduced the thickness of granulation tissue, and decreased the number of Ki67-positive cells and CD31 positive vessels in granulation tissue. Knockdown of Wip1 by shRNAs suppressed the proliferation and migration of HaCaT and HUVEC cells and induced notably apoptosis in the two cells. In western blot, Wip1 knockdown enriched p53 and ATM proteins, while decreased activated AKT, mTOR and activated S6 ribosomal protein (pS6) levels in HaCaT and HUVEC cells. Ectopic expression of Wip1 decreased the p53 and ATM proteins, while increased activated AKT, mTOR and pS6 levels in HaCaT and HUVEC cells. And in primary keratinocytes from mice tail skin, Wip1 knockout increased p53 and ATM, while decreased activated AKT, mTOR and pS6 protein levels. CONCLUSION: Our study directly supports that Wip1 regulated skin wound healing possibly by affecting bioactivities including proliferation, migration and apoptosis of keratinocytes and endothelial cells at least through by modulating ATM-p53 and mTOR signaling.

The Arabidopsis Receptor-like Kinase CAP1 Promotes Shoot Growth under Ammonium Stress.

High levels of ammonium (NH4+) in soils inhibit plant growth and nitrogen utilization efficiency. Elucidating the underlying mechanisms of NH4+ toxicity is essential for alleviating the growth inhibition caused by high NH4+. Our previous work showed that [Ca2+]cyt-associated protein kinase 1 (CAP1) regulates root hair growth in response to NH4+ in Arabidopsis thaliana, and the cap1-1 mutant produces short root hairs under NH4+ stress conditions. However, it is unclear whether CAP1 functions in other physiological processes in response to NH4+. In the present study, we found that CAP1 also plays a role in attenuating NH4+ toxicity to promote shoot growth. The cap1-1 mutant produced smaller shoots with smaller epidermal cells compared with the wild type in response to NH4+ stress. Disruption of CAP1 enhanced the NH4+-mediated inhibition of the expression of cell enlargement-related genes. The cap1-1 mutant showed elevated reactive oxygen species (ROS) levels under NH4+ stress, as well as increased expression of respiratory burst oxidase homologue genes and decreased expression of catalase genes compared with the wild type. Our data reveal that CAP1 attenuates NH4+-induced shoot growth inhibition by promoting cell wall extensibility and ROS homeostasis, thereby highlighting the role of CAP1 in the NH4+ signal transduction pathway.

Molecular subtypes predict second breast events of ductal carcinoma in situ after breast-conserving surgery.

PURPOSE: Currently, the prognostic value of molecular subtypes in ductal carcinoma in situ (DCIS) remains unclear. In this study, we explored whether molecular subtypes could predict second breast events (SBEs) in patients after breast-conserving surgery (BCS). METHODS: From January 2008 to December 2016, 291 DCIS patients treated with BCS were retrospectively analyzed. Patients were classified into four molecular subtypes: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) overexpression, and triple-negative breast cancer (TNBC). The SBE incidence was calculated by the competing risk model and compared by Gray's test. The disease-free survival rates were estimated by the Kaplan-Meier method and compared by the log-rank test. Prognostic factors were evaluated by univariate and multivariate COX proportional hazards regression model. RESULTS: With a median follow-up of 66 months, 12 SBEs were identified. The 5-year overall SBE incidence of luminal A, luminal B, HER2 overexpression, and TNBC was 2.18%, 4.25%, 15.15%, and 0.00%, respectively. In the univariate analysis, the HER2 overexpression subtype was the predictor of overall (p = 0.005), in situ (p = 0.004), and ipsilateral SBEs (p = 0.008). Patients with endocrine therapy were less likely to develop in situ SBEs (p = 0.039). Additionally, patients with closed (<2 mm) or involved margins were related to a higher risk of contralateral SBEs (p = 0.029). In the multivariate analysis, the HER2 overexpression subtype remained of prognostic values for overall (p = 0.006), in situ (p = 0.029), and ipsilateral SBEs (p = 0.012). CONCLUSIONS: The molecular subtype, especially the HER2 overexpression subtype, was the independent prognostic factor for DCIS patients who underwent BCS.

Characteristics, prognosis, risk factors, and management of recently diagnosed ductal carcinoma in situ with microinvasion.

BACKGROUND: Ductal carcinoma in situ with microinvasion (DCISM) represents ~1% of all breast cancer cases and is arguably a more aggressive subtype of ductal carcinoma in situ (DCIS). Lacking studies with a large population, the survival outcomes of DCISM are still poorly understood and the treatment recommendations remain controversial. This study aims to investigate the long-term outcome of patients with DCISM, potential risk factors for their prognosis, and the difference of survival between patients treated with breast-conserving surgery plus radiotherapy (BCT + RT) and mastectomy only. METHODS: In total, 1299 patients from 2008 to 2019 with DCISM were retrospectively retrieved. Clinicopathological features were analyzed. Subgroup analysis was conducted between patients who underwent BCT + RT and mastectomy only. Univariate and multivariate analyses were performed to identify prognostic factors for survival. Differences of survival between two groups were compared using the log-rank test. RESULTS: Totally, 1286 patients had follow-up information, the median follow-up is 54.57 months, the 5-year local-regional-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were 98.6%, 97.1%, and 99.4%, respectively, two deaths were due to breast cancer. Multivariate analysis identified age <40 (p = 0.028) and close margin (≤2 mm) as independent negative prognostic factors for LRFS. No prognostic factors were identified for DMFS and OS. The 5-year LRFS, DMFS, and OS of patients who had DCIS component ≥5 cm and underwent mastectomy without adjuvant radiotherapy were 100%, 98.4%, and 98.4%, respectively. After propensity score matching (PSM), no survival difference was observed between patients treated with BCT + RT or mastectomy only. CONCLUSIONS: DCISM patients had a good survival, even those with DCIS component ≥5 cm. Patients aged <40 or with close margin (≤2 mm) had a poorer LRFS, but not DMFS or OS. BCT + RT is a feasible choice for DCISM patients.

Outcomes in Patients with pT3N0M0 Breast Cancer with and without Postmastectomy Radiotherapy.

PURPOSE: The role of adjuvant postmastectomy radiotherapy (PMRT) remains controversial for patients with pT3N0M0 breast cancer, especially when patients are treated with the updated adjuvant chemotherapy. Our study aimed to compare locoregional recurrence-free survival (LRFS), disease-free survival (DFS), and breast cancer-specific survival (BCSS) in pT3N0M0 patients with and without postmastectomy radiotherapy. PATIENTS AND METHODS: Between October 2000 and 8 September 2016, the database of the Breast Cancer Center of Shanghai yielded 114 patients with node-negative non-metastatic breast cancer larger than 5 cm. Univariate and multivariate analyses were performed to assess the risk factors for survivals. Differences between the two groups were compared using the Log rank test. RESULTS: Fifty-nine (51.8%) of the patients received adjuvant PMRT. The median follow-up was 62.3 months. Five-year LRFS was 100% in the PMRT group vs 98.1% in the non-PMRT group (P=0.17); 5-year DFS was 97.1% for the entire cohort, 98.0% for the PMRT group vs 96.2% for the non-PMRT group (P=0.18). Univariate analysis identified that family history of malignant tumors, lymphovascular invasion (LVI), or triple-negative breast cancer (TNBC) molecular subtype were associated with higher locoregional recurrence (LRR) (P<0.05). No PMRT was the only risk factor independently associated with poorer DFS (P=0.048) on multivariate analysis. No difference in BCSS was observed between the two groups. CONCLUSION: The present study demonstrated a low LRR rate and good survival for node-negative breast cancer >5 cm. Patients with family history of malignant tumors, TNBC subtype, LVI positivity, or grade 3 disease are at high risk for LRR and might benefit from PMRT.

CDK4/6 inhibitors: a novel strategy for tumor radiosensitization.

Recently, the focus of enhancing tumor radiosensitivity has shifted from chemotherapeutics to targeted therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are a novel class of selective cell cycle therapeutics that target the cyclin D-CDK4/6 complex and induce G1 phase arrest. These agents have demonstrated favorable effects when used as monotherapy or combined with endocrine therapy and targeted inhibitors, stimulating further explorations of other combination strategies. Multiple preclinical studies have indicated that CDK4/6 inhibitors exhibit a synergistic effect with radiotherapy both in vitro and in vivo. The principal mechanisms of radiosensitization effects include inhibition of DNA damage repair, enhancement of apoptosis, and blockade of cell cycle progression, which provide the rationale for clinical use. CDK4/6 inhibitors also induce cellular senescence and promote anti-tumor immunity, which might represent potential mechanisms for radiosensitization. Several small sample clinical studies have preliminarily indicated that the combination of CDK4/6 inhibitors and radiotherapy exhibited well-tolerated toxicity and promising efficacy. However, most clinical trials in combined therapy remain in the recruitment stage. Further work is required to seek optimal radiotherapy-drug combinations. In this review, we describe the effects and underlying mechanisms of CDK4/6 inhibitors as a radiosensitizer and discuss previous clinical studies to evaluate the prospects and challenges of this combination.

Changed hemodynamics in acute vasoreactivity testing: prognostic predictors in chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is similar to pulmonary arterial hypertension (PAH) in its pathogenesis. Changed hemodynamic parameters in acute vasoreactivity testing (AVT) have proved to be prognostic predictors of PAH. We wanted to determine whether these changed indices also impacted the prognosis of CTEPH. Data was retrieved for 86 CTEPH patients who underwent right heart catheterization (RHC) with AVT at Shanghai Pulmonary Hospital from 2009 to 2018 and following up for 20 ± 15 months for event. Cox proportional hazards models were performed to determine the predictors of independent event-free survival. Receiver operating characteristic curve was plotted to determine the cut-off value of independent parameters in CTEPH. Kaplan-Meier method and log-rank test were used to perform the Survival analyses. Forty seven patients had an event. Many hemodynamic indices improved after AVT. The event-free group had better mean right atrial pressure, mean pulmonary arterial pressure, pulmonary vascular resistance (PVR) and oxygen saturation of mixed venous blood (SvO2) both at baseline and after AVT. The event-free group also showed higher cardiac output (CO) and cardiac index (CI) after AVT. Among the changed hemodynamic parameters during the AVT, ΔCO, ΔCO/baseline CO, ΔCI, ΔCI/baseline CI and ΔPVR/baseline PVR were significantly higher in the event-free group. Foremost, ΔPVR/baseline PVR, PVR after AVT and baseline SvO2 were independent predictors for event-free survival. Patients with SvO2 ≥ 61.65% at baseline or PVR < 8.09 WU after AVT or ΔPVR/baseline PVR ≥ 0.054 had significantly better survival. Hemodynamic indices both at baseline and after AVT as well as the changes in these indices reflected the severity of CTEPH. Baseline SvO2, PVR after AVT, and ΔPVR/baseline PVR could be used as independent predictors to estimate the outcomes of CTEPH patients.

Variable predictors of acute pulmonary embolism recurrence with duration of follow-up.

BACKGROUND: Acute pulmonary embolism (PE) is a critical disease and often leads to a high mortality and morbidity. Several studies have identified predictors of PE recurrence, but whether these predictors have prognostic value and how they vary during varied follow-up periods remain unclear. METHODS: We retrospectively assessed the occurrence of recurrent PE and the survival time of patients with a diagnosis of acute PE at Shanghai Pulmonary Hospital from May 2007 to May 2018. Potential predictors of recurrent PE were evaluated at different points (1, 3, 6, 12, 24, 60 and 120-month) during a long-term follow-up for each patient. Patients were stratified into two groups by gender to analyze the impact of sex in period-guided prognostic prediction. Receiver operating characteristic curve analysis, survival analysis and multivariate Cox proportional hazards analysis were implemented as statistical analysis methods. RESULTS: In total, 597 acute PE patients were included, of whom 62 reported a PE recurrence. Male patients tend to have a lower risk of PE recurrence than female patients during 3- to 60-month follow-up period but have a higher risk of PE recurrence than female patients during 120-month follow-up period. The independent predictors of recurrence-free survival varied among different follow-up periods: In all patients, diabetes was an independent predictor only within 30 days follow-up period and female was considered as an independent predictor during 3- to 120-month follow-up period. Among male patients, hyperlipidemia and Log D-dimer (cut-off value =3.436) was observed as a predictor of recurrent PE within 6-month and over 12-month follow-up respectively. However, there is no unified independent prognostic indicator for female patients identified. CONCLUSIONS: In the early stage of follow-up, male PE patients have better prognosis, but with the extension of follow-up, female PE patients have better prognosis. The independent predictors of recurrence-free survival vary in different follow-up periods in PE patients when stratified based on gender and associated medical conditions.

Sex differences of hemodynamics during acute vasoreactivity testing to predict the outcomes of chronic thromboembolic pulmonary hypertension.

BACKGROUND: Acute vasoreactivity testing (AVT) which reflects the compliance of the pulmonary vascular bed has been proven to be of prognostic value. The purpose of the present study is to explore the sex differences of hemodynamics during the AVT and their impact on event-free survival in patients with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: Eighty-six patients underwent a right heart catheterization and AVT at Shanghai Pulmonary Hospital from February 2009 to February 2018. Univariate and multiple stepwise regression analysis were performed to determine the predictors of independent event-free survival, and receiver operating characteristic curve was plotted to determine the cut-off value of independent parameters in CTEPH. RESULTS: There were no significant differences in both demographics and hemodynamics between male and female patients with CTEPH. Except ΔPVR/PVR showed a significantly higher difference in female than male patients (P = 0.034). Male patients had higher mRAP of pre- and post-AVT than female patients in the event-free subgroup, while, female patients showed higher PVR of pre-AVT than male patients in the event subgroup (P < 0.05). The mRAP and SvO2 were independent predictors of event-free survival in female patients both before and after the AVT, whereas ΔSvO2 was an independent predictor of event-free survival in male patients. CONCLUSION: Hemodynamics during the AVT varied between male and female patients with CTEPH. Both sexes displayed unique hemodynamic responses that were independently able to predict event-free survival. Therefore, better estimates of prognosis in CTEPH can be made when sex differences are also taken into consideration.