Cav3.2 T-Type calcium channels downregulation attenuates bone cancer pain induced by inhibiting IGF-1/HIF-1α signaling pathway in the rat spinal cord.

Background: Bone cancer pain (BCP) is one of the most ubiquitous and refractory symptoms of cancer patients that needs to be urgently addressed. Substantial studies have revealed the pivotal role of Cav3.2 T-type calcium channels in chronic pain, however, its involvement in BCP and the specific molecular mechanism have not been fully elucidated. Methods: The expression levels of Cav3.2, insulin-like growth factor 1(IGF-1), IGF-1 receptor (IGF-1R) and hypoxia-inducible factor-1α (HIF-1α) were detected by Western blot in tissues and cells. X-ray and Micro CT used to detect bone destruction in rats. Immunofluorescence was used to detect protein expression and spatial location in the spinal dorsal horn. Electrophoretic mobility shift assay used to verify the interaction between HIF-1α and Cav3.2. Results: The results showed that the expression of Cav3.2 channel was upregulated and blockade of this channel alleviated mechanical allodynia and thermal hyperalgesia in BCP rats. Additionally, inhibition of IGF-1/IGF-1R signaling not only reversed the BCP-induced upregulation of Cav3.2 and HIF-1α, but also decreased nociceptive hypersensitivity in BCP rats. Inhibition of IGF-1 increased Cav3.2 expression levels, which were abolished by pretreatment with HIF-1α siRNA in PC12 cells. Furthermore, nuclear HIF-1α bound to the promoter of Cav3.2 to regulate the Cav3.2 transcription level, and knockdown of HIF-1α suppresses the IGF-1-induced upregulation of Cav3.2 and pain behaviors in rats with BCP. Conclusion: These findings suggest that spinal Cav3.2 T-type calcium channels play a central role during the development of bone cancer pain in rats via regulation of the IGF-1/IGF-1R/HIF-1α pathway.

Mitophagy-related gene signature predicts prognosis, immune infiltration and chemotherapy sensitivity in colorectal cancer.

BACKGROUND: Mitophagy plays essential role in the development and progression of colorectal cancer (CRC). However, the effect of mitophagy-related genes in CRC remains largely unknown. AIM: To develop a mitophagy-related gene signature to predict the survival, immune infiltration and chemotherapy response of CRC patients. METHODS: Non-negative matrix factorization was used to cluster CRC patients from Gene Expression Omnibus database (GSE39582, GSE17536, and GSE37892) based on mitophagy-related gene expression. The CIBERSORT method was applied for the evaluation of the relative infiltration levels of immune cell types. The performance signature in predicting chemotherapeutic sensitivity was generated using data from the Genomics of Drug Sensitivity in Cancer database. RESULTS: Three clusters with different clinicopathological features and prognosis were identified. Higher enrichment of activated B cells and CD4+ T cells were observed in cluster III patients with the most favorable prognosis. Next, a risk model based on mitophagy-related genes was developed. Patients in training and validation sets were categorized into low-risk and high-risk subgroups. Low risk patients showed significantly better prognosis, higher enrichment of immune activating cells and greater response to chemotherapy (oxaliplatin, irinotecan, and 5-fluorouracil) compared to high-risk patients. Further experiments identified CXCL3 as novel regulator of cell proliferation and mitophagy. CONCLUSION: We revealed the biological roles of mitophagy-related genes in the immune infiltration, and its ability to predict patients' prognosis and response to chemotherapy in CRC. These interesting findings would provide new insight into the therapeutic management of CRC patients.

Short-term outcomes of reduced-port laparoscopic surgery versus conventional laparoscopic surgery for total gastrectomy: a single-institute experience.

BACKGROUND: The efficacy of reduced-port laparoscopic surgery (RLS) for total gastrectomy remains unclear. This study focused on evaluating the short-term outcomes of RLS compared with conventional laparoscopic surgery (CLS) for total gastrectomy. METHODS: One hundred and ten patients who underwent completed laparoscopic total gastrectomy for gastric cancer between September 2018 and June 2022 were retrospectively collected and classified into two groups (65 CLS and 45 RLS) according to different operation approach. Twenty-four RLS cases underwent single-incision plus two ports laparoscopic surgery (SILS + 2) and twenty-one underwent single-incision plus one port laparoscopic surgery (SILS + 1). Surgical outcomes, pain intensity, cosmetic and postoperative morbidity, and mortality were compared between groups. RESULTS: The overall incidence of postoperative complications was similar between the CLS group and the RLS group (16.9% vs. 8.9%, P = 0.270). It was also comparable in the Clavien-Dindo classification (P = 0.774). However, compared with the CLS group, the RLS group had a significantly shorter total length of incision (5.6 ± 1.0 cm vs. 7.1 ± 0.7 cm, P = 0.000); shorter time to first ambulation (24.9 ± 5.9 h vs. 27.6 ± 5.0 h, P = 0.009), flatus (3.0 ± 0.8 d vs. 3.5 ± 1.0 d, P = 0.022) and oral intake (4.0 ± 1.6 d vs. 6.1 ± 5.1 d, P = 0.011); lower white blood cell count on the third day after the operation (9.8 ± 4.0*109/L vs. 11.6 ± 4.7*109/L, P = 0.037); and lower visual analogue scale score on postoperative days 1 and 3(3.0 ± 0.7 vs. 3.3 ± 0.7, P = 0.044 and 0.6 ± 0.7 vs. 1.6 ± 0.6, P = 0.000 respectively). On the other hand, it didn't find any difference in short-term outcomes between the SILS + 2 group and the SILS + 1 group (P > 0.05). But the proximal resection margin was longer in the SILS + 2 group than in the SILS + 1 group (2.6 ± 0.7 cm vs. 1.5 ± 0.9 cm, P = 0.046) in patients with adenocarcinoma of the esophagogastric junction (AEG). CONCLUSIONS: RLS for total gastrectomy is a feasible and safe technique when performed by an experienced laparoscopic surgeon. Moreover, compared with SILS + 1, SILS + 2 might have some advantages in AEG patients.

Gestational palmitic acid suppresses embryonic GATA-binding protein 4 signaling and causes congenital heart disease.

Dysregulated maternal fatty acid metabolism increases the risk of congenital heart disease (CHD) in offspring with an unknown mechanism, and the effect of folic acid fortification in preventing CHD is controversial. Using gas chromatography coupled to either a flame ionization detector or mass spectrometer (GC-FID/MS) analysis, we find that the palmitic acid (PA) concentration increases significantly in serum samples of pregnant women bearing children with CHD. Feeding pregnant mice with PA increased CHD risk in offspring and cannot be rescued by folic acid supplementation. We further find that PA promotes methionyl-tRNA synthetase (MARS) expression and protein lysine homocysteinylation (K-Hcy) of GATA4 and results in GATA4 inhibition and abnormal heart development. Targeting K-Hcy modification by either genetic ablation of Mars or using N-acetyl-L-cysteine (NAC) decreases CHD onset in high-PA-diet-fed mice. In summary, our work links maternal malnutrition and MARS/K-Hcy with the onset of CHD and provides a potential strategy in preventing CHD by targeting K-Hcy other than folic acid supplementation.

BMI and pelvimetry help to predict the duration of laparoscopic resection for low and middle rectal cancer.

BACKGROUND: In rectal cancer surgery, recent studies have found associations between clinical factors, especially pelvic parameters, and surgical difficulty; however, their findings are inconsistent because the studies use different criteria. This study aimed to evaluate common clinical factors that influence the operative time for the laparoscopic anterior resection of low and middle rectal cancer. METHODS: Patients who underwent laparoscopic radical resection of low and middle rectal cancer from January 2018 to December 2020 were retrospectively analyzed and classified according to the operative time. Preoperative clinical and magnetic resonance imaging (MRI)-related parameters were collected. Logistic regression analysis was used to identify factors for predicting the operative time. RESULTS: In total, 214 patients with a mean age of 60.3 ± 8.9 years were divided into two groups: the long operative time group (n = 105) and the short operative time group (n = 109). Univariate analysis revealed that the male sex, a higher body mass index (BMI, ≥ 24.0 kg/m2), preoperative treatment, a smaller pelvic inlet (< 11.0 cm), a deeper pelvic depth (≥ 10.7 cm) and a shorter intertuberous distance (< 10.1 cm) were significantly correlated with a longer operative time (P < 0.05). However, only BMI (OR 1.893, 95% CI 1.064-3.367, P = 0.030) and pelvic inlet (OR 0.439, 95% CI 0.240-0.804, P = 0.008) were independent predictors of operative time. Moreover, the rate of anastomotic leakage was higher in the long operative time group (P < 0.05). CONCLUSION: Laparoscopic rectal resection is expected to take longer to perform in patients with a higher BMI or smaller pelvic inlet.

Pharmacological Effects of Resveratrol in Intervertebral Disc Degeneration: A Literature Review.

Intervertebral disc degeneration (IDD) is a high incidence disease of musculoskeletal system that often leads to stenosis, instability, pain and even deformity of the spinal segments. IDD is an important cause of discogenic lower back pain and often leads to large economic burden to families and society. Currently, the treatment of IDD is aimed at alleviating symptoms rather than blocking or reversing pathological progression of the damaged intervertebral disc. Resveratrol (RSV) is a polyphenol phytoalexin first extracted from the Veratrum grandiflflorum O. Loes and can be found in various plants and red wine. Owing to the in-depth study of pharmacological mechanisms, the therapeutic potential of RSV in various diseases such as osteoarthritis, neurodegenerative diseases, cardiovascular diseases and diabetes have attracted the attention of many researchers. RSV has anti-apoptotic, anti-senescent, anti-inflammatory, anti-oxidative, and anabolic activities, which can prevent further degeneration of intervertebral disc cells and enhance their regeneration. With high safety and various biological functions, RSV might be a promising candidate for the treatment of IDD. This review summarizes the biological functions of RSV in the treatment of IDD and to facilitate further research.

Short-term Outcomes of Laparoscopy-Assisted vs Open Surgery for Patients With Low Rectal Cancer: The LASRE Randomized Clinical Trial.

Importance: The efficacy of laparoscopic vs open surgery for patients with low rectal cancer has not been established. Objective: To compare the short-term efficacy of laparoscopic surgery vs open surgery for treatment of low rectal cancer. Design, Setting, and Participants: This multicenter, noninferiority randomized clinical trial was conducted in 22 tertiary hospitals across China. Patients scheduled for curative-intent resection of low rectal cancer were randomized at a 2:1 ratio to undergo laparoscopic or open surgery. Between November 2013 and June 2018, 1070 patients were randomized to laparoscopic (n = 712) or open (n = 358) surgery. The planned follow-up was 5 years. Data analysis was performed from April 2021 to March 2022. Interventions: Eligible patients were randomized to receive either laparoscopic or open surgery. Main Outcomes and Measures: The short-term outcomes included pathologic outcomes, surgical outcomes, postoperative recovery, and 30-day postoperative complications and mortality. Results: A total of 1039 patients (685 in laparoscopic and 354 in open surgery) were included in the modified intention-to-treat analysis (median [range] age, 57 [20-75] years; 620 men [59.7%]; clinical TNM stage II/III disease in 659 patients). The rate of complete mesorectal excision was 85.3% (521 of 685) in the laparoscopic group vs 85.8% (266 of 354) in the open group (difference, -0.5%; 95% CI, -5.1% to 4.5%; P = .78). The rate of negative circumferential and distal resection margins was 98.2% (673 of 685) vs 99.7% (353 of 354) (difference, -1.5%; 95% CI, -2.8% to 0.0%; P = .09) and 99.4% (681 of 685) vs 100% (354 of 354) (difference, -0.6%; 95% CI, -1.5% to 0.5%; P = .36), respectively. The median number of retrieved lymph nodes was 13.0 vs 12.0 (difference, 1.0; 95% CI, 0.1-1.9; P = .39). The laparoscopic group had a higher rate of sphincter preservation (491 of 685 [71.7%] vs 230 of 354 [65.0%]; difference, 6.7%; 95% CI, 0.8%-12.8%; P = .03) and shorter duration of hospitalization (8.0 vs 9.0 days; difference, -1.0; 95% CI, -1.7 to -0.3; P = .008). There was no significant difference in postoperative complications rate between the 2 groups (89 of 685 [13.0%] vs 61 of 354 [17.2%]; difference, -4.2%; 95% CI, -9.1% to -0.3%; P = .07). No patient died within 30 days. Conclusions and Relevance: In this randomized clinical trial of patients with low rectal cancer, laparoscopic surgery performed by experienced surgeons was shown to provide pathologic outcomes comparable to open surgery, with a higher sphincter preservation rate and favorable postoperative recovery. Trial Registration: ClinicalTrials.gov Identifier: NCT01899547.

Systematic analysis of critical genes and pathways identified a signature of neuropathic pain after spinal cord injury.

Spinal cord injury (SCI) damages sensory systems, producing chronic neuropathic pain that is resistant to medical treatment. The specific mechanisms underlying SCI-induced neuropathic pain (SCI-NP) remain unclear, and protein biomarkers have not yet been integrated into diagnostic screening. To better understand the host molecular pathways involved in SCI-NP, we used the bioinformatics method, the PubMed database and bioinformatics methods to identify target genes and their associated pathways. We reviewed 2504 articles on the regulation of SCI-NP and used the text mining of PubMed database abstracts to determine associations among 12 pathways and networks. Based on this method, we identified two central genes in SCI-NP: interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α). Adult male Sprague-Dawley rats were used to build the SCI-NP models. The threshold for paw withdrawal was significantly reduced in the SCI group, and TLR4 was activated in microglia after SCI. Enzyme-linked immunosorbent assay（ELISA) analysis of TNF-α and IL-6 levels was significantly higher in the SCI group than in the sham group. Western blot showed that expressions of the TLR4/MyD88/NF-κB inflammatory pathway protein increased dramatically in the SCI group. Using the TLR4 inhibitor TAK-242, the pain threshold and expressions of inflammatory factors and proteins of the proteins of the inflammatory signal pathway were reversed, TLR4 in microglia was suppressed, suggesting that SCI-NP was related to neuroinflammation mediated by the TLR4 signalling pathway. In conclusion, we found that TNF-α and IL-6 were the neuroinflammation-related genes involved in SCI-NP that can be alleviated by inhibiting the inflammatory pathway upstream of the TLR4/MyD88/NF-κB inflammatory pathway.

Comparison of short-term outcomes between single-incision plus one-port laparoscopic surgery and conventional laparoscopic surgery for distal gastric cancer: a randomized controlled trial.

Background: The technical safety and efficacy of single-incision plus one-port laparoscopic surgery (SILS+1) for distal gastric cancer remain unclear. This study was performed to compare the short-term outcomes of patients with distal gastric cancer undergoing SILS+1 versus conventional laparoscopic surgery (CLS). Methods: This randomized controlled trial involved patients with clinical stage cT1b-3N0-2M0 distal gastric cancer. The patients were randomized to the CLS group or SILS+1 group. The surgical and pathologic outcomes, postoperative mortality, and pain intensity were compared between the two groups. Results: From January 2019 to April 2021, 117 patients were enrolled and assigned to either the CLS group (n=59) or SILS+1 group (n=58). The clinical characteristics, including blood loss, tumor diameter, pathologic stage, number of lymph nodes harvested, and postoperative recovery, were similar between the two groups (P>0.05). There were no statistically significant differences in the overall postoperative complication rates between the CLS group and SILS+1 group (10.2% vs. 6.9%, respectively; P=0.743). The Clavien-Dindo classification was also comparable (P=0.435). However, the operating time was significantly longer in the CLS group than SILS+1 group (207.0±41.2 vs. 185.1±40.7 min, respectively; P=0.005), and the total incision length was significantly shorter in the SILS+1 group than CLS group (6.1±0.6 vs. 7.6±0.7 cm, respectively; P=0.000). Moreover, on the third day after surgery, the visual analog scale (VAS) score was significantly higher in the CLS group than SILS+1 group (1.6±0.6 vs. 0.6±0.7, respectively; P=0.000). Conclusions: The results of this study suggest that SILS+1 for distal gastric cancer performed by an experienced surgeon might be a feasible and safe technique with better cosmetic results and less pain in strictly selected patients. Trial Registration: This trial was registered at www.chictr.org.cn (ChiCTR2100051491).

Incidence and risk factors for postoperative pancreatic fistula in 2089 patients treated by radical gastrectomy: A prospective multicenter cohort study in China.

OBJECTIVE: To determine the incidence of clinically relevant postoperative pancreatic fistula (CR-POPF) following radical gastrectomy and to identify independent risk factors of CR-POPF. BACKGROUND: CR-POPF and its sequelae are potential complications following radical gastrectomy. The reported incidence of CR-POPF was quite different across various regions, and no consensus was reached. METHODS: Between December 2017 to November 2018, patients who underwent radical gastrectomy from 22 centers across 13 regions in China were prospectively recruited. The primary endpoint was the occurrence of CR-POPF, defined by the International Study Group of Pancreatic Fistula (ISGPF) in 2016. Clinically relevant change and short-term outcomes were recorded to diagnose and grade the POPF. Multivariate regression analyses were performed to identify independent risk factors of clinically relevant postoperative pancreatic fistula (CR-POPF). RESULTS: A total of 2089 cases were analyzed. The incidence of biochemical leakage (BL) and CR-POPF were 19.6% and 1.1% respectively. All CR-POPF patients recovered well after appropriate treatment and no Grade C POPF were recorded. Logistic regression analysis showed pTNM III (OR, 2.940; 95% CI 1.180-7.325; P = 0.021) and LigaSure usage (OR, 6.618; 95% CI 1.847-23.707; P = 0.004) were independent risk factors of CR-POPF. LigaSure usage (OR, 4.817; 95% CI 1.184-19.598; P = 0.028), the drain amylase content (D-AMY) on postoperative day 3 (POD3) ≥5 times the upper limit of normal amylase (OR, 3.476; 95% CI 1.240-9.744; P = 0.018) and open surgery (OR, 2.463; 95% CI 1.003-6.050; P = 0.049) were independent predictors for identifying CR-POPF from BL. CONCLUSION: In rich-experienced gastric cancer centers, there is high prevalence of BL secondary to radical gastrectomy without clinical impact. Fewer patients suffered Grade B POPF, and Grade C POPF was less common. The patients with pTNM III or LigaSure usage were prone to suffer CR-POPF. Surgery procedure, LigaSure usage combined with D-AMY measurement on POD3 are promising for early identification of CR-POPF.

Perioperative sleep deprivation activates the paraventricular thalamic nucleus resulting in persistent postoperative incisional pain in mice.

Background: The duration of postsurgical pain is closely correlated with perioperative stress. Most patients suffer short-term sleep disorder/deprivation before and/or after surgery, which leads to extended postsurgical pain by an undetermined mechanism. The paraventricular thalamus (PVT) is a critical area that contributes to the regulation of feeding, awakening, and emotional states. However, whether the middle PVT is involved in postoperative pain or the extension of postoperative pain caused by perioperative sleep deprivation has not yet been investigated. Methods: We established a model of postoperative pain by plantar incision with perioperative rapid eye movement sleep deprivation (REMSD) 6 h/day for 3 consecutive days in mice. The excitability of the CaMKIIα+ neurons in the middle PVT (mPVTCaMKIIα) was detected by immunofluorescence and fiber photometry. The activation/inhibition of mPVTCaMKIIα neurons was conducted by chemogenetics. Results: REMSD prolonged the duration of postsurgical pain and increased the excitability of mPVTCaMKIIα neurons. In addition, mPVTCaMKIIα neurons showed increased excitability in response to nociceptive stimuli or painful conditions. However, REMSD did not delay postsurgical pain recovery following the ablation of CaMKIIα neurons in the mPVT. The activation of mPVTCaMKIIα neurons prolonged the duration of postsurgical pain and elicited anxiety-like behaviors. In contrast, inhibition of mPVTCaMKIIα neurons reduced the postsurgical pain after REMSD. Conclusion: Our data revealed that the CaMKIIα neurons in the mPVT are involved in the extension of the postsurgical pain duration induced by REMSD, and represented a novel potential target to treat postoperative pain induced by REMSD.

Insight into the pharmacological effects of andrographolide in musculoskeletal disorders.

Andrographis paniculata (A. paniculata) is a traditional herbal medicine that has been widely used in Asian countries for hundreds of years. Andrographolide (AG) is a diterpene lactone extracted from A. paniculata. Owing to the in-depth study of pharmacological mechanisms, the therapeutic potential of AG, including its anti-inflammatory, anti-tumor, and immunoregulatory attributes, has attracted the attention of many researchers. Studies testing the therapeutic effects of AG have demonstrated desirable results in the treatment of a variety of clinical diseases. With high safety and various biological functions, AG might be a promising candidate for the treatment of musculoskeletal disorders. Here, we review all available literatures to summarize the pharmacological effects of AG and facilitate further researches on musculoskeletal diseases.

Raf1 interacts with OIP5 to participate in oxaliplatin-induced neuropathic pain.

AIMS: Oxaliplatin is an effective anti-cancer platinum-based chemotherapy drug which can cause severe chronic neuropathy, but the molecular mechanism underlying this adverse effect is still unclear. Opa interacting protein 5 (OIP5) is a member of the cancer/testis antigen (CTA) family and is involved in a variety of cancers. Studies have shown that Raf1, which is a serine/threonine-protein kinase, can directly combine with OIP5 to promote its expression. Whether Raf1 and OIP5 can participate in oxaliplatin-induced neuropathic pain has not been reported. MAIN METHODS: In this study, the oxaliplatin-induced neuropathic pain model was prepared by intraperitoneal injection of oxaliplatin. OIP5 and Raf1 were knocked down by intrathecal injection of siRNA against Raf1 and OIP5 (siRaf1, siOIP5). Von Frey fiber and acetone were used to detect pain behavior, and western blot was used to detect the protein expression changes of OIP5 and Raf1 in the dorsal root ganglion (DRG). KEY FINDINGS: The expression levels of p-Raf1 and OIP5 were increased in DRGs of oxaliplatin-induced neuropathic pain rats. Intrathecal administration of siOIP5 to inhibit the expression of OIP5 not only effectively alleviated oxaliplatin-induced mechanical allodynia and cold hyperalgesia, but also decreased the protein expression of Raf1. Intrathecal administration of siRaf1 inhibited the expression of OIP5 and attenuated oxaliplatin-induced neuropathic pain. SIGNIFICANCE: This study confirmed that Raf1 interacts with OIP5 to participate in oxaliplatin-induced neuropathic pain. The restricted expression of OIP5 in normal tissues may make it an ideal drug target for the treatment of oxaliplatin-induced neuropathic pain.

Effectiveness and Safety of Apatinib Plus Chemotherapy as Neoadjuvant Treatment for Locally Advanced Gastric Cancer: A Nonrandomized Controlled Trial.

Importance: Apatinib is a novel treatment option for chemotherapy-refractory advanced gastric cancer (GC), but it has not been evaluated in patients with locally advanced GC. Objective: To investigate the effectiveness and safety of apatinib combined with S-1 plus oxaliplatin (SOX) as a neoadjuvant treatment for locally advanced GC. Design, Setting, and Participants: This multicenter, prospective, single-group, open-label, phase 2 nonrandomized controlled trial was conducted in 10 centers in southern China. Patients with M0 and either clinical T2 to T4 or N+ disease were enrolled between July 1, 2017, and June 30, 2019. Statistical analysis was performed from December 1, 2019, to January 31, 2020. Interventions: Eligible patients received apatinib (500 mg orally once daily on days 1 to 21 and discontinued in the last cycle) plus SOX (S-1: 40-60 mg orally twice daily on days 1 to 14; oxaliplatin: 130 mg/m2 intravenously on day 1) every 3 weeks for 2 to 5 cycles. A D2 gastrectomy was performed 2 to 4 weeks after the last cycle. Main Outcomes and Measures: The primary end point was R0 resection rate. Secondary end points were the response rate, toxic effects, and surgical outcome. Results: A total of 48 patients (mean [SD] age, 63.2 [8.2] years; 37 men [77.1%]) were enrolled in this study. Forty patients underwent surgery (38 had gastrectomy, and 2 had exploratory laparotomy), with an R0 resection rate of 75.0% (95% CI, 60.4%-86.4%). The radiologic response rate was 75.0%, and T downstaging was observed in 16 of 44 patients (36.4%). The pathological response rate was 54.2% (95% CI, 39.2%-68.6%); moreover, this rate was significantly higher in patients who achieved a radiologic response compared with those who did not (12 [80.0%] vs 1 [20.0%]; P = .03) and in those who had an Eastern Cooperative Oncology Group Performance Status score of 0 (20 [76.9%] vs 10 [45.5%]; P = .03) or had tumors located in the upper one-third of the stomach (16 [61.5%] vs 7 [31.8%]; P = .04). Patients who achieved a pathological response (vs those who did not) had significantly less blood loss (median [range]: 60 [10-200] mL vs 80 [20-300] mL; P = .04) and significantly more lymph nodes harvested (median [range]: 40 [24-67] vs 32 [19-51]; P = .04) during surgery. Postoperative complications were observed in 7 of 38 patients (18.4%). Grade 3 toxic effects occurred in 16 of 48 patients (33.3%), and no grade 4 toxic effects or preoperative deaths were observed. Conclusions and Relevance: This nonrandomized controlled trial found that apatinib combined with SOX was effective and had an acceptable safety profile as a neoadjuvant treatment for locally advanced GC. A large-scale randomized clinical trial may be needed to confirm the findings. Trial Registration: ClinicalTrials.gov Identifier: NCT03192735.

Low chorionic villous succinate accumulation associates with recurrent spontaneous abortion risk.

Dysregulated extravillous trophoblast invasion and proliferation are known to increase the risk of recurrent spontaneous abortion (RSA); however, the underlying mechanism remains unclear. Herein, in our retrospective observational case-control study we show that villous samples from RSA patients, compared to healthy controls, display reduced succinate dehydrogenase complex iron sulfur subunit (SDHB) DNA methylation, elevated SDHB expression, and reduced succinate levels, indicating that low succinate levels correlate with RSA. Moreover, we find high succinate levels in early pregnant women are correlated with successful embryo implantation. SDHB promoter methylation recruited MBD1 and excluded c-Fos, inactivating SDHB expression and causing intracellular succinate accumulation which mimicked hypoxia in extravillous trophoblasts cell lines JEG3 and HTR8 via the PHD2-VHL-HIF-1α pathway; however, low succinate levels reversed this effect and increased the risk of abortion in mouse model. This study reveals that abnormal metabolite levels inhibit extravillous trophoblast function and highlights an approach for RSA intervention.

Analysis of Approaches in the Microsurgical Treatment of 102 Cases of Petroclival Meningioma in a Single Center.

Objectives: We identified the optimal approaches for treating the diverse tumor subtypes of petroclival meningioma (PM) by analyzing the clinical benefits of various surgical approaches adopted for each subtype. Methods: Tumors in 102 PM patients from a single center who underwent surgical treatment were classified as upper clivus (UC), cavernous sinus (CS), tentorium (TE), or petrous apex (PA) types based on the attachment site of the tumor base and the displacement of the trigeminal nerve. The therapeutic effects of different surgical approaches among the subtypes were evaluated according to the patient outcomes. Results: The subtemporal (33.33%), retrosigmoid (16.67%), and Kawase approaches (50%) were used for the UC type. Simpson I/II resection was achieved in 46.66% of patients with the Kawase approach. Significant differences were found between the other two approaches (P = 0.044) and in the follow-up Karnofsky performance scale (KPS) scores (P = 0.008). The subtemporal (60%) and Kawase approaches (40%) were used for the CS type; neither approach achieved Simpson I/II resection. The retrosigmoid (25.81%) and Kawase approaches (74.19%) were used for the TE type. The Simpson I/II resection rates of the two approaches were 55.55 and 86.95%, respectively, and a significant difference was observed between them (P = 0.039). The retrosigmoid (43.75%) and Kawase approaches (56.25%) were used for the PA type. The Simpson I/II resection rates of the two approaches were 31.25 and 50%, respectively. The resection degrees of the two approaches and the KPS scores at follow-up were significantly different (P = 0.034). Conclusion: The individual microsurgical approaches adopted for the various PM tumor subtypes can provide maximal safe resection and good KPS scores. The Kawase approach is more suitable for PM, especially for UC- and PA-type PM tumors.

Prognostic Significance of Preoperative Serum Carcinoembryonic Antigen Varies with Lymph Node Metastasis Status in Colorectal Cancer.

BACKGROUND: Preoperative serum level of carcinoembryonic antigen (pCEA) is generally recognized as a prognostic factor for colorectal cancer (CRC), but the stage-specific role of pCEA in colorectal cancer remains unclear. OBJECTIVE: We investigated the prognostic significance of pCEA levels in different tumor stages of nonmetastatic CRC patients. METHODS: Six hundred and fifteen CRC patients at stage I-III were retrospectively analyzed. All of them received curative tumor resection. The X-tile program was used to generate stage-specific cutoff values of pCEA for all patients and two subpopulations (lymph node-positive or -negative). The prognostic significance of pCEA was assessed using Kaplan-Meier analysis and Cox proportional hazards regression analysis. A nomogram model that combined pCEA score and clinical feature indexes was established and evaluated. RESULTS: Two cutoff values were identified in the study population. At a cutoff value of 4.9 ng/mL, a significantly higher 5-year overall survival (OS) rate (82.16%) was observed in the pCEA-low group (<4.9 ng/mL) compared with 65.52% in the pCEA-high group (≥4.9 ng/mL). Furthermore, at the second cutoff value of 27.2 ng/mL, 5-year OS was found to be only 40.9%. Stratification analysis revealed that preoperative serum level of pCEA was an independent prognostic factor (OR = 1.991, P < 0.01) in the subpopulation of lymph node metastasis (stage III) patients, and the relative survival rates in the pCEA-low (≤4.9 ng/mL), pCEA-medium (4.9-27.2 ng/mL), and pCEA-high (≥27.2 ng/mL) groups were 73.4%, 60.5%, and 24.8%, respectively (P < 0.05). However, no such effect was observed in the lymph node nonmetastasis (stage I and II) subgroup. The established nomogram showed acceptable predictive power of the 5-year OS rate (C-index: 0.612) in lymph node-positive CRC patients, with an area under the curve value of 0.772, as assessed by ROC curve analysis. CONCLUSIONS: Pretreatment serum CEA levels had different prognostic significance based on the lymph node metastasis status. Among stage III CRC patients, pCEA was an independent prognostic factor. Five-year OS rates could be predicted according to the individual pCEA level at the different cutoff values.

Primary large B-cell lymphoma involving the cerebellopontine angle: a case report.

Primary large B-cell lymphomas involving the cerebellopontine angle (CPA) are uncommon. Fewer than 20 cases of large B-cell lymphoma at the CPA have been reported worldwide. Herein, we report a rare case of B-cell lymphoma in a 67-year-old woman who presented with dysphagia and dizziness and showed a lesion involving the right CPA on magnetic resonance imaging (MRI). The primary diagnosis was metastatic tumor; however, postoperative pathology confirmed a diffuse large B-cell lymphoma. The initial symptoms were resolved completely at the 2-month postoperative follow-up, and the postoperative course was uneventful. Large B-cell lymphoma should be included in the differential diagnosis of CPA lesions.

Performance of a Nomogram Based on the Integration of Inflammation Markers with Tumor Staging in Prognosis Prediction of Stage III Colorectal Cancer.

INTRODUCTION: The aim of the present study was to evaluate a nomogram model for predicting the 5-year overall survival (OS) in lymph node-metastatic colorectal cancer (CRC) patients by combining inflammation markers with some traditional prognostic factors. METHODS: A total of 399 patients with stage III (pTXN1-3M0) CRC operated from January 2007 to December 2012 were enrolled in this retrospective study. All patients underwent D2 lymphadenectomy in the hospital. A prognostic nomogram based on the integration of traditional prognostic factors and NLR (neutrophil-to-lymphocyte ratio) and PLR (platelet-to-lymphocyte ratio) was established and compared with the nomogram based on the traditional prognostic factors alone. ROC curves were further applied to verify the predictive accuracy of the established model. RESULTS: Both NLR (P=0.00) and PLR (P=0.01) predicted the 5-year OS. In multivariate analysis, age, T3 category, T4 category, N2 category, N3 category, Pgp (P-glycoprotein), NLR and PLR are proven to be independent (all P≤0.05). The established nomogram showed better predictive power than that of traditional profile (c-index: 0.66 versus 0.63) in both training and validation cohorts. External assessment by ROC curve analysis demonstrated that the established model had a good prediction accuracy of 5-year OS in stage III CRC patients, with area under curve values of 0.657 and 0.629 in training and validating sets, respectively. CONCLUSION: A nomogram based on the integration of traditional prognostic factors and inflammatory markers (NLR and PLR) could provide more precise long-term prognosis information for lymph node-metastatic CRC patients than the model based on traditional profile alone. This model might be useful for clinical application in personalized evaluation.