PD-1 antibody in combination with chemotherapy for the treatment of SMARCA4-deficient advanced undifferentiated carcinoma of the duodenum: Two case reports.

BACKGROUND: SMARCA4 is a component of chromatin remodeling of SWItch/sucrose-nonfermenting (SWI/SNF) complexes and plays an essential role in oncogenesis. SMARCA4-deficient malignancies arising from the gastrointestinal tract are rare and have a poor prognosis. There is no standard treatment for advanced and undifferentiated SMARCA4-deficient duodenal malignancies. Programmed death 1 (PD-1) antibodies, known as immune checkpoint inhibitor antibodies, potentially play a role in treating gastrointestinal tract malignancies. CASE SUMMARY: We present two patients with SMARCA4 deficiency and TP53 gene mutation in advanced undifferentiated carcinomas of the duodenum. For both patients, SMARCA4 deficiency was confirmed by immunohistochemical staining for the BRG1 protein, while TP53 gene mutations were observed via next-generation sequencing. Both patients were administered chemotherapy in combination with an anti-PD-1 antibody. The two patients exhibited completely different responses to treatment and had different prognoses. Case 1 experienced rapid progression after PD-1 infusion and chemotherapy, case 2 experienced a remarkable response after treatment, and the progression-free survival was more than 6 months. CONCLUSION: This study described our clinical and pathological observations of SMARCA4-deficient advanced undifferentiated carcinoma of the duodenum. PD-1 combined with chemotherapy showed a certain efficacy in select patients, providing options for treating these highly malignant tumors. Patients with liver metastases had a worse prognosis than did those with only lymph node metastasis.

Electroacupuncture Alleviates Pain Responses and Inflammation in Collagen-Induced Arthritis Rats via Suppressing the TLR2/4-MyD88-NF-κB Signaling Pathway.

Results: EA intervention and OxPAPC injection could relieve mechanical allodynia and thermal hyperalgesia caused by CIA. Paw edema and pathological damage of synovium were significantly ameliorated after EA intervention and OxPAPC injection. Furthermore, EA intervention and OxPAPC injection markedly reduced the contents of serum TNF-α, IL-1ß, and IL-6, as well as the protein expression levels of synovial TLR2, TLR4, MyD88, and NF-κB p-p65. In particular, the expression of TLR2 and TLR4 on synovial fibroblasts and macrophages in synovium was significantly reduced by EA intervention. Conclusions: Repeated EA stimulation at ST36 and SP6 can effectively relieve joint pain and synovial inflammation caused by RA in CIA rats. The analgesic and anti-inflammatory effect of EA may be closely related to the inhibition of innate immune responses driven by the TLR2/4-MyD88-NF-κB signaling pathway in the synovium.

[Effects of transcutaneous auricular vagus nerve stimulation on bone and cartilage destruction in rats with rheumatoid arthritis].

OBJECTIVE: To observe the alleviating effect of transcutaneous auricular vagus nerve stimulation (taVNS) on articular cartilage and bone destruction in rats with collagen-induced arthritis (CIA), and explore the cellular and molecular mechanisms of taVNS against rheumatoid arthritis (RA). METHODS: The male SD rats were randomly divided into normal control group (n=12), model group (n=12), and taVNS group (n=12). The CIA rat model was established by multi-point injection of emulsion prepared from type Ⅱ bovine collagen and Freund's incomplete adjuvant into the root of rat tail. The rats in the taVNS group were treated with taVNS at bilateral auricular conchae, 30 min per time, once a day, for consecutive 28 d. The cartilage destruction of the ankle joint was observed by safranin O-fast green staining, the production of osteoclasts in the joint tissue by tartrate-resistant acid phosphatase (TRAP) staining, and the bone erosion by X-ray and Micro-CT imaging. The protein expression levels of matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, receptor activator of nuclear factor-κB ligand (RANKL), and osteoprotegerin (OPG) in the synovial tissues were detected by Western blot. RESULTS: Compared with the normal control group, the CIA rats presented with typical RA symptoms and elevated arthritis index (AI,P<0.05). After intervention with taVNS, the AI remarkably declined in comparison with that in the model group (P<0.05). Compared with the control group, the model group displayed loss of cartilage matrix in the ankle joint, thinned cartilage layer, obvious cartilage damage, and increased number of osteo-clasts in the joint (P<0.01); the imaging results showed bone loss and three-dimensional structural destruction of ankle joint and aggravated bone erosion (P<0.01); the expression levels of MMP-1, MMP-3 and MMP-13, and RANKL/OPG ratio were significantly elevated in the synovial tissue of ankle joint (P<0.01, P<0.05), while the expression level of OPG was decreased (P<0.05). Compared with the model group, taVNS resulted in relatively intact cartilage layer of ankle joint, alleviated cartilage destruction, decreased number of osteoclasts (P<0.01), improved bone erosion, loss, and three-dimensional structural destruction (P<0.01), and diminished MMP-1, MMP-3, and MMP-13 expression and RANKL/OPG ratio in the synovial tissue of ankle joint (P<0.05, P<0.01), while the expression level of OPG was increased (P<0.05). CONCLUSION: taVNS effectively relieves bone and cartilage destruction in CIA rats, which might be related to its efficacy in reducing the production of osteoclasts in joint tissues and down-regulating the expression levels of MMP-1, MMP-3 and MMP-13, and RANKL/OPG ratio.

[Effect of electroacupuncture on articular morphological changes and serum inflammatory factors and synovial MMPs in collagen-induced arthritis rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) of "Zusanli"(ST36) and "Sanyinjiao"(SP6) on serum TNF-α, IL-1ß, and IL-6 and expression of synovial matrimetalloproteinases (MMPs) and articular morphology in collagen-induced arthritis (CIA) rats, so as to explore its mechanisms underlying relief of arthritis. METHODS: Thirty male SD rats were randomly divided into normal control, CIA model and EA groups (n=10 rats per group). The arthritis model was induced by multi-point intradermal injection of bovine type Ⅱ collagen emulsion. EA (2 Hz/100 Hz, 1 mA) was applied to bilateral ST36 and SP6 for 30 min, once a day for 28 days. The hind-limb paw volume was measured and the arthritis index (AI) score given according to the swelling degree, rigidity and deformity of the ankle joint (0-4 points). After EA intervention, the morphological damage of the affected ankle joints was revealed by H.E. staining, safranin O-fast green staining, and tartrate-resistant acid phosphatase (TRAP) staining, separately. The levels of serum TNF-α, IL-1ß, and IL-6 were measured by ELISA, and the expression levels of MMP-1, MMP-3, MMP-13, and receptor activator of nuclear factor Kappa B ligand (RANKL) in the synovial tissue were detected by Western blot. RESULTS: Compared with the normal control group, the paw volume, AI score, TRAP-revealed number of osteoclasts, contents of serum TNF-α, IL-1ß and IL-6, and expression levels of MMP-1, MMP-3, MMP-13 and RANKL proteins were significantly increased in the model group (P<0.01, P<0.05). Following the intervention, the paw volume, AI score, number of osteoclasts, contents of serum TNF- α, IL-1ß and IL-6, and expression levels of MMP-1, MMP-3, MMP-13 and RANKL proteins were significantly decreased in the EA group (P<0.05, P<0.01) in contrast to the model group. H.E. and safranin O-fast green staining showed rough articular cartilage surface with thinned cartilage layer, obvious hyperplasia of the synovial tissue with many inflammatory cells, and serious damage and degradation of the cartilage matrix in the model group, these situations were relatively milder in the EA group. CONCLUSION: EA of ST36 and SP6 can reduce the articular damage in collagen-induced arthritis rats, which is associated with its function in reducing inflammatory response and down-regulating the expression of synovial MMP-1, MMP-3, MMP-13 and RANKL proteins.

Contribution of GABAergic modulation in DRGs to electroacupuncture analgesia in incisional neck pain rats.

PURPOSE: Acupuncture therapy is effective for relieving postoperative pain. Our previous study showed that electroacupuncture (EA) at Futu (LI18) and Hegu (LI4)-Neiguan (PC6) could alleviate incisional neck pain, which was related with its effect in upregulating γ-aminobutyric acid (GABA) expression in cervical (C3-6) dorsal root ganglions (DRGs); but whether its receptor subsets GABAAα2R and GABABR1 in C3-6 DRGs are involved in EA analgesia or not, it remains unknown. MATERIALS AND METHODS: Seventy-five male Sprague Dawley rats were randomized to normal control, model, LI18, LI4-PC6, and Zusanli (ST36)-Yanglingquan (GB34) groups. The incisional neck pain model was established by making a longitudinal incision along the midline of the rats' neck, followed by repeated mechanical stimulation. EA was applied to bilateral LI18, LI4-PC6, or ST36-GB34 for 30 minutes at 4, 24, and 48 hours after operation. The thermal pain threshold of the neck was detected by a tail-flick unit, and the C3-6 DRGs were removed for assaying the immunoactivity of substance P (SP), GABAAα2R, glial fibrillary acidic protein (GFAP; a marker of satellite glial cells [SGCs]), and GABABR1 and the expression of GABAAα2R and GABABR1 mRNA and proteins using immunofluorescence, real-time PCR, and Western blotting, respectively. RESULTS: The cervical thermal pain threshold was significantly lower in the model group than the normal group (P<0.001), indicating hyperalgesia after neck incision, and was considerably increased in both EA-LI18 and LI4-PC6 groups (P<0.001), but not in ST36-GB34 group compared with model group (P>0.05). Immunofluorescence staining showed that GABAAα2 R expressed on SP+ neurons, and GABABR1 on SGCs. EA of LI18 and LI4-PC6 markedly suppressed the modeling-induced upregulation of the immunoactivity of SP (P<0.001 and P<0.01, respectively) and GFAP (P<0.01 and P<0.001, respectively) and significantly reversed neck incision-induced downregulation of the expression of GABAAα2R and GABABR1 mRNAs and proteins (P<0.05). CONCLUSION: EA of LI18 and LI4-PC6 has an analgesic effect in incisional neck pain rats, which is related to its effects in upregulating GABAergic inhibitory modulation on nociceptive peptidergic neurons and SGCs in cervical DRGs.

[Electroacupuncture of Multiple Acupoints Is Significantly Superior to That of Single Acupoint in Improving Sleep by Regulating Serum Sleep-promoting and Awakening-promoting Factors in Insomnia Rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation of single and multiple acupoints on sleep and concentrations of interlukin-1 ß(IL-1 ß), brain-derived neurotrophic factor (BDNF), prostaglandin D2(PGD2) and melatonin (MLT, sleep-promoting factors) and corticosterone (CORT, awakening-promoting factor) in the serum in insomnia rats, so as to explore its efficacy difference and the mechanism underlying improving sleep. METHODS: Fifty-four male SD rats were randomly divided into control, model, EA-Baihui (GV 20), EA-Shenmen (HT 7), EA-Sanyinjiao (SP 6) and EA-GV 20＋HT 7＋SP 6 groups (n＝9 rats in each group). The insomnia model was established by intraperitoneal injection of para-chlorophenylalanine (PCPA, 300 mg/kg) once daily for 2 days. In the EA-GV 20, EA-HT 7, EA-SP 6 and EA-GV 20＋HT 7＋SP 6 groups, EA stimulation was administrated for 30 min, once a day for 4 days. The sleep onset latency and sleep duration were measured after intraperitoneal injection of pentobarbital sodium (35 mg/kg). The concentrations of IL-1 ß， BDNF, MLT, PGD2and CORT in the serum were detected by ELISA. RESULTS: After EA stimulation of GV 20, HT 7, SP 6 and GV 20＋HT 7＋SP 6, the sleep latency was significantly shortened (P<0.05, P<0.01, except SP 6), and the sleep duration was remarkably prolonged in comparison with the model group (P<0.05, P<0.01), and the therapeutic effects of EA-GV 20＋HT 7＋SP 6 were significantly superior to those of EA-GV 20, EA-HT 7 and EA-SP 6 in shortening the sleep latency and lengthening the sleep duration (P<0.05). Following modeling, the concentrations of IL-1 ß， BDNF, PGD2 and MLT were significantly down-regulated, and the CORT level was markedly up-regulated in the model group relevant to the control group (P<0.05). Following EA，modeling induced dramatic decrease of serum IL-1 ß， BDNF, PGD2 and MLT was considerably up-regulated, and the increased CORT level markedly down-regulated in the EA-GV 20, EA-HT 7, EA-SP 6 and EA-GV 20＋HT 7＋SP 6 groups (P<0.05). The effects of EA-GV 20＋HT 7＋SP 6 were evidently superior to those of EA-GV 20 and EA-SP 6 in up-regulating serum IL-1 ß， BDNF and PGD2levels, and to those of HT 7, GV 20 and SP 6 in up-regulating serum MLT level, and significantly superior to those of EA-ST 7 and EA-SP 6 in down-regulating serum CORT (P<0.05). CONCLUSION: EA stimulation of HT 7, GV 20, SP 6 and GV 20＋HT 7＋ SP 6 can significantly improve the sleep in insomnia rats, which is closely associated with its effects in regulating serum sleep-promoting factors and awakening-promoting factor. Joint administration of EA of GV 20＋HT 7＋ SP 6 has a better effect than the single acupoint mentioned above.

Gastrointestinal stromal tumor (GIST) with liver metastases: An 18-year experience from the GIST cooperation group in North China.

Approximately 40% to 50% of gastrointestinal stromal tumor (GIST) patients will have recurrence or metastases after resection of the primary lesion, and the most common affected sites will be liver and peritoneum. Imatinib has been considered as the first-line therapy of metastatic GIST. Surgery for metastases is proposed when possible. Furthermore, there are controversies concerning hepatic resection and systemic tyrosin kinase inhibitors (TKIs). The therapeutic conditions and long-term outcome of GIST patients with liver metastases in northern China remain unknown.The clinical, pathological, and follow-up data of 144 GIST patients, who had liver metastases between June 1996 and June 2014 from 3 tertiary cancer centers in northern China, were reviewed.Thirty-two cases (22.2%) had hepatectomy with 23 (23/32, 71.9%) R0 resections and 9 (9/32, 28.1%) R1/R2 resections, respectively. Twenty-three patients were given imatinib postoperatively. Furthermore, 98 (68.1%) patients were given TKIs only to control disease progression, and sunitinib was considered after imatinib failure in 12 patients. The 1-, 3- and 5-year survival rate was 82%, 51%, and 24%, with a median overall survival of 48 months for all patients. Patients who had hepatic resection combined with TKIs had a tendency of improved outcome, and the median survival time was 89 months. This was in contrast to patients who received TKIs only, in which median survival time was 53 months. Patients who received imatinib plus sunitinib had a tendency of longer survival time, compared with patients who received imatinib only (not reached vs 50 months).TKIs combined with hepatic resection had a role in improving the outcome of GIST patients with liver metastases.

Prevalence, clinical manifestations and endoscopic features of eosinophilic esophagitis: a pathological review in China.

OBJECTIVE: We aimed to determine the prevalence of eosinophilic esophagitis (EoE) and define its clinical and endoscopic characteristics in Chinese patients. METHODS: Esophageal specimens obtained from January 2006 to December 2010 in the First Affiliated Hospital of Sun Yat-sen University were reviewed, and the data on clinical characteristics and endoscopic findings of patients were obtained. Patients with eosinophils ≥15 per high power field (HPF) were identified as having EoE. RESULTS: A total of 12 patients met the criteria for EoE, establishing a prevalence of 0.34%. These patients presented with dysphagia (4/12, 33.3%), gastroesophageal reflux disease (GERD)-like symptoms (3/12, 25.0%), abdominal pain (3/12, 25.0%) and others (2/12, 16.7%). The most common endoscopic finding was plaques (5/12, 41.7%), and other findings were irregular Z-line (2/12, 16.7%), erosive esophagitis (2/12, 16.7%), white exudates (1/12, 8.3%), linear furrows (1/12, 8.3%), Schatzki ring (1/12, 8.3%), ulcers (1/12, 8.3%) and erythema (1/12, 8.3%). CONCLUSIONS: The prevalence of EoE was 0.34% in our patients. Clinicians should pay attention to patients manifested with dysphagia and GERD-like symptomes with endosopic findings of white exudates, plaques, Schatzki ring and linear furrows.