Haidong Tan

Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function

The interaction between tumor and the immune system is still poorly understood. Significant clinical responses have been achieved in cancer patients treated with antibodies against the CTLA4 and PD-1/PD-L1 checkpoints; however, only a small portion of patients responded to the therapies, indicating a need to explore additional co-inhibitory molecules for cancer treatment. B7-H3, a member of the B7 superfamily, was previously shown by us to inhibit T-cell activation and autoimmunity. In this study, we have analyzed the function of B7-H3 in tumor immunity. Expression of B7-H3 was found in multiple tumor lines, tumor-infiltrating dendritic cells, and macrophages. B7-H3-deficient mice or mice treated with an antagonistic antibody to B7-H3 showed reduced growth of multiple tumors, which depended on NK and CD8+ T cells. With a putative receptor expressed by cytotoxic lymphocytes, B7-H3 inhibited their activation, and its deficiency resulted in increased cytotoxic lymphocyte function in tumor-bearing mice. Combining blockades of B7-H3 and PD-1 resulted in further enhanced therapeutic control of late-stage tumors. Taken together, our results indicate that the B7-H3 checkpoint may serve as a novel target for immunotherapy against cancer.

Characteristics and operative treatment of extremely giant liver hemangioma >20 cm

Background: Giant liver hemangioma >20 cm may cause severe complications; therefore, operative treatment can be highly difficult and risky. No studies have been performed to determine the characteristics of this subgroup. Methods: A retrospective study was performed on 141 patients who underwent operative treatment for liver hemangioma. The patients were divided into an extremely giant hemangioma group (>20 cm, 36 cases) and a giant hemangioma group (>10 cm but <20 cm, 105 cases). A comparison was then made between the groups. For patients in the extremely giant hemangioma group, further comparison was also made between liver resection and enucleation. Results: Compared with the giant hemangioma group, patients in the extremely giant hemangioma group had greater rates of leukopenia (P < .001), anemia (P < .001), thrombocytopenia (P < .001), pancytopenia (P < .001), prolonged prothrombin time (P < .001), and Kasabach‐Merritt syndrome (P = .001). Patients in the extremely giant hemangioma group also had greater rates of compression of the hepatic vein (P < .001), inferior vena cava (P < .001), and porta hepatis (P < .001). The extremely giant hemangioma group had more blood loss (P < .001) and autologous transfusion (P < .001), greater rates of blood transfusion (P < .001), and greater postoperative stays (P < .001). Morbidity was greater in the extremely giant hemangioma group; however, this difference was not statistically significant (P = .076). For patients in the extremely giant hemangioma group, no differences were detected regarding autologous transfusion, blood transfusion, or morbidity between enucleation and liver resection. Conclusion: Extremely giant hemangiomas may cause abnormalities in the hematologic and coagulation systems. Operative treatment may be difficult and risky but can be completed safely.

Co-inhibitory Molecule B7 Superfamily Member 1 Expressed by Tumor-Infiltrating Myeloid Cells Induces Dysfunction of Anti-tumor CD8+ T Cells

SUMMARY The molecular mechanisms whereby CD8+ T cells become “exhausted” in the tumor microenvironment remain unclear. Programmed death ligand‐1 (PD‐L1) is upregulated on tumor cells and PD‐1‐PD‐L1 blockade has significant efficacy in human tumors; however, most patients do not respond, suggesting additional mechanisms underlying T cell exhaustion. B7 superfamily member 1 (B7S1), also called B7‐H4, B7x, or VTCN1, negatively regulates T cell activation. Here we show increased B7S1 expression on myeloid cells from human hepatocellular carcinoma correlated with CD8+ T cell dysfunction. B7S1 inhibition suppressed development of murine tumors. Putative B7S1 receptor was co‐expressed with PD‐1 but not T cell immunoglobulin and mucin‐domain containing‐3 (Tim‐3) at an activated state of early tumor‐infiltrating CD8+ T cells, and B7S1 promoted T cell exhaustion, possibly through Eomes overexpression. Combinatorial blockade of B7S1 and PD‐1 synergistically enhanced anti‐tumor immune responses. Collectively, B7S1 initiates dysfunction of tumor‐infiltrating CD8+ T cells and may be targeted for cancer immunotherapy. Graphical Abstract Figure. No caption available. HighlightsUpregulated B7S1 expression on APCs correlates with CD8+ T dysfunction in human cancerInhibition of B7S1 promotes CD8+ T cell‐mediated tumor immunity in murine cancer modelsB7S1, via its receptor expressed on early activated CD8+ TILs, drives T cell exhaustionCo‐blockade of B7S1 and PD‐1 can more potently reinvigorate anti‐tumor responses In Brief Mechanisms driving T cell exhaustion have not been understood. Li et al. demonstrate that B7S1 on tumor‐infiltrating myeloid cells initiates exhaustion of activated CD8+ TILs through upregulating Eomes, thus proposing B7S1 as a promising target to enhance the efficacy of anti‐PD‐1 therapy.

Perioperative nutritional support and fluid therapy in patients with liver diseases.

The prevalence of liver dysfunction and malnutrition is common among patients with obstructive jaundice or cirrhosis, the poor nutrition status in patients with indications for hepatic resection increases the risk of postoperative complications and/or mortality. Hepatic surgery significantly affects bodys metabolism and environment. Therefore, it is very important for patients with liver diseases undergoing hepatic surgery to receive essential nutritional support and fluid therapy during perioperative period. There are several principles in nutritional support and fluid therapy that surgeons need to pay attention to, for example, time, nutritional approach, fluid volume, choice of fat emulsions and amino acids. Some issues, such as albumin and plasma application, choice of crystalloid and colloid, liver protective therapy, also need further attention.

A randomized controlled trial for evaluation of lower abdominal laparoscopic cholecystectomy

Abstract Background: To improve minimally invasive outcomes, we designed a new procedure, lower abdominal laparoscopic cholecystectomy (LALC). This study was conducted to evaluate the effects of LALC versus classical (CLC) and single-incision (SILC) laparoscopic cholecystectomy on reducing systemic acute inflammatory response, improving cosmesis, and postoperative pain relief. Material and methods: Beginning from July 2014, 105 patients meeting the inclusion criteria were randomly assigned to three groups: LALC, CLC, and SILC. The primary endpoint was the determination of systemic inflammatory response to the surgery. Other outcome measures included cosmesis, postoperative pain, and perioperative indices. Results: Each of the three groups consisted of 35 patients. The duration of the operation was significantly longer in the SILC group (p= .005). The rates of adverse events were similar. Changes in interleukin-6 (pu2009= u2009.001) and tumor-necrosis factor-α (pu2009= u2009.016) measured before and after surgery differed significantly; patients who underwent LALC had the smallest change in inflammatory response. Cosmesis scores at one (pu2009= u2009.002) and 12 (pu2009= u2009.004) weeks after surgery favored LALC and SILC. Significant differences in pain scores at four (pu2009= u2009.011) and 12u2009h (pu2009= u2009.024) postoperatively were also observed. Conclusions: In selected patients, LALC shows more advantages in terms of lower systemic inflammatory response, improved cosmesis, and a favorable postoperative pain profile when compared with CLC and SILC.

Fever of Unknown Origin Caused by Giant Hepatic Hemangioma

Case presentationA 33-year-old man had fever for 2xa0months. He was admitted by the physician with the suspicion of pneumonia. However, both chest X-ray and computed tomography (CT) showed no abnormality. Tuberculosis and hematological and autoimmune diseases were all excluded. A giant hepatic lesion (20xa0cm) was detected by ultrasonography with the diagnosis of hemangioma. Contrast enhanced CT scan was conducted and hepatic hemangioma was confirmed. Some areas of the hepatic lesion had lower density compared to surrounding tissues and necrosis of the tumor was suspected.TreatmentRight trisectionectomy was then performed and the symptom of fever disappeared after the operation. No bacteria grew in the culture of the necrosis tissue. Pathological examination confirmed the diagnosis of hemangioma and the necrosis.ResultsHe was followed up for 5xa0months and no fever occurred.

Giant liver hemangioma with adult Kasabach-Merritt syndrome: Case report and literature review

Rationale: Adult Kasabach-Merritt syndrome associated with giant liver hemangioma is rare; to date, most reports have been single-case reports, and no multi-case reports or literature reviews are available. Diagnoses: We conducted a retrospective analysis of 5 cases of adult Kasabach-Merritt syndrome associated with giant liver hemangioma treated at our hospital between 2011 and 2016. All 5 patients had varying severities of leukopenia, anemia, thrombocytopenia, prolonged prothrombin time, and hypofibrinogenemia. Interventions: All the patients underwent surgery: 2 patients had left hemihepatectomy; 1 had enucleation; 1 had a right hemihepatectomy; and 1 had a left trisectionectomy. Outcomes: The 5 patients had an average operative time of 6.9u200ahours and an average blood loss of 3200u200amL. One patient developed a biliary fistula (grade II) after the operation. There was no mortality among 5 patients. The white blood cell counts, hemoglobin, platelets, and prothrombin times of all 5 patients returned to normal after the operation. To date, a total of 11 cases of adult Kasabach-Merritt syndrome associated with giant liver hemangioma have been reported, of which 8 patients underwent surgery, and their platelets and coagulation returned to normal after the operation. Lessons: Adult Kasabach-Merritt syndrome associated with giant liver hemangioma is uncommon, and surgical treatment is risky. However, resection of the tumor corrected the abnormalities in hematological and coagulative systems.

Differentiation of benign and malignant hilar bile duct stenosis

BACKGROUNDnFailure to differentiate benign and malignant hilar bile duct stenosis may lead to inappropriate treatment. We retrospectively analyzed the methods for differentiation.nnnMATERIALS AND METHODSnA total of 53 patients with hilar bile duct stenosis were included, comprising 41 malignant cases (hilar cholangiocarcinoma) and 12 benign cases (six primary sclerosing cholangitis and six IgG4-associated sclerosing cholangitis). Data of clinical histories, laboratory tests, imaging studies, and liver pathologies were collected, and comparison was made between benign and malignant groups.nnnRESULTSnCompared with malignant group, patients in the benign group were more likely to have multiorgan involvement of clinical histories (Pxa0<xa00.001). There was no difference on bilirubin, liver enzyme, and serum tumor marker between the two groups, whereas serum IgG4 levels were higher in the benign group (Pxa0=xa00.003). Patients in the benign group were more likely to have pancreatic changes (Pxa0<xa00.001) and multiple-segmental bile duct stenosis (Pxa0<xa00.001) on imaging. Compared with the malignant group, patients in the benign group were more likely to show severe periportal inflammation in noninvolved liver (Pxa0<xa00.001), fibrosis around intrahepatic bile duct (Pxa0<xa00.001), and more IgG4-positive plasma cells (Pxa0<xa00.001) on liver pathology.nnnCONCLUSIONSnBenign lesion should be considered for patients with history of multiorgan involvement, pancreas changes, or multiple-segmental bile duct stenosis on imaging. Liver biopsy could be helpful for differential diagnosis before surgery.

Patient age affects the growth of liver haemangioma

BACKGROUNDnThe aim of this study was to report the prevalence of liver haemangioma and describe growth rates by age.nnnMETHODSnA retrospective study of people undergoing a health examination. The collected data included gender, age, presence or absence and size of liver haemangioma. A second database of liver haemangioma patients with a minimum follow up period of 5 years was analysed. The collected data included gender, initial age at diagnosis, follow-up period, initial and final size.nnnRESULTSnPatients were divided into four age groups: 20-29 years, 30-39 years, 40-49 years and ≥50 years. Patients in the 20-29 years group had the lowest prevalence of liver haemangioma (1.78%) and the smallest size (1.3 ± 0.7 cm), while 40-49 years group had the highest prevalence (3.94%) and largest size (1.9 ± 1.3 cm). Patients between 30 and 39 years had the greatest increase in haemangioma size (4.0 cm, (3.0, 6.0) cm), while patients of ≥50 years had the least (1.4 cm (0.5, 3.8) cm). The proportion of patients without an increase in haemangioma size increased with age (P = 0.031).nnnCONCLUSIONnAge is an important factor affecting the prevalence and growth rate of liver haemangioma.

Expression of the inhibitory B7 family molecule VISTA in human colorectal carcinoma tumors.

Colorectal carcinoma (CRC) is one of the most common malignancies in the world. PD-1/PD-L1 inhibitors have benefited cancer patients with multiple tumor types. However, their efficacy for CRC is low and this treatment in melanoma patients results in adaptive resistance through upregulation of VISTA, another checkpoint inhibitory pathway. Thus, there is an urgent need to explore additional co-inhibitory molecular pathways such as VISTA for CRC treatment. In this study, C10orf54 (encoding VISTA) expression was analyzed by RNA-seq data from 367 CRC patients in human cancer datasets. Moreover, 28 clinical CRC specimens were used to assess VISTA protein expression. Human cancer datasets showed that CRC tumors expressed higher levels of C10orf54 than CD274 (encoding PD-L1). Moreover, C10orf54 mRNA expression was significantly correlated with genes responsible for tumor immune evasion. VISTA protein expression was high in tumors compared with para-tumors and normal tissues, which is similar to PD-L1 expression. However, in contrast to PD-L1, VISTA was mainly expressed by tumor-infiltrating lymphocytes. This study is the first investigation of VISTA expression in human resected CRC tumors, and the results justify the need for future studies on the role of VISTA in anti-CRC immunity in clinical samples.