Response to immune checkpoint inhibitor combination therapy in metastatic RET-mutated lung cancer from real-world retrospective data.

BACKGROUND: The impact of immune checkpoint inhibitors (ICIs) based treatments on non-small cell lung cancers (NSCLCs) with RET fusions remains poorly understood. METHODS: We screened patients with RET fusions at the First Affiliated Hospital of Zhengzhou University and included those who were treated with ICIs based regimens for further analysis. We evaluated clinical indicators including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). RESULTS: A total of 232 patients with RET fusions were included in the study. Of these, 129 patients had their programmed death-ligand 1 (PDL1) expression levels tested, with 22 patients (17.8%) having a PDL1 level greater than or equal to 50%. Additionally, tumor mutational burden (TMB) status was evaluated in 35 patients, with the majority (30/35, 85.8%) having a TMB of less than 10 mutations per megabase. Out of the 38 patients treated with ICI based regimens, the median PFS was 5 months (95% confidence interval [CI]: 2.4-7.6 months) and the median OS was 19 months (95% CI: 9.7-28.3 months) at the time of data analysis. Stratification based on treatment lines did not show any significant differences in OS (18 vs. 19 months, p = 0.63) and PFS (6 vs. 5 months, p = 0.86). The ORR for patients treated with ICIs was 26.3%. Furthermore, no significant differences were found for PFS (p = 0.27) and OS (p = 0.75) between patients with positive and negative PDL1 expression. Additionally, there was no significant difference in PD-L1 levels (p = 0.10) between patients who achieved objective response and those who did not. CONCLUSIONS: Patients with RET fusion positive NSCLCs may not benefit from ICI based regimens and therefore should not be treated with ICIs in clinical practice.

Efficacy of immune checkpoint inhibitors in advanced large cell neuroendocrine carcinoma of the lung: A single­institution experience.

Large cell neuroendocrine carcinoma (LCNEC) is a rare and highly invasive lung cancer subtype with an overall poor prognosis. Due to its low incidence rate and unusual pathological features, the clinical management of LCNEC remains controversial. The present study aimed to assess the effect of immune checkpoint inhibitors (ICIs) on treatment response and survival outcomes in patients with advanced LCNEC. The clinical data from 148 patients with LCNEC treated with ICIs at The First Affiliated Hospital of Zhengzhou University (Zhengzhou, China) between January 2019 and September 2021 were retrospectively analyzed. Kaplan-Meier and multivariable Cox regression analyses were used to evaluate associations between clinicopathological variables and patient outcomes. Patients treated with ICIs demonstrated extended median overall survival (mOS) times [23.5 months; 95% confidence interval (CI), 18.524-28.476] compared with patients who did not receive ICIs (11.2 months; 95% CI, 4.530-18.930) (P<0.001). Univariate analysis revealed that histological subtype (P=0.043), lymph node metastases (P=0.032) and number of metastatic organs (P=0.009) were associated with a poor prognosis. The heterogeneity of pathological components was associated with prognosis, and the mOS time was shorter for mixed LCNEC than that for pure LCNEC (P=0.043). The median progression-free survival (mPFS) (9.78 vs. 9.37 months; P=0.82) and mOS (20.70 vs. 25.79 months; P=0.181) times showed no significant association with regard to different regimens of immuno-based combination therapy (chemotherapy combined with ICIs vs. anti-angiogenic agents combined with ICIs). Poor Eastern Cooperative Oncology Group performance status score (P=0.04), multiple organ metastases (P=0.02) and high cancer antigen 125 levels (P=0.01) were independent risk factors of a poor prognosis. The present findings offer valuable insights into potential prognostic markers and highlight the favorable impact of ICIs on OS in advanced LCNEC. Prospective clinical studies are required to validate the therapeutic value of ICIs in LCNEC.

Successful treatment of lung adenocarcinoma complicated with a rare compound EGFR mutation L833V/H835L using aumolertinib: a case report and literature review.

Background: The deletion of exon 19 and the Leu858Arg mutation of exon 21 are the most frequently observed mutations in the epidermal growth factor receptor (EGFR) gene, and patients with these mutations have shown significant benefits from EGFR-tyrosine kinase inhibitors (TKIs). However, there exists a small subgroup of patients with uncommon/rare mutations of EGFR, including compound mutations, which display a high degree of heterogeneity in terms of clinical features and variable sensitivities to EGFR-TKIs. The understanding of these uncommon mutations and their response to targeted therapy is still unclear and requires further investigation. Case presentation: We presented a case of a never-smoking patient with lung adenocarcinoma and brain metastasis. Initially, she received chemotherapy plus immune checkpoint inhibitor as first-line therapy as no EGFR mutations were detected by amplification-refractory mutation system-polymerase chain reaction. However, disease progressed rapidly. Subsequently, next-generation sequencing was carried out and revealed a rare compound mutation, L833V/H835L, in exon 21 of EGFR. As a result, she was switched to second-line therapy with the third-generation TKI aumolertinib, which demonstrated good efficacy. The patient was evaluated for a remarkable progression-free survival of 18 months and an overall survival of 29 months. Conclusion: The present study supports that aumolertinib might be a good treatment option for advanced NSCLC patients with EGFR L833V/H835L mutation, particularly in patients with brain metastasis. Furthermore, conducting a comprehensive screening for gene mutations is crucial in effectively identifying potential oncogenic driver mutations and guiding mutation-targeted therapy decisions in clinical practice.

Corrigendum: Advanced HCC with amplified mesenchymal epithelial transition factor receptor responds well to savolitinib: a case report.

[This corrects the article DOI: 10.3389/fmed.2023.1130012.].

Advanced HCC with amplified mesenchymal epithelial transition factor receptor responds well to savolitinib: a case report.

Objective: Current treatment agents for HCC are mostly immune checkpoint inhibitors (ICIs) plus bevacizumab and multitarget tyrosine kinase inhibitors (TKIs); however, their limited overall response rate and shorter median progression-free survival (PFS) discourage their frequent use. The development of Mesenchymal Epithelial Transition Factor receptor (MET) Tyrosine Kinase Inhibitors (MET-TKI) has transformed the treatment pattern in MET-altered solid tumors and improved their prognosis. However, the benefits of MET-TKIs in MET-amplified hepatocellular carcinoma (HCC) remain unclear. Methods: Here, we present a case of advanced HCC amplified with MET treated with savolitinib, a MET-TKI, after progression from first-line treatment with bevacizumab plus sintilimab. Results: The patient achieved a partial response (PR) to savolitinib in the second line setting. The progression-free survival (PFS) of first-line of bevacizumab plus sintilimab and sequential second-line treatment with MET-TKI, savolitinib, are 3 and over 8 months, respectively. furthermore, the patient still had continuous PR status with manageable toxicities. Conclusions: The present case report provides first-hand evidence that savolitinib may be beneficial for patients with advanced MET-amplified HCC and offers a promising treatment option.

Alectinib versus crizotinib in ALK-positive advanced non-small cell lung cancer and comparison of next-generation TKIs after crizotinib failure: Real-world evidence.

BACKGROUND: Anaplastic lymphoma kinase (ALK) fusion is a prognostic indicator for patients with non-small cell lung cancer (NSCLC) receiving tyrosine kinase inhibitors (TKIs). The real-world data of ALK TKIs remain a major concern. METHODS: Patients with ALK-positive advanced NSCLC, who received crizotinib or alectinib treatment in first line, were retrospectively reviewed. ALK status was detected using immunohistochemistry (IHC) or next-generation sequencing (NGS). Clinical outcomes have been comprehensively analyzed between TKIs, ALK fusions, EML4-ALK variants, and next-generation TKIs after crizotinib failure. RESULTS: One hundred sixty-eight patients were successively enrolled (crizotinib, n = 109; alctinib, n = 59). Alectinib showed consistent superiority in progressive-free survival (PFS) over crizotinib (hazard ratio [HR]: 0.43, 95% confidential interval [CI]: 0.24-0.77, p = 0.004). Multivariate Cox regression showed chemotherapy (CT) prior to TKIs or synchronous chemotherapy seemed not to improve PFS compared to ALK inhibitors alone (p > 0.05). And, alectinib was superior to crizotinib in prolonging intracranial PFS (HR 0.12, 95% CI: 0.03-0.49, p = 0.003). Patients in EML4 group had a better prognosis than those in non-EML4 group after alectinib administration (HR 0.13, 95% CI: 0.03-0.60, p = 0.009). TP53 co-mutations were relatively common (34.0%) and associated with adverse outcome in ALK-positive patients (adjusted HR 2.22, 95% CI: 1.00-4.92, p = 0.049). After crizotinib failure, 33 patients received a sequential application of next-generation ALK TKIs. Compared to ceritinib and brigatinib, alectinib might have better PFS (p = 0.043). CONCLUSION: Our results revealed alectinib had better PFS and higher intracranial efficacy compared to crizotinib in ALK-positive NSCLC, and might improve PFS by comparison with ceritinib and brigatinib after crizotinib failure.

BRAF-Mutated Non-Small Cell Lung Cancer: Current Treatment Status and Future Perspective.

V-Raf murine sarcoma viral oncogene homolog B (BRAF) kinase, which was encoded by BRAF gene, plays critical roles in cell signaling, growth, and survival. Mutations in BRAF gene will lead to cancer development and progression. In non-small cell lung cancer (NSCLC), BRAF mutations commonly occur in never-smokers, women, and aggressive histological types and accounts for 1%-2% of adenocarcinoma. Traditional chemotherapy presents limited efficacy in BRAF-mutated NSCLC patients. However, the advent of targeted therapy and immune checkpoint inhibitors (ICIs) have greatly altered the treatment pattern of NSCLC. However, ICI monotherapy presents limited activity in BRAF-mutated patients. Hence, the current standard treatment of choice for advanced NSCLC with BRAF mutations are BRAF-targeted therapy. However, intrinsic or extrinsic mechanisms of resistance to BRAF-directed tyrosine kinase inhibitors (TKIs) can emerge in patients. Hence, there are still some problems facing us regarding BRAF-mutated NSCLC. In this review, we summarized the BRAF mutation types, the diagnostic challenges that BRAF mutations present, the strategies to treatment for BRAF-mutated NSCLC, and resistance mechanisms of BRAF-targeted therapy.

Patients harboring uncommon EGFR exon 19 deletion-insertion mutations respond well to first-generation EGFR inhibitors and osimeritinib upon acquisition of T790M.

BACKGROUND: In the existing next generation sequencing (NGS) system, epidermal growth factor receptor (EGFR) exon 19 deletion-insertion (19delins) is still interpreted into the category of EGFR exon 19 deletion (19del). However, the controversy exists whether the two mutation types have the similar responses and resistant mechanisms to first-generation EGFR tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC) patients. METHODS: We successively and retrospectively reviewed the NGS data of 3054 patients diagnosed as advanced NSCLC from November 2017 to September 2020. Finally, 41 patients with EGFR 19delins mutation and 41 patients with EGFR 19del mutation who received first-generation EGFR TKIs as first-line therapy were included in the study. RESULTS: A total of 17 genotypes were identified in this study, including L747_P753delinsS (10/41), L747_A750delinsP (9/41), L747_T751delinsP (6/41) and E746_S752delinsV (3/41). Under the same baseline characteristics, the population of EGFR 19delins respond well to first line EGFR TKIs as well as those of EGFR 19del, with little difference in median progression-free survival (mPFS): 10.4 months vs. 13.1 months, p = 0.1076). Interestingly, patients with L747_T751delinsP seem to have a better mPFS than others (18.7 months vs. 13.1 months, p = 0.035). After the disease progression, both EGFR 19delins and EGFR 19del had similar rates of developing EGFR T790M mutation resistance (45.8% vs. 57.8%), and those receiving osimeritinib as second-line treatment obtain the similar survival benefits (mPFS: 12.0 months vs. 12.2 months (p = 0.97). CONCLUSIONS: This retrospective cohort study furnish the evidence that therapeutic responses and survival of untreated NSCLC population with EGFR 19delins mutation are equal to those with common EGFR 19del mutation after administration of EGFR TKIs therapy.

[Characteristics of Epidermal Growth Factor Receptor with Rare Mutations in Non-small Cell Lung Cancer and the Effect of EGFR Tyrosine Kinase Inhibitors on Them].

BACKGROUND: Adenocarcinoma is the most common type of lung cancer. It has been clinically evaluated that therapiestargeting against the epidermal growth factor receptor (EGFR) as the clinical standard first-line treatment. The response and outcome of EGFR-tyrosine kinase inhibitors (TKIs) in patients harboring common mutations in EGFR kinase domain (deletion in exon19 and L858R in exon 21) has been well demonstrated, but not in rare or complex mutations. METHODS: A total of 150 patients that harbored rare or complex mutations in EGFR diagnosed by histopathology were included in this retrospective study. The clinical-pathological characteristics of all 150 patients as well as the response and progression-free survival (PFS) in 48 patients that received EGFR-TKIs in first/second/third line treatments weredescribed and analyzed. RESULTS: Patients were divided into four groups based on the mutation types: single G719X point mutation in exon 18 (n=46, 30.7%), single L861Q point mutation in exon 21 (n=45, 30.0%), other single rare mutation (n=14, 9.3%) and complex mutations (n=45, 30.0%). The result indicated thatthere was no correlation of EGFR mutation typeswith other parameters such as gender, age, clinical stage, pathology and smoking history. For the 48 patients that received EGFR-TKIs treatment, there were no significant differencesamong 4 groups in terms of objective response rate (ORR) and disease control rate (DCR) (54.5% vs 30.0% vs 0.0% vs 35.7%, χ²=3.200, P=0.34; 90.9% vs 85.0% vs 66.7% vs 92.9%, χ²=2.162, P=0.59). The median progress-free survival (mPFS) was 11.0 months (95%CI: 4.4-17.6), and in each group of different EGFR mutation types are 15.8 months (95%CI: 9.5-22.2), 8.0 months (95%CI: 5.1-11.0), 4.9 months (95%CI: 1.4-8.4) and 23.1 months (95%CI: 15.8-30.4)(χ²=7.876, P=0.049). CONCLUSIONS: The efficiency of targeting EGFR-TKIs on different types of rare or complex mutations was heterogeneous. The PFS may be better in patients that harbored complex mutations than those with single rare mutations. Further studies with larger sample size are necessary. Moreover, to discover novel therapeutic targets and develop new drugs are imminentfor those patientswith no response to the existing treatments.

[Association between the HER2 Gene Status and the Efficacy of First-line Pemetrexed Combined with Platinum Chemotherapy in Patients with Advanced Lung 
Adenocarcinoma].

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is one of the driver genes of non-small cell lung cancer (NSCLC). Several studies have shown that the efficacy of pemetrexed in HER2-mutant NSCLC is controversial. The aim of this study is to investigate the efficacy of pemetrexed combined with platinum chemotherapy in patients with HER2-mutant and HER2 wild-type lung adenocarcinoma. METHODS: The clinical data of 106 cases of EGFR, ALK, ROS-1, KRAS, BRAF, RET and MET-negative patients with advanced lung adenocarcinoma patients who diagnosed by histopathology in the First Affiliated Hospital of Zhengzhou University were retrospectively reviewed. The relationships between HER2 gene status, clinical characteristics and response and progression-free survival (PFS) were analyzed. RESULTS: All of the 106 patients' HER2 status were determined. HER2 mutations occurred in 32 cases (30.2%), no mutations in 74 cases (69.8%). HER2 mutations were common in young, non-smoking and female patients. All patients received first-line pemetrexed and platinum-based chemotherapy. The objective response rate (ORR) and disease control rate (DCR) of patients with HER2-mutant lung adenocarcinoma were significantly higher than those without HER2 mutations (40.6% vs 14.9%, χ²=8.464, P=0.004; 93.8% vs 68.9%, χ²=6.327, P=0.012), and the difference was statistically significant. According to univariate analysis, the PFS was significantly associated with the brain metastases, maintenance chemotherapy and HER2 gene status (P<0.05), but not with age, gender, smoking history, oligometastases, liver metastases and type of platinum (P>0.05). Cox multivariate analysis indicated that HER2 mutation was an independent positive prognostic factor of PFS (P=0.038). CONCLUSIONS: HER2-mutant lung adenocarcinoma patients with first-line pemetrexed combined with platinum chemotherapy have greater clinical benefit than HER2 wild-type patients.

[Association between the ALK Gene Status and the Efficacy of First-line 
Pemetrexed Chemotherapy in Patients with Advanced Lung Adenocarcinoma].

BACKGROUND: Anaplastic lymphoma kinase (ALK) is one of the major driver genes of non-small cell lung cancer (NSCLC). Several studies have shown that the efficacy of pemetrexed in ALK-positive lung cancer is controversial. The aim of this study is to explore the efficacy of pemetrexed-based chemotherapy in patients with ALK-positive and negative lung adenocarcinoma. METHODS: The clinical data of 98 cases of epidermal growth factor receptor (EGFR), kirsten rat sarcoma viral oncogene (KRAS), V-rafmurine sarcoma viral oncogene homolog B1 (BRAF)-negative patients with advanced lung adenocarcinoma patients who diagnosed by histopathology from January 2015 to April 2016 in the First Affiliated Hospital of Zhengzhou University were collected. The relationships between ALK gene status, clinical characteristics and response and progression-free survival (PFS) were analyzed. RESULTS: All of the 98 patients' ALK status were determined. ALK gene fracture fusion occured in 34 cases (34.7%), no fracture fusion in 64 cases (65.3%). All patients underwent first-line pemetrexed and platinum-based chemotherapy, the objective response rate (ORR) was 21.4% and the disease control rate (DCR) was 84.7%. The ORR and DCR of patients with ALK fracture fusion were higher than those without fracture fusion (41.2% vs 10.9%, χ2=23.389, P<0.001; 91.2% vs 81.3%, χ2=4.153, P=0.042), the difference was statistically significant. ALK gene status was not related to age, gender, smoking history and clinical stage. The median PFS of ALK-positive lung adenocarcinoma was 7.1 months (95%CI: 6.1-8.1) and negative was 4.7 months (95%CI: 3.818-5.582), and the difference was statistically significant (χ2=13.269, P<0.001). Cox multivariate analysis indicates that PFS of pemetrexed combined with platinum chemotherapy was independent of gender, age, smoking, staging and platinum. ALK gene fracture fusion is an independent factor affecting PFS (HR=0.392, 95%CI: 0.243-0.634, P<0.001). CONCLUSIONS: ALK-positive lung adenocarcinoma patients with first-line pemetrexed-based chemotherapy have greater clinical benefit than ALK-negative patients.

Askin's tumor: 11 cases and a review of the literature.

Askin's tumor is a peripheral primitive neruoectodermal tumor within the thoracopulmonary region, which primarily occurs in children and young adults. In addition, Askin's tumor is commonly misdiagnosed, as it is rare and easily mistaken for other small round-cell tumors. The present study aimed to investigate the clinical characteristics, prognostic factors and treatment outcomes of patients diagnosed with Askin's tumor. Computed tomography (CT) scans, histopathology and immunohistochemical analysis were used for diagnosis. Patients were treated with combined (surgery-chemotherapy-radiotherapy) or mono-therapy (chemotherapy or radiotherapy) methods. A total of 11 consecutive patients with Askin's tumor (aged 8-22 years) were treated at the First Affiliated Hospital of Zhengzhou University between April 2010 and June 2013; nine patients underwent combined therapy and two patients were treated using mono-therapy. Chest lumps, swelling and pain were the most common presenting symptoms. Patients were followed up for ≤24 months post surgery and the results revealed that the median survival time of the combined and mono-therapy treatment groups were 15 and 7 months, respectively. Primary tumor size, metastasis, lactate dehydrogenase indicators and tumor stages were found to be important prognostic factors affecting patient outcome. In conclusion, the results of the present study demonstrated that the combination of surgery, chemotherapy and radiotherapy resulted in the optimal outcome for Askin's tumor patients.

Effect of yangxinkang tablets on chronic heart failure: A multi-center randomized double-blind placebo-controlled trial.

OBJECTIVES: To investigate the safety and efficacy of yangxinkang tablets in patients with chronic heart failure (CHF) and syndrome of qi and yin deficiency, blood stasis, and water retention. METHODS: In a double-blinded, randomized, placebo-controlled, multicenter clinical trail, 228 patients with CHF New York Heart Association (NYHA) class II or III in stage C were assigned by randomized block method to two groups in a 1:1 ratio to undergo either conventional Western treatment or conventional treatment plus yangxinkang tablets for 4 weeks. The outcome measure were effect of cardiac function, Chinese medicine (CM) syndromes, scores of symptoms, signs, and quality of life measured by Minnesota Living with heart failure questionnaire (MLHFQ) before and after the treatment. RESULTS: Totally 112 patients were analyzed in the treatment group and 109 in the control group. They were comparable in NYHA functional class, basic parameters and primary diseases before treatment. Cardiac function and CM syndromes were greatly ameliorated in both groups after treatment. Total effective rates of cardiac function and CM syndrome in the treatment group were significantly higher than those in the control group (P<0.05). Total symptom score and sign score in the treatment group decreased significantly after treatment (P<0.01), which were significantly lower than those in the control group (P<0.05). There were statistically significant differences in post-treatment scores of gasp, cough with phlegm, pulmonary rales and jugular vein engorgement between the two groups (P<0.05 or P<0.01). Three MLHFQ scores decreased significantly in both groups after treatment (P<0.01). Post-treatment total scale score and physical subscale score in the treatment group and the reduction of them showed statistically significant differences (P<0.05) as compared with the control group. There was no significant difference between the two groups in emotional subscale score and the reduction after treatment (P>0.05). There was no obvious adverse reaction in either group noted during the study. CONCLUSIONS: Yangxinkang tablets were safe and efficacious in improving cardiac function, CM syndromes, symptoms, signs, and quality of life in patients with CHF class II or III in stage C on the base of conventional treatment.

Prognosis of the intrahepatic cholangiocarcinoma after resection: hepatitis B virus infection and adjuvant chemotherapy are favorable prognosis factors.

AIM: The incidence and mortality associated with intrahepatic cholangiocarcinoma is increasing in many countries and documentation of disease outcome is sparse. The present study was undertaken to investigate the prognostic factors for intrahepatic cholangiocarcinoma (ICC) following surgical resection. The impact of pre-existing HBV virus infection and adjuvant chemotherapy on the overall survival was also evaluated. METHODS: Clinical and pathological data were collected retrospectively from 81 patients undergoing surgery for ICC between 2005 and 2011, at The Henan Province Tumor Hospital and the First Affiliated Hospital of Zheng Zhou University. Survival and prognosis were analyzed using the Kaplan-Meier method and COX regression model. RESULTS: The population included 37 patients who were HBsAg + or anti-HBc+, 21 patients who were anti-HBs + positive and 18 patients who received adjuvant chemotherapy. The overall 1- and 3-year survival rates were 51% and 20%, respectively. The median survival was 12.2 months. Univariate analysis identified the following prognostic factors: HBV virus infection or HBV vaccine prior to resection (P = 0.017); adjuvant chemotherapy (P = 0.001); preoperative serum CA19-9 (> 200 U/mL; P = 0.015); GGT (> 64 U/L; P = 0.008), ALP (> 119 U/L; P = 0.01); lymph node metastasis (P = 0.005); radical resection (P = 0.021); intrahepatic metastasis (P = 0.015) and diabetes (P = 0.07). Multivariate analysis identified chronic HBV infection (RR = 0.583; P = 0.041), anti-HBs positivity (RR = 0.680; P = 0.050), adjuvant chemotherapy (RR = 0.227; P < 0.001), lymph node metastasis (RR = 2.320; P = 0.001), and intrahepatic duct stones (RR = 0.473; P = 0.032) as independent prognostic factors. CONCLUSIONS: HBV virus infection or HBV vaccination prior to resection, together with adjuvant chemotherapy, were independently associated with improved survival in patients undergoing surgery for ICC.

Pulmonary sarcomatoid carcinoma: a clinicopathologic study and prognostic analysis of 51 cases.

BACKGROUND: Pulmonary sarcomatoid carcinoma is a diagnostically challenging group of tumors. It's a rare histologic subtype of non-small cell lung cancer.There are five subgroups of pulmonary sarcomatoid carcinoma, they are identified as pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and pulmonary blastoma. We explored the clinicopathologic features and prognostic factors of this tumor. METHODS: We analyzed retrospectively the clinicopathological data of 51 patients with pulmonary sarcomatoid carcinoma who were treated in the First Affiliated Hospital of Zhengzhou University, Henan Cancer Hospital and Henan People Hospital from January 2005 to December 2012. The correlation between prognosis and age, sex, smoking history, tumor size, TNM staging, and treatment modality was analyzed by the statistical software SPSS 17.0. The survival analysis was conducted using the Kaplan-Meier method. The factors influencing survival were analyzed using univariate (Log-rank) and multivariate (Cox) models. RESULTS: The overall survival rates at 1, 2, 3 and 5 years were 45.5%, 35.8%, 28.2% and 20.1%, respectively. Cox univariate analyses revealed that age, tumor size, T stage, M stage, surgery or not, and postoperative chemotherapy or not, were prognostic factors. Cox multivariate analysis found that tumor size and M stage were independent prognostic factors for PSC. CONCLUSIONS: Due to its rarity and the lack of large-scale clinical trial evidence, few studies about PSC have been reported, its clinical and pathological characteristics remain unclear, and its preoperative diagnosis and investigation of novel treatment approaches are imperative. In our study, the main factors affecting the prognosis of tumor size and M staging are the crucial prognostic factors for PSC. Surgical resection and postoperative adjuvant chemotherapy might result in better prognosis.

Phenotypic and immunoregulatory characteristics of monocytic iris cells.

The introduction of antigen into the anterior chamber of an eye induces the antigen-specific suppression of cell-mediated immunity and the antigen-induced production of immunoglobulin G2 antibodies. To define further the role of iris monocytic cells in the systemic suppression of cell-mediated immunity that follows the entry of foreign antigen into the anterior chamber, murine iris wholemounts or cell suspensions of iris cells were stained with fluorescent anti-F4/80 and/or anti-CD11c, anti-CD11b antibodies and examined by confocal microscopy or flow cytometry, respectively. Monocytic cells in iris cell suspensions were recovered from mice receiving an injection of trinitrophenylated bovine serum albumin (TNP-BSA) into an anterior chamber and Percoll-enriched iris cells separated into cells expressing F4/80 or CD11c were injected intravenously into TNP-BSA-immunized or naive recipients. The recipients were challenged to induce delayed-type hypersensitivity (DTH) or were provided with splenocytes or thymocytes that transfer the suppression of DTH. The homing of monocytic bone marrow cells to the iris was determined by the intravenous injection of bone marrow cells from green fluorescent protein (GFP)-transgenic donors into C57 mice, and the staining of recipient iris wholemounts with anti-F4/80 antibodies. Iris cells with a dendritic morphology expressing both F4/80 and/or CD11c and CD11b, some cells expressing only F4/80 or CD11c, were detected. The irides of irradiated GFP- mice that received intravenous GFP+ bone marrow cells contained GFP+ F4/80+ cells. F4/80+ and CD11c+ cells from the irides of donors that received intracameral TNP-BSA transferred the suppression of DTH when injected intravenously into TNP-BSA-immunized recipients, activated immunoregulatory thymocytes and activated antigen-specific splenic regulatory effector cells. These results support the hypothesis that iris monocytic cells may participate in the systemic induction of regulatory T cells.

[The distribution of donor hematopoietic stem cell and the ratio of lymphocytes from donor origin to recipient origin in recipient mice after allogeneic bone marrow transplantation].

OBJECTIVE: To explore the hematopoietic stem cell distribution and lymphocyte proliferation and differentiation in recipient mice after allogeneic bone marrow transplantation (allo-BMT). METHODS: BALB/c (H-2(d)) mice were total body irradiated 5.5 Gy x 2 by (137)Cs and then transplanted with bone marrow cells from GFP transgenic C57BL/6J (H-2(b)) mice. The femur, spleen, Peyer patches, thymus, liver and peripheral blood of the host were collected on days 3, 7, 21, 35 and 70 post transplantation, and their sections were observed by fluorescent microscopy. The green fluorescent cells were counted with FACS. The phycoerythrin (PE) labeled antibodies to CD4, CD8 and B220 were used for sorting T and B lymphocytes. RESULTS: (1) On day 3 and day 7 after allo-BMT, there were (1.06 +/- 0.02)% and (76.60 +/- 1.80)% of donor's green bone marrow cells in host's spleen respectively, whereas only (0.37 +/- 0.06)% and (39.70 +/- 5.38)% in the bone marrow, respectively. (2) In bone marrow and other organs of 21 day-old chimerism mice, over 60% cells were of donor origin. (3) There were (0.36 +/- 0.04)% donor's bone marrow cells lodging at host's Peyer patches, similar to that in bone marrow. CONCLUSION: (1) The engrafted allogeneic hematopoietic stem cell can move into spleen, bone marrow, Peyer patches and thymus. The spleen is the main lodging place of the engrafted cells early after all-BMT. (2) The majority of cells in chimerism mice immunologic organs were of donor origin. (3) Peyer patches is another lodging place early after allo-BMT.

Stimulated release of tissue plasminogen activator from artery wall sympathetic nerves: implications for stress-associated wall damage.

Recurrent stress is clinically associated with early onset hypertension and coronary artery disease. A mechanism linking emotion to pathogenic remodeling of the artery wall has not been identified. Stress stimulates acute regulated release of tissue plasminogen activator (t-PA) into the circulation, which is presently attributed to the vascular endothelium. Sympathetic neurons also synthesize t-PA and axonally transport it to the arterial smooth muscle. Unlike release by the endothelium, a stress-stimulated sympathetic discharge would potentially accelerate degradation of the wall matrix by plasmin. To assess whether sympathetic axons are the principal source of acute stress-induced arterial release of t-PA, we compared the output from small densely innervated and large sparsely innervated isolated artery segments before and after sympathetic stimulation, and after ablations. Following phenylephrine infusion densely-innervated microvessels in uveal eyecups were released over 60-fold greater amounts of active t-PA per milligram than the sparsely innervated aorta; and ten-fold more than carotid artery segments. Mesenteric artery release was 4.8-fold greater than release by the carotid artery. In vivo, uveal release of t-PA increased more than three-fold within one minute following superior cervical sympathetic ganglion electrical stimulation, and after phenylephrine, or nicotine infusions of the anterior chamber. Circulating levels of t-PA fell 70% following chemical sympathectomy. We propose that sympathetic nerves are the primary source of stress-induced release of t-PA into and from the densely innervated resistance arteries and arterioles, where dysregulated plasmin-induced proteolysis could damage the wall matrix.

The induction of splenic suppressor T cells through an immune-privileged site requires an intact sympathetic nervous system.

Antigen injection into the eye's anterior chamber (AC) induces the antigen-specific suppression of delayed-type hypersensitivity (DTH) that is mediated by NKT cells and splenic CD8+ suppressor T cells. Because the AC, uveal tissues, the thymus and spleen required to induce anterior chamber-associated immune deviation (ACAID) have dense sympathetic innervations, we examined the effects of chemical sympathectomy of mice by 6-hydroxydopamine (6-OHDA) on the induction of the suppression of contact sensitivity to trinitrophenol (TNP) induced by the injection of TNP-bovine serum albumin (BSA) into the anterior chamber. DTH measured as contact sensitivity to picrylchloride was not induced in mice that received 6-OHDA before immunization with TNP-BSA. Although spleen cells from 6-OHDA-treated TNP-BSA-immunized mice produced IFN-gamma when stimulated by TNP-BSA, the number of DTH-initiating hepatic NKT cells was reduced markedly in 6-OHDA-treated mice. Chemically denervated mice did not produce splenic suppressor T cells or thymic NKT cells that activate splenic suppressor T cells. We suggest that an intact sympathetic nervous system (SNS) is required to maintain cellular immunoregulation.