Prognostic significance of high mobility group A2 (HMGA2) in pancreatic ductal adenocarcinoma: malignant functions of cytoplasmic HMGA2 expression

Purpose HMGA2 has frequently been found in benign as well as malignant tumors and a significant association between HMGA2 overexpression and poor survival in different malignancies was described. In pancreatic ductal adenocarcinoma (PDAC), nuclear HMGA2 expression is associated with tumor dedifferentiation and presence of lymph node metastasis. Nevertheless, the impact of HMGA2 occurrence in other cell compartments is unknown. Methods Intracellular distribution of HMGA2 was analyzed in PDAC (n = 106) and peritumoral, non-malignant ducts (n = 28) by immunohistochemistry. Findings were correlated with clinico-pathological data. Additionally, intracellular HMGA2 presence was studied by Western blotting of cytoplasmic and nuclear fractions of cultured cells. Results HMGA2 was found in the cytoplasm and in the nucleus of cultured cells. In human tumor tissue, HMGA2 was also frequently found in the cytoplasm and the nucleus of tumor cells, however, nuclear staining was generally stronger. Direct comparison from tumor tissue with corresponding non-neoplastic peritumoral tissue revealed significantly stronger expression in tumors (p = 0.003). Of note, the nuclear staining was significantly stronger in lymph node metastatic cell nuclei compared to primary tumor cell nuclei (p = 0.049). Interestingly, cytoplasmic staining positively correlated with lymph vessel (p = 0.004) and venous invasion (p = 0.046). Conclusion HMGA2 is a prognostic marker in PDAC. Firstly, we found a positive correlation for cytoplasmic HMGA2 expression with lympho-vascular invasion and, secondly, we found a significantly stronger nuclear expression of HMGA2 in cancer-positive lymph node nuclei compared to primary tumor cell nuclei. So far, the role of cytoplasmic HMGA2 is nearly unknown, however, our data lend support to the hypothesis that cytoplasmic HMGA2 expression is involved in nodal spread.

Application Research of Individualized Conditional Reprogramming System to Guide Treatment of Gastric Cancer

BackgroundGastric cancer (GC) is one of the most common causes of malignant tumors in the world. Due to the high heterogeneity of GC and lack of specificity of available chemotherapy regimens, these tumors are prone to resistance, recurrence, and metastasis. Here, we formulated an individualized chemotherapy regimen for GC using a modified individual conditional reprogramming (i-CR) system. We established a primary tumor cell bank of GC cells and completed drug screening in order to realize individualized and accurate GC treatment.MethodsWe collected specimens from 93 surgical or gastroscopy GC cases and established a primary tumor cell bank using the i-CR system and PDX models. We also completed in vitro culture and drug sensitivity screening of the GC cells using the i-CR system. Whole-exome sequencing (WES) of the i-CR cells was performed using P0 and P5. We then chose targeted chemotherapy drugs based on the i-CR system results.ResultsOf the 72 cases that were collected from surgical specimens, 26 cases were successfully cultured with i-CR system, and of the 21 cases collected from gastroscopy specimens, seven were successfully cultured. Among these, 20 cases of the PDX model were established. SRC ± G3 had the highest culture success rate. The i-CR cells of P0 and P5 appeared to be highly conserved. According to drug sensitivity screening, we examined the predictive value of responses of GC patients to chemotherapeutic agents, especially in neoadjuvant patients.ConclusionThe i-CR system does not only represent the growth characteristics of tumors in vivo, but also provides support for clinical drug use. Drug susceptibility results were relatively consistent with clinical efficacy.

NNDR Salvage Biochemotherapy Regimens for Therapy-Refractory Leukemia and Lymphoma Patients: A Report from the Parker Hughes Cancer Center.

We examined the activity of vinorelbine-based salvage biochemotherapy regimens NNDR-I (Vinorelbine [Navelbine] 25 mg/m2 d1, d8, Mitoxantrone [Novantrone] 10 mg/m2 d1, Dexamethasone [Decadron] 20 mg BID d1 through 7, Rituximab [Rituxan] 375 mg/m2 d1,8,15,29) and NNDR-II (Vinorelbine 25 mg/m2 d1, Mitoxantrone 10 mg/m2 d1, Dexamethasone 20 mg BID d1 through7, Rituximab 375 mg/m2 d1,8,15,22, Fludarabine 25 mg/m2 d1, d2, d3) in 26 patients with lymphohematopoietic malignancies, including 3 adult chronic myeloid leukemia (CML) patients in blast crisis, 2 adult chronic lymphocytic leukemia (CLL) patients with rapidly progressive leukemia, 10 acute lymphoblastic leukemia (ALL)(2 adults, 8 children) patients in therapy refractory relapse, and 11 adult non-Hodgkin’s lymhoma (NHL) patients (9 in relapse with progressive lymphoma). All patients completed their salvage therapy as an outpatient without infectious disease complications or hospitalizations. Of the 26 patients, 20 had objective responses, including 14 complete remissions (CR). The median survival was 1.3 (95% CI:0.5–3.9) y and the probability of survival was 53± 10% at 1 year and 37 ± 10% at 3 years (Figure 1). All 3 CML patients achieved a CR; two subsequently underwent allogeneic stem cell transplantation and remain alive free of leukemia at 4.5 y and 5.0 y, respectively, post blast crisis. One died with progressive disease at 0.7y. Both CLL patients achieved a CR and remain alive in CCR at 0.6y and 4.5y, respectively. Of the 10 ALL patients, 5 achieved a CR; of these 5, 2 died of pulmonary Aspergillosis at 0.3 y, 1 died of CMV pneumonitis at 0.7 y, 1 relapsed and died of gram negative sepsis at 1.2 y during reinduction, and 1 remains alive at 4.5 y in continued CR on maintenance chemotherapy. The median survival was 4 months. Of the 11 NHL patients, 4 achieved a CR and 5 achieved a PR. The median survival was 1.5y and 4 remain alive disease-free at 2.5y, 2.5y, 3.5y and 4.0y, respectively. Drug sensitivity profiling of primary tumor cells was performed in 14 patients: the vinorelbine sensitivity of the patients’ leukemia/lymphoma cells predicted their clinical response to the NNDR regimens. Of the 9 responders tested, 8 were vinorelbine sensitive at the primary tumor cell level. Of the 5 non-responders tested, only one was vinorelbine sensitive at the primary tumor cell level. Taken together, these findings demonstrate that patients with high risk/poor prognosis leukemias and lymphomas can achieve meaningful objective responses in an outpatient setting using vinorelbine-based salvage regimens. Future application if the drug sensitivity profiling of primary tumor cells might help tailor the NNDR regimens to those who are most likely to respond. Figure 1. Treatment Outcome of Leukemia/Lymphoma Patients receiving NNDR I/II Therapy Figure 1. Treatment Outcome of Leukemia/Lymphoma Patients receiving NNDR I/II Therapy