Hypoxia-inducible hexokinase-2 enhances anti-apoptotic function via activating autophagy in multiple myeloma

Multiple myeloma (MM) is an incurable hematopoietic neoplasm derived from plasma cells, and existing in the bone marrow. Recent developments in the field of myeloma onco-biology have enabled the use of proteasome inhibitors (PIs) as key drugs for MM. PIs can increase cell sensitivity to endoplasmic reticulum stress, leading to apoptosis of myeloma cells. PI cannot kill all myeloma cells, however; one reason of this might be activation of autophagy via hypoxic stress in the bone marrow microenvironment. Hypoxia-inducible gene(s) that regulate autophagy may be novel therapeutic target(s) for PI-resistant myeloma cells. Here, a hypoxia-inducible glycolytic enzyme hexokinase-2 (HK2) was demonstrated to contribute by autophagy activation to the acquisition of an anti-apoptotic phenotype in myeloma cells. We found that hypoxic stress led to autophagy activation accompanied by HK2 upregulation in myeloma cells. Under hypoxic conditions, HK2 knockdown inhibited glycolysis and impaired autophagy, inducing apoptosis. The cooperative effects of a PI (bortezomib) against immunodeficient mice inoculated with HK2-knocked down myeloma cells were examined and significant tumor reduction was observed. An HK2 inhibitor, 3-bromopyruvate (3-BrPA), also induced apoptosis under hypoxic rather than normoxic conditions. Further examination of the cooperative effects between 3-BrPA and bortezomib on myeloma cells revealed a significant increase in apoptotic myeloma cells. These results strongly suggested that HK2 regulates the activation of autophagy in hypoxic myeloma cells. Cooperative treatment using PI against a dominant fraction, and HK2 inhibitor against a minor fraction, adapted to the bone marrow microenvironment, may lead to deeper remission for refractory MM

Surgical Management of Spontaneous Haemopneumothorax

We report 2 cases of spontaneous haemopneumothorax treated surgically. Case 1, a 19-year-old man was referred to our hospital because of trapped lung after continuous tube drainage for 3 weeks. The chest roentgenogram showed a left haemopneumothorax with collapsed lung. At thoracotomy, 200g of clot blood was evacuated and decortication was performed. Case 2, a 20-year-old man was admitted complaining of chest pain and dyspnea. X-ray examination showed a moderate lung collapse and homogenous density. Chest tube drainage yealded 480ml of blood. However, bleeding was continuous and expansion of the right lung was poor, emergency thoracotomy was carried out and 950g of clot blood was obtained. Recovery was uneventful and complete expansion of the right lung was observed. From our experience, early thoracotomy for spontaneous haemopneumothorax is recommended

The Efficacy of Postoperative Chemotherapy with Cisplatinum and Pepleomycine for Esophageal Cancer

From May 1984 to August 1991, 58 patients without preoperative adjuvant therapy underwent resection of the esophagus for esophageal cancer. Three weeks after esophagectomy, one cycle of postoperative chemotherapy, consisting of intravenously infused cisplatinum at a dose of 70mg/m2 on day 1 and intramuscular pepleomycine at a dose of 5mg/body from day 1 to day 5, was administered in the 24 patients. In all patients receiving chemotherapy, mild fatigue or poor appetite occurred after drug administration, but severe drug toxicity, such as bone marrow depression, gastrointestinal bleeding or pulmonary fibrosis, did not occur. Eighteen patients (75%) died from cancer. The 3-year survival rate was 22.9% and the 5-year surival rate was 17.1%. In the patients who underwent curative operations, the 3-year and 5-year survival rates were 46.2% and 27.7%. However, there was no significant difference in the survival rates between the patients with postoperative chemotherapy and patients with esophagectomy alone. We conclude that one cycle of postoperative chemotherapy with cisplatinum and pepleomycin does not affect the survival of patients undergoing esophagectomy for esophageal cancer

Results of Surgical Treatment for Small Cell Lung Cancers

We analyzed the data for patients with small cell lung cancer, especially as regards comparison of the results of surgical treatment before and after the introduction of multimodal chemotherapy treatments. Sixty cases with small cell lung cancer were admitted in our department between January, 1955 and December, 1993. Among them, 38 cases underwent pulmonary resection. To evaluate the efficacy of the multimodal treatment including cisplatin with surgical therapy, patients were devided whether pulmonary resection was performed before 1983 (Group A) or after 1984 (Group B). There were no differences in sex and stage between two groups, but ages and operative proceduress were significantly different (p <0.05). Ages were older in Group B (65.5 years) than in Group A (58.1 years) and operations were lesser in Group B (lobectomy or segmentectomy 87.0 %) than in Group A (pneumonectomy or bilobectomy 53.5 %). The operative mortality rates were 13.3 % (2/15) in Group A and 4.3 % (1/23) n Group B. Survival rate at 3 years of Group A was only 6.7 % and no patients survived more than 4 years. While, survival rates of Group B at 3 and 5 years were 24.2 %. The 5 years survival rate of patients with Stage I and II of Group B was 46.9 % and that of Stage III and IV was 8.5%. It is concluded that surgical resection of limited small cell lung cancer (Stage I and II) with intensive chemotherapy is an efficient therapeutic approach

Downregulation of miR-26 promotes invasion and metastasis via targeting interleukin-22 in cutaneous T-cell lymphoma

It has been reported that certain microRNAs (miRNA) are associated with the pathogenesis of lymphoma. We have previously demonstrated that histone deacetylase inhibitors restore tumor-suppressive miRNAs, such as miR-16, miR-29, miR-150, and miR-26, in advanced cutaneous T-cell lymphoma (CTCL). Among these, the function of miR-26 remains unclear. In this study, we aimed to reveal the function of miR-26 in CTCL oncogenesis. First, we confirmed that the miR-26 family was markedly dysregulated in CTCL cell lines and primary samples. In vivo analysis using miR-26a-transduced CTCL cells injected into immunodeficient NOG mice demonstrated the significant prolonged survival of the mice, suggesting that the miRNA had a tumor-suppressive function. We performed gene expression assays and identified 12 candidate miR-26 targets, namely RGS13, FAM71F1, OAF, SNX21, CDH2, PTPLB, IL22, DNAJB5, CASZ1, CACNA1C, MYH10, and CNR1. Among these, IL22 was the most likely candidate target because the IL-22–STAT3–CCL20–CCR6 cascade is associated with tumor invasion and metastasis of advanced CTCL. In vitro analysis of IL22 and IL22RA knockdown and miR-26 transduction demonstrated inhibited CTCL cell migration. In particular, IL22 knockdown induced cell apoptosis. Finally, we conducted in vivo inoculation analysis of mice injected with shIL22-transfected CTCL cells, and found no tumor invasion or metastasis in the inoculated mice, although the control mice showed multiple tumor invasions and metastases. These results, along with our previous data, demonstrated that miR-26 is a tumor suppressor that is associated with tumor invasion and the metastasis of advanced CTCL by regulating the IL-22–STAT3–CCL20 cascade. Therefore, a IL-22-targeting therapy could be a novel therapeutic strategy for advanced CTCL

Surgery for Early Esophageal Carcinoma

Early esophageal carcinomas are clinicopathologically evaluated in 11 patients whose carcinomas are limited to the epithelium (ep) and the mucosa (mm). Most of ep and mm carcinomas were detected by mass-screening without any symptom. Even when mass examination for gastric lesion is attempted, precise examination of the esophagus should be made at the same time. It is assured that a ep and mm esophageal carcinoma ensured satisfactory outcome. It is emphasized that early detection is only a way to improve the surgical outcome of the treatment for esophageal carcinomas

Class II MHC Antigen Expression in Bronchial Lavage Cells in a Canine Lung Allograft Model using FK506 Immunosuppression

Footnotes: Katsunobu Kawahara, MD., The First Department of Surgery, Nagasaki University School Medicine, Sakamoto-machi 7-1 #852, Nagasaki, Japan, TEL 0958-47-2111, FAX 0958-47-5034 Abbreviations: MHC: Major histocompatibility antigens, CsA: Cyclosporine A, BAL: Bronchoalveolar lavage, APC: Antigen presenting cell To assess the effect of FK506 on class II MHC antigen expression on lymphocytes recovered from bronchoalveolar lavage (BAL) in dogs following left lung allotransplantation, flow cytometric anlysis with OKIa-1 monoclonal antibody was performed. Dogs were divided into two groups: Group 1 (n = 6), control group (dogs without surgery); Group 2 (n = 23), dogs recieving left lung allotransplantation and immunosuppression using FK506 (0.1mg/kg/day intramuscularly). No significant difference existed in the percentage of OKIa-1 positive lymphocytes recovered from control animals (31.2 ± 11.2%) vs. normal allografts in Group 2 (34.8 ± 8.5%, n = 16). With rejection, however, the percentage of OKIa-1 positive lymphocytes increases significantly in Group 2: 56.2 ± 10.3% in mild rejection (n = 6) and 91.4 ± 4.3% in moderate or severe rejection (n = 4) (p < 0.01). Chest radiographs appeared normal in allografted lungs with histologically mild rejection. The percentage of the OKIa-1 positive lymphocytes in BAL did not significantly change during the first, second, or third week following transplantation, ((32.2 ± 6.4 (n = 5), 36.4 ± 4.2 (n = 4), and 35.8 ± 12.3 (n = 7), respectively)) in the allografted lungs without rejection. FK506 does not affect the class II MHC antigen expression of lymphocytes recovered from BAL in canine allografted lungs without rejection. Furthermore, this compound does not change in class II antigen expression seen with allograft rejection

CEA in Esophageal Cancer Tissues

The presence of carcinoembryonic antigen (CEA) was assessed in cancer tissues of 53 patients with esophageal carcinoma. Positive rates of CEA staining in tissues were 81.1%. Well differentiated carcinomas tended to be well stained. The survival time in positive tissue CEA patients was longer than that in negative one. The measurement of a presence of tissue CEA is of help to judge the prognosis

Availability of Low Potassium UW Solution for a 24 Lung

A comparative study of preservation solution was made in a 24 hour storaged donor lung between original UW (University of Wisconsin) solution (k = 120mEq/l) and Low potassium UW (k = 30mEq/l) solution. Preservation of a donor lung with low potassium UW solution was superior to that with original UW solution in terms of static compliance and pulmonary vascular resistance. In conclusion, the use of low potassium UW solution is of great value to storage a donor lung

Surgery for Traumatic Injury of the Trachea and Bronchus

Surgery for traumatic disruption of the trachea and the bronchus was evaluated with respect to the surgical outcome in three with tracheal injury and four with bronchial injury. In this series, the results were satisfied except for one who underwent delayed operation. Experience seems to indicate that the primary care to ensure security of air way is of great value in life-saving and guarantee of the outcome including pulmonary function following surgery. In conclusion, it is emphasized that the fortuitous result and preservation of pulmonary function are mandatory for pertinent treatment with expediously precise diagnosis