Evaluation of miR-429 as a novel serum biomarker for pancreatic ductal adenocarcinoma and analysis its tumor suppressor function and target genes.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer. Various microRNAs have been identified to play an important role in PDAC. The study aimed to explore the role of miR-429 in PDAC. PATIENTS AND METHODS: The expression and prognostic value of miR-429 were first analyzed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Next, miR-429 expression was evaluated in the tissues and serum of 90 patients with PDAC. CCK8, SRB, wound healing and transwell assays were used to determine the effect of miR-429 on the proliferation, invasion, and migration of PDAC cells, respectively. Weighted gene co-expression network analysis (WGCNA), correlation analysis, TargetScan, and miRDB databases were used to screen and identify the target genes of miR-429. RESULTS: The results revealed that the expression of miR-429 was downregulated in PDAC tissues and the serum compared with those in normal tissues and the serum of healthy volunteers, respectively. The decreased expression of miR-429 was significantly associated with shorter overall survival. The overexpression of miR-429 significantly inhibited the proliferation, invasion, and migration of PDAC cells. Potential target genes of miR-429 were identified using WGCNA and bioinformatics analysis, and the results showed that cadherin 11 (CDH11), inositol polyphosphate-4-phosphatase type I (INPP4A), laminin gamma 1 (LAMC1), low density lipoprotein receptor-related protein 1 (LRP1), and quaking (QKI) were potential target genes of miR-429 in PDAC. Lower expression of CDH11 and QKI was associated with a more favorable prognosis in patients with PDAC. The overexpression of miR-429 could inhibit the expression of CDH11 and QKI. A nomogram model, involving miR-429, CDH11, and QKI, was subsequently constructed to determine their ability to accurately predict overall and disease-free survival in patients with PDAC. CONCLUSIONS: Taken together, miR-429 is involved in the development and progress of PDAC. MiR-429 could be recommended as a prognostic biomarker and therapeutic indicator in PDAC diagnosis.

Using ileocolic artery for successful graft salvage in a recipient with hepatic artery thrombosis after living donor liver transplantation: case report.

Hepatic artery (HA) occlusion is a sinister complication after liver transplantation. It frequently leads to graft loss if untreated. Urgent arterial reconstruction with thrombectomy may reduce the need for retransplantation. Living donor liver transplantation (LDLT) offers further challenges due to smaller-caliber vessels, shorter vascular stumps, and occasional multiple HA. Alternatives to the HA are needed when the native HA cannot be used or when HA complications develop. We describe the use of the recipient's ileocolic artery as an alternate HA in adult LDLT. Graft revascularization and timely salvage resulted in good patient recovery. A 6-month computed tomography angiography follow-up showed patency of the alternate vessels reconstructed.

Serious pulmonary toxicity in patients with Hodgkin's lymphoma with SGN-30, gemcitabine, vinorelbine, and liposomal doxorubicin is associated with an FcγRIIIa-158 V/F polymorphism.

BACKGROUND: Based on in vitro synergistic cytotoxicity when anti-CD30 antibodies are combined with gemcitabine, the Cancer and Leukemia Group B conducted a double-blind, randomized, phase II trial of SGN-30 with gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD) in patients with relapsed Hodgkin's lymphoma. PATIENTS AND METHODS: In part 1 of the trial, 16 patients received SGN-30 with GVD to assess the safety of the combination. In part 2, patients were randomly allocated to SGN-30 (n = 7) or placebo (n = 7) with GVD to determine overall response rate (ORR). RESULTS: ORR in all 30 patients was 63% (65% with SGN-30 plus GVD, n = 23, and 57% with placebo plus GVD, n = 7). Median event-free survival was 9.0 months, with no difference between the two arms. Grades 3-5 pneumonitis occurred in five patients receiving SGN-30 and GVD, leading to premature closure of the trial. All five patients with pulmonary toxicity had a V/F polymorphism in the FcγRIIIa gene (P = 0.008). CONCLUSIONS: Together with historical data demonstrating a 2% incidence of pulmonary events with GVD, these results indicate that SGN-30 cannot safely be administered concurrently. The risk of pneumonitis with SGN-30 and GVD is greatest in patients with an FcγRIIIa V/F polymorphism.

Vascular stents in the management of portal venous complications in living donor liver transplantation.

To evaluate the efficacy of stent placement in the treatment of portal vein (PV) stenosis or occlusion in living donor liver transplant (LDLT) recipients, 468 LDLT records were reviewed. Sixteen (10 PV occlusions and 6 stenoses) recipients (age range, 8 months-59 years) were referred for possible interventional angioplasty (dilatation and/or stent) procedures. Stent placement was attempted in all. The approaches used were percutaneous transhepatic (n = 10), percutaneous transsplenic (n = 4), and intraoperative (n = 2). Technical success was achieved in 11 of 16 patients (68.8%). The sizes of the stents used varied from 7 mm to 10 mm in diameter. In the five unsuccessful patients, long-term complete occlusion of the PV with cavernous transformation precluded catherterization. The mean follow-up was 12 months (range, 3-24). The PV stent patency rate was 90.9% (10/11). Rethrombosis and occlusion of the stent and PV occurred in a single recipient who had a cryoperserved vascular graft to reconstruct the PV during the LDLT operation. PV occlusion of >1 year with cavernous transformation seemed to be a factor causing technical failure. In conclusion, early treatment of PV stenosis and occlusion by stenting is an effective treatment in LDLT. Percutaneous transhepatic and transsplenic, and intraoperative techniques are effective approaches depending on the situation.

Management guidelines for the use of alemtuzumab in chronic lymphocytic leukemia.

The consensus views of an expert roundtable meeting are presented as updated management guidelines for using alemtuzumab in chronic lymphocytic leukemia. Since the publication of previous management guidelines in 2004, clinical experience with alemtuzumab has grown significantly, especially regarding its efficacy and safety, management of cytomegalovirus (CMV) reactivation, identification of patient subgroups likely to benefit from alemtuzumab therapy and subcutaneous administration of alemtuzumab. The updated recommendations include (1) alemtuzumab monotherapy can be safely used as first-line therapy; (2) suitable patient subgroups for alemtuzumab therapy include elderly patients, patients with 17p deletion, patients with refractory autoimmune cytopenias and patients with profound pancytopenia at baseline due to heavily infiltrated bone marrow; (3) alemtuzumab treatment should be continued for 12 weeks (36 doses) whenever possible, and bone marrow examination may be considered at week 12 to evaluate response; (4) monitoring CMV reactivation by weekly PCR is mandated during therapy; when CMV reactivation becomes symptomatic or viremia increases, alemtuzumab therapy should be interrupted and anti-CMV therapy started; (5) subcutaneous administration is safe, easy to perform and appears equally effective compared with intravenous infusion and (6) our strong recommendation is that alemtuzumab combination therapy and consolidation therapy shall not be used outside carefully controlled clinical studies.

A phase I/II study of rituximab and etanercept in patients with chronic lymphocytic leukemia and small lymphocytic lymphoma.

Rituximab has modest activity in relapsed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma but is associated with tumor necrosis factor-alpha (TNF-alpha) release that can cause CLL proliferation and inhibit apoptosis. We examined whether disruption of TNF-alpha by etanercept improves response to rituximab in CLL. Eligible patients had previously treated CLL with performance status 0-3. Patients received etanercept 25 mg subcutaneously twice weekly (weeks 1-5) and rituximab 375 mg/m(2) intravenously thrice weekly (weeks 2-5) using a phase I/II design. Primary end points were response and toxicity. The 36 enrolled patients had a median of two prior treatments; 50% were fludarabine refractory and 22% had del(17p13.1). Of the 34 response-evaluable patients, 10 (29%) responded, including 9 partial responses and 1 complete remission. Response was not affected by prior rituximab or fludarabine-refractory status, but no patients with del(17p13.1) responded. Median progression-free survival for responders was 9.0 months (range 1-43). Ten patients have had treatment-free intervals exceeding 12 months, including four who have remained untreated for 32, 43, 46 and 56 months. Adverse events were mild, including mild infusion reactions, transient cytopenias and grade 3 infections in 14% of the patients. The combination of etanercept and thrice weekly rituximab produces durable remissions in non-del(17p13.1) CLL patients and is well tolerated.

Epidemiological evidence of altered cardiac autonomic function in overweight but not underweight subjects.

BACKGROUND: Little is known about the altered cardiac autonomic function (CAF) across different levels of body mass index (BMI), including underweight, normal weight, overweight and obesity. This study provides a thorough analysis to clarify the CAF change in subjects with underweight, overweight and obesity. METHODS: According to the World Health Organization (WHO) Asia-Pacific BMI cutoffs, a total of 1437 participants were classified as underweight (n=74), normal weight (n=588), overweight (n=313), obesity I (n=390) and obesity II (n=72). CAF was determined by standard deviation of normal-to-normal (SDNN) intervals or RR intervals, power spectrum in low (LF) and high frequency (HF) (LF, 0.04-0.15 Hz; HF, 0.15-0.40 Hz), and LF/HF ratio at supine for 5 min, the ratio between the 30th and the 15th RR interval after standing from the supine position (30/15 ratio) and the average heart-rate change while taking six deep breaths in 1 min (HR(DB)). RESULTS: There were significant differences in age, gender, socioeconomic status, blood pressure, HOMA insulin resistance index, fasting glucose, cholesterol, triglyceride and high-density lipoprotein (HDL)-C, and the prevalence of hypertension, ischemic/left bundle branch block (LBBB) electrocardiography (EKG) pattern, current smoking and alcohol use among subjects with underweight, normal weight, overweight, obesity I and II. Univariate analysis showed that SDNN, HR(DB), HF power and the square root of the LF/HF ratio differed among these five groups. Multivariate analysis showed that obesity I and II were inverse correlates of HR(DB) and HF power. Overweight, obesity I and II were positively associated with the square root of the LF/HF ratio. No BMI status was related to SDNN, 30/15 ratio or LF power. Underweight was not the independent correlate of any CAF indices. CONCLUSIONS: The risk for altered CAF is significant in overweight and obese subjects, independent of cardiovascular risk factors. Underweight is not apparently associated with CAF change.

Alemtuzumab (Campath-1H) in the treatment of chronic lymphocytic leukemia.

Alemtuzumab (Campath-1H) is a humanized IgG1 monoclonal antibody that targets the human CD52 antigen. CD52 is expressed by a variety of lymphoid neoplasms and most human mononuclear cell subsets. In 2001, alemtuzumab was approved for marketing in the United States and Europe for use in patients with fludarabine-refractory chronic lymphocytic leukemia (CLL). In heavily pretreated patients with CLL, the overall response rate (ORR) is approximately 35%, and in previously untreated patients the ORR is greater than 80%, with a recent randomized study suggesting it is superior to alkylator-based therapy. Importantly, alemtuzumab is effective in patients with high-risk del(17p13.1) and del(11q22.3) CLL. Alemtuzumab combination studies with fludarabine and/or monoclonal antibodies such as rituximab have demonstrated promising results. Alemtuzumab is also being studied in CLL patients as consolidation therapy for treatment of minimal residual disease, in preparation for stem cell transplantation and to prevent acute and chronic graft versus host disease. Alemtuzumab is frequently associated with acute 'first-dose' reactions when administered intravenously, but is much better tolerated when administered subcutaneously without loss of therapeutic efficacy. Additional potential adverse events associated with alemtuzumab administration include myelosuppression as well as profound cellular immune dysfunction with the associated risk of viral reactivation and other opportunistic infections. Additional studies detailing the mechanism of action of alemtuzumab as well as new strategies for prevention of opportunistic infections will aid in the future therapeutic development of this agent.

Esophageal schwannoma with tracheal compression.

An esophageal schwannoma was found in a 73-year-old woman with cough, exertional dyspnea, and progressive dysphagia. Chest imaging showed an upper mediastinal mass (apex, right thoracic cavity) with direct lower tracheal compression. Esophagography and esophagoscopy revealed a tumor in the cervical and upper thoracic esophagus; it was resected from the upper thoracic esophagus followed by cervical esophageal repair. Histology showed oval-to-fusiform cells with palisading and lymphocytic stromal infiltration (immunohistochemistry, S-100 protein-positive). The patient was well one year afterward.

Filgrastim and alemtuzumab (Campath-1H) for refractory chronic lymphocytic leukemia.

Alemtuzumab (anti-CD52; Campath-1H) is effective in fludarabine-refractory chronic lymphocytic leukemia (CLL), but is associated with infection and early onset neutropenia. To reduce toxicity, filgrastim (G-CSF) was administered concurrently with alemtuzumab. In total, 14 CLL patients (median age 59) with a median of 3.5 prior regimens (range 1--12) received i.v. alemtuzumab, stepped up from 3 to 30 mg the first week, then 30 mg thrice weekly for 12 weeks. Filgrastim 5 microg/kg was administered daily 5 days before and throughout alemtuzumab therapy. Six patients developed cytomegalovirus (CMV) reactivation 3--6 weeks into treatment; six patients developed fever, three neutropenia, and one pneumonia. The patient with CMV pneumonia died; ganciclovir cleared CMV in the other patients. Five patients developed early neutropenia (weeks 2--5). Four patients developed delayed neutropenia (weeks 10--13) unassociated with CMV reactivation. Nine patients ceased therapy because of infectious and hematologic toxicity. Five partial responses were noted, all in patients with lymph nodes>cm, lasting a median of 6.5 months (range 5--13). Filgrastim and alemtuzumab were given concurrently with manageable infusion toxicity and clinical activity, but the efficacy of this regimen was limited by delayed neutropenia of unclear etiology and CMV reactivation. Filgrastrim should not be administered prophylactically during alemtuzumab therapy outside clinical trials.

Cyclooxygenase-2 in human non-small cell lung cancer.

AIM: Recent studies report that the expression of cyclooxygenase (COX) in non-small cell lung cancer (NSCLC) is increased, especially in adenocarcinoma. Platelet activating factor (PAF), n-sodium butyrate (n-BT), and phorbol myristate acetate (PMA) are important mediators of the inflammatory process. METHOD: Expression of COX-2 in 67 stage 1 NSCLC paraffin-embedded tumor samples was determined by immunohistochemistry (IHC). Four NSCL cell lines were incubated and stimulated by PAF, n-BT and PMA for 48 h. Expression of COX-2 was determined by IHC, immunoblotting, and reverse transcription-polymerase chain reaction (RT-PCR). RESULT: IHC showed increasing immunoreactivity in 35 of 67 (52%) in stage I NSCLC, 31 of 53 (59%) in adenocarcinoma and 13 of 15 (87%) in bronchoalveolar cell carcinoma, but only 2 of 12 (17%) in epidermoid carcinoma. The COX-2 expression in NSCLC cells was 75% (3/4) and the COX-1 expression in NSCLC cells was 100% (4/4). After stimulation with PMA, n-BT, PAF and n-BT + PAF, the COX-2 expression in NSCLC cells was significantly increased in all cell lines. CONCLUSIONS: The expression of COX-2 in NSCLC cells is high and was up-regulated by PMA, n-BT and PAF. We consider that COX-2 inhibitors will play an important role in the therapy of NSCLC.

Needlescopic thoracic sympathetic block by clipping for craniofacial hyperhidrosis: an analysis of 28 cases.

BACKGROUND: Endoscopic thoracic sympathectomy or sympathicotomy of the lower part of the stellate ganglion is an efficient method for the treatment of craniofacial hyperhidrosis, but postoperative compensatory sweating may be troublesome in some patients. Needlescopic thoracic sympathetic block by clipping may achieve a similar effect as well as providing a possible reverse operation for patients who suffer from intolerable postoperative compensatory sweating. METHODS: Between January 1998 and June 2000, we collected a total of 28 patients with craniofacial hyperhidrosis. There were 15 men and 13 women with a mean age of 39.2 years (ranges, 19-50). All patients were placed under single-lumen intubated anesthesia in a semisitting position. Two ports were needed. We used a 2-mm 0 degrees thoracoscope and endo clips to perform a sympathetic block by clipping the lower third of the stellate ganglion at the second intercostal space. RESULTS: The operation was usually accomplished within 20 min (ranges, 15-30). All patients were discharged within 4 h after the operation. There were no surgical complications or surgical mortality cases. All patients achieved improvement of craniofacial hyperhidrosis without recurrent symptoms after a mean of 25.3 months (range, 12-41) of follow-up. Twenty-five patients (85.7%) developed compensatory sweating of the trunk and lower limbs. One of these patients could not tolerate this postoperative sweating; he therefore underwent a reverse operation and obtained improvement of the compensatory sweating 18 days after removal of the endo clips. CONCLUSION: Needlescopic thoracic sympathetic block by clipping is a safe and effective method for the treatment of craniofacial hyperhidrosis; compensatory sweating may be improved after a reverse operation and removal of the endo clips.

Second autologous stem cell transplant for multiply relapsed Hodgkin's disease.

Therapeutic options for patients with Hodgkin's disease who relapse after high-dose chemotherapy with autologous stem cell support are limited. Salvage chemotherapy is not curative, and allogeneic stem cell transplantation in this setting is associated with mortality rates of 40-65%. We report our institution's experience with second autologous transplants in this patient population. Five patients (median age 36) with relapsed Hodgkin's disease underwent a second autologous stem cell transplant at a median of 66 months after first transplant. Four patients received CBV, and one patient received BuCy as conditioning. Neutrophil and platelet engraftment occurred by days +10 and +16, respectively. All patients achieved a complete response, and no relapses have occurred after a median follow-up of 42 months. All four patients who received CBV developed interstitial pneumonitis, and two patients died of pulmonary complications 37 and 48 months following second transplant. Three patients remain alive and disease-free 41, 42 and 155 months after second transplant. These data indicate that second autologous transplantation should be considered for selected patients who relapse after a prolonged response to first autologous transplant. However, BCNU pneumonitis is the major toxicity in patients who have undergone previous mantle radiation and received busulfan with first transplant.

Endoscopic thoracic sympathetic block by clipping for palmar and axillary hyperhidrosis in children and adolescents.

Endoscopic thoracic sympathectomy or sympathicotomy is a safe and effective method of treating primary hyperhidrosis (PH), but postoperative compensatory sweating may be a problem. There are few reports of sympathetic blockade by clipping for PH. We present our experience of endoscopic thoracic sympathetic block (ETSB) by clipping in treating palmar (PAH) and axillary hyperhidrosis (AH) in children and adolescents. Between May 1997 and June 1998, a total of 78 patients with PAH or AH underwent ETSB by clipping using an 8-mm, 0 degrees thoracoscope. There were 33 males and 45 females with a mean age of 14.1 years (range 9-16 y). All patients were placed in a semi-sitting position under single-lumen intubation anesthesia; 52 patients with PAH underwent T2 sympathetic block by clipping at the 2nd and 3rd rib beds, and T3 and T4 sympathetic block was performed at the 3rd, 4th and 5th rib beds in 26 patients with AH. A total of 156 sympathetic blocks by clipping were achieved. The operation was usually accomplished within 20 min (range 16-30 min). Most patients were discharged within 4 h after the operation. There were neither surgical complications nor mortality. The mean postoperative follow-up period was 32.7 months (range 26-40). Improvement of PAH or AH could be obtained in all cases; 70 patients (85.4%) developed compensatory sweating of the trunk and lower limbs. One patient with PAH underwent a reverse operation with improvement of the sweating 14 days after removal of the endo-clips. ETSB by clipping is thus a safe and effective method for treating PH in children and adolescents; compensatory sweating may be improved after a reverse operation with removal of the endo-clip.

Video-assisted thoracoscopic "resympathicotomy" for palmar hyperhidrosis: analysis of 42 cases.

BACKGROUND: There are rare reports of video-assisted thoracoscopic resympathicotomy for patients with palmar hyperhidrosis. I present our experience in treating a persistent or recurrent palmar hyperhidrosis after primary endoscopic sympathectomy or sympathicotomy and discuss the perioperative management. METHODS: We reoperated on 42 patients using a technique of video-assisted thoracoscopic resympathicotomy. All patients were placed in a semi-sitting position under single- or double-lumen intubated anesthesia. An 8-mm, 0 degrees thoracoscope was used to interrupt the nerve conduction to the palms from the T2 and T3 ganglia, through one or two 0.8-cm subaxillary incisions. RESULTS: The reasons for failure of endoscopic sympathectomy or sympathicotomy in 26 patients included pleural adhesion (15 of 26, 57.7%), incorrect identification of T2 ganglion (3 of 26, 11.5%), vessel overriding or close to sympathetic nerve (3 of 26, 11.5%), incomplete interruption of sympathetic nerve (2 of 26, 7.7%), medially located sympathetic nerve (2 of 26, 7.7%), and aberrant venous arch (1 of 26, 3.8%). The causes of recurrent palmar hyperhidrosis after primary transthoracic endoscopic sympathicotomy or sympathectomy (TES) in 16 patients included a possible effect of T3 ganglion (8 of 16, 50%), Kuntz fiber (3 of 16, 18.8%), nerve regeneration (3 of 16, 18.8%), and incomplete interruption of T2 ganglion (2 of 16, 12.5%). Surgical complications included pneumothorax (1 patient, 2.4%), hemothorax (1 patient, 2.4%), and compensatory sweating (36 patients, 86%). All patients had obtained successful bilateral sympathectomies and had satisfactory results after a mean of 32.1 months of follow-up. CONCLUSIONS: Video-assisted thoracoscopic resympathicotomy is an effective and safe method for a previously unsuccessful sympathectomy or recurrent palmar hyperhidrosis if the surgeon acknowledges possible anatomic variations and can overcome the problems related to pleural adhesions.

Synthesis and biological evaluation of L- and D-configurations of 2',3'-dideoxy-4'-C-methyl-3'-oxacytidine analogues.

Novel L- and D-configuration 2',3'-dideoxy-4'-C-methyl-3'-oxacytidine and their 5-fluoro analogues have been synthesized from 1-benzyloxy-2-propanone and L-ascorbic acid in eight steps and evaluated for biological activity.