King F. Kwong

MicroRNA-24 regulates XIAP to reduce the apoptosis threshold in cancer cells

MicroRNAs have been implicated as important mediators of cancer cell homeostasis, and accumulating data suggest compelling roles for them in the apoptosis pathway. X-linked inhibitor of apoptosis protein (XIAP) is a potent caspase inhibitor and an important barrier to apoptotic cell death, but the mechanisms that determine the diverse range of XIAP expression seen in cancer remains unclear. In this study, we present evidence that miR-24 directly targets the 3′UTR of the XIAP messenger RNA (mRNA) to exert translational repression. Using a heuristic algorithm of bioinformatics analysis and in vitro screening, we identified miR-24 as a candidate regulator of XIAP expression. Array comparative genomic hybridization and spectral karyotype analysis reveal that genomic copy number loss at the miR-24 locus is concordant with the loss of endogenous miR-24 in cancer cells. Using a luciferase construct of the XIAP 3′UTR, we showed that miR-24 specifically coordinates to the XIAP mRNA. Interference with miR-24′s binding of the critical seed region, resulting from site-directed mutagenesis of the 3′UTR, significantly abrogated miR-24′s effects on XIAP expression. Moreover, miR-24 overexpression can overcome apoptosis resistance in cancer cells via downregulation of XIAP expression, and the resulting cancer cell death induced by tumor necrosis factor-related apoptosis-inducing ligand is executed by the canonical caspase-mediated apoptosis pathway. In summary, our data suggest a novel mechanism by which miR-24 directly modulates XIAP expression level and consequently the apoptosis threshold in cancer cells.

The GYMSSA trial: a prospective randomized trial comparing gastrectomy, metastasectomy plus systemic therapy versus systemic therapy alone

BackgroundThe standard of care for metastatic gastric cancer (MGC) is systemic chemotherapy which leads to a median survival of 6-15 months. Survival beyond 3 years is rare. For selected groups of patients with limited MGC, retrospective studies have shown improved overall survival following gastrectomy and metastasectomies including peritoneal stripping with continuous hyperthermic peritoneal perfusion (CHPP), liver resection, and pulmonary resection. Median survival after liver resection for MGC is up to 34 months, with a five year survival rate of 24.5%. Similarly, reported median survival after pulmonary resection of MGC is 21 months with long term survival of greater than 5 years a possibility. Several case reports and small studies have documented evidence of long-term survival in select individuals who undergo CHPP for MGC.DesignThe GYMSSA trial is a prospective randomized trial for patients with MGC. It is designed to compare two therapeutic approaches: gastrectomy with metastasectomy plus systemic chemotherapy (GYMS) versus systemic chemotherapy alone (SA). Systemic therapy will be composed of the FOLFOXIRI regimen. The aim of the study is to evaluate overall survival and potential selection criteria to determine those patients who may benefit from surgery plus systemic therapy. The study will be conducted by the Surgery Branch at the National Cancer Institute (NCI), National Institutes of Health (NIH) in Bethesda, Maryland. Surgeries and followup will be done at the NCI, and chemotherapy will be given by either the local oncologist or the medical oncology branch at NCI.Trial RegistrationClinicalTrials.gov ID. NCT00941655

Phase I/II Trial of Hyperfractionated Radiation and Chemotherapy Followed by Surgery in Stage III Lung Cancer

BACKGROUND We have previously demonstrated that high-dose chemoradiotherapy followed by resection for patients selected on the basis of mediastinal sterilization was feasible and resulted in excellent outcomes. This study was designed to determine the ability to intensify our prior approach utilizing hyperfractionated radiation and more aggressive consolidative chemotherapy. METHODS Patients with documented stage IIIA/B nonsmall-cell lung cancer, performance status 0 to 2, and adequate organ function were eligible. A phase I portion utilized escalating doses of carboplatin and vinorelbine, commencing with areas under the curve of 1 and 5 mg/m(2), respectively, and concurrent 69.6 Gy hyperfractionated radiotherapy. A phase II portion utilized the identical radiotherapy with carboplatin/vinorelbine at the maximum tolerated dose established in phase I. Patients for whom mediastinal nodal clearance was demonstrated underwent resection. All patients were to receive consolidation chemotherapy consisting of carboplatin/vinorelbine for three cycles, followed by docetaxel for three cycles. Prophylactic cranial irradiation was offered to patients after completion of therapy. RESULTS Forty-seven patients participated in the study (33 IIIA, 14 IIIB; 15 men, 32 women; median age, 56 years). The maximum tolerated dose for concurrent carboplatin/vinorelbine and hyperfractionated radiotherapy was established at areas under the curve of 1 and 10 mg/m(2), respectively. Twenty-eight patients completed trimodality treatment including surgery. Median survival time for the entire study cohort (n = 47) is 29.6 months, and it is 55.8 months for patients with mediastinal clearance who underwent resection (n = 28). CONCLUSIONS Surgical resection of locally advanced stage IIIA and IIIB nonsmall-cell lung cancer after induction hyperfractionated radiation and concurrent chemotherapy is safe and well tolerated. Whether this approach is superior to less aggressive therapy is uncertain and will require comparative studies.

Thoracoscopy/laparoscopy in the staging of esophageal cancer: Maryland experience.

Precise clinical staging of esophageal cancer before treatment is important. Thoracoscopic/laparoscopic (Ts/Ls) staging has been proposed as a promising staging method. This study was conducted to evaluate the potential benefits of Ts/Ls staging over conventional noninvasive clinical staging in patients with esophageal cancer. From 1991 to 1999, 111 patients with esophageal cancer underwent Ts/Ls staging by the University of Maryland Medical System. Pretreatment staging workup included computed tomography, magnetic resonance imaging, and esophageal ultrasonography, followed by Ts/Ls surgical staging. Thoracoscopy was successfully performed in 102 patients and was aborted in 4 patients because of pleural adhesions. Laparoscopy was successfully done in 76 patients and was aborted in 1 patient because of peritoneal adhesion. Sixty-seven patients had both Ts and Ls staging, whereas 35 patients and 9 patients, respectively, had only Ts or Ls staging. Thirteen of 19 patients with clinical T4 disease were downstaged to T3 disease, and 8 patients with clinical T3 disease were upstaged to T4 by Ts/Ls staging. No clinical T1–2 disease was found to be associated with local invasion (T4) by Ts/Ls. Forty-eight and 19 patients had mediastinal and celiac lymph node metastases clinically diagnosed, respectively. Nine (18.8%) and 12 (63.2%) of them were proved by Ts and Ls, respectively. An additional 5 and 16 patients were found to have unexpected mediastinal and celiac lymph node metastases, respectively, by Ts/Ls. Biopsy specimens of pleura, lung, or liver were obtained by Ts/Ls procedures in 17 patients because of suspicious findings of routine imaging studies or unexpected findings during the staging operation. Five patients were found to have distant metastasis, and the presence of metastases in others was excluded. The correlation between Ts/Ls staging and conventional noninvasive clinical staging in the diagnosis of T4 disease, mediastinal lymph node metastasis, celiac lymph node metastasis, and M1 disease was 18.8%, 14.5%, 25.5%, and 20.0%, respectively. Ts/Ls provides more accurate information for evaluating local invasion, lymph node metastasis, and distant metastasis. The poor correlation of staging diagnosis between Ts/Ls and conventional noninvasive clinical examinations suggests that the accuracy of current noninvasive clinical staging is questionable and needs to be improved.

Pneumonectomy for Lung Cancer After Preoperative Concurrent Chemotherapy and High-Dose Radiation

BACKGROUND We studied the clinical characteristics and outcomes of patients undergoing pneumonectomy after preoperative concurrent chemoradiation for non-small cell lung cancer. METHODS Clinical records of patients with non-small cell lung cancer who underwent pneumonectomy at our institution between 1995 and 2005 after preoperative concurrent chemoradiation were reviewed retrospectively. RESULTS Twenty-nine patients underwent pneumonectomy after preoperative concurrent chemoradiation. Of the 21 men and 8 women who were treated, 1 had stage IIB (T3N0M0) and the remainder had stage IIIA or IIIB non-small cell lung cancer. Mean patient age at surgery was 53.4 years. There were 15 right pneumonectomies, of which 2 were for pancoast tumors. All patients received concurrent preoperative chemoradiation. Mean total radiation dose was 61.1 Gy. All patients went on to have complete (R0) resection by pneumonectomy. Pathologic complete response was found in 16 patients (55.2%). All patients were discharged alive from the hospital after pneumonectomy. Median hospital length of stay was 5 days (mean 8.6). Ninety-day mortality after surgery was 3.4% (n = 1). Recurrences have been found in 11 patients (38%), including brain metastases (n = 6), bone metastases (n = 4), liver metastases (n = 2), and cervical lymph node metastases (n = 2). One patient had a contralateral new primary lung cancer develop 70 months after undergoing pneumonectomy. Estimated 5-year disease-free survival is 48%. Median survival time has not been reached. CONCLUSIONS Pneumonectomy can be performed safely after preoperative concurrent chemoradiation, even with high-dose radiation. The frequency of disease recurrence in the brain underscores the need to evaluate the role of prophylactic cranial radiation in non-small cell lung cancer.

Stratified Analysis of Clinical Outcomes in Thoracoscopic Sympathicotomy for Hyperhidrosis

BACKGROUND The primary goal of this study is to identify clinical variables associated with successful surgical treatment for hyperhidrosis and facial blushing. METHODS Six hundred eight thoracoscopic sympathicotomies were performed in 304 patients. Retrospective stratified analysis of patients after thoracoscopic sympathicotomy for hyperhidrosis or facial blushing and having completed follow-up of at least 6 months (n = 232) was performed. Preoperative and postoperative quality-of-life indices (range, 0 to 3) were used to measure impact of surgery, and comparisons were indexed to preoperative symptoms. Postoperative compensatory sweating was analyzed with respect to the level(s) of sympathetic chain division. RESULTS Thoracoscopic sympathicotomy was performed at level T2 alone in 5% of patients; levels T2 to T3 in 63% of patients; levels T3 to T4 in 3% of patients; levels T2 to T4 in 14% of patients; and more than three levels in 14% of patients. In hyperhidrosis patients, mean preoperative quality-of-life index was 2.0 and postoperative quality-of-life index was 0.4 (p < 0.001). Facial blushers had preoperative and postoperative quality-of-life index of 2.6 and 1.0, respectively. Significant compensatory sweating was seen in 33% patients overall and occurred in 29% of patients with palmar symptoms, 26% of axillary patients, and 42% of facial blushers. Significant compensatory sweating in relation to the level(s) of sympathetic chain division occurred in T2 alone, 45%; T2 to T3, 30%; T3 to T4, 14%; T2 to T4, 38%; and more than three levels, 49%. CONCLUSIONS Significant improvement in quality of life can result from surgery for hyperhidrosis. However, the incidence of postoperative compensatory sweating may be dependent on the level of sympathicotomy performed. The choice of sympathicotomy level(s) should be directed toward reducing the incidence of significant compensatory sweating while simultaneously ensuring relief of primary preoperative symptoms.

Neuroendocrine ACTH-Producing Tumor of the Thymus—Experience with 12 Patients over 25 Years

CONTEXT ACTH-producing neuroendocrine tumor (NET) of the thymus is a rare cause of Cushings syndrome (CS). The literature consists mainly of isolated case reports. PATIENTS We studied 12 cases (eight males and four females) diagnosed between 1986 and 2010 with CS and thymic NET who underwent surgical resection. MAIN OUTCOME MEASURES We measured time from onset of CS to diagnosis of thymic NET, tumor size, histological grade, time to recurrence, and survival and performed a meta-analysis of other published cases of CS associated with thymic NET. RESULTS Eleven of 12 patients presented with classic features of CS at a median age of 21 yr (range, 7-51). Four were children. The 24-h urine free cortisol was greater than 16-fold of normal, and biochemical testing was consistent with ectopic ACTH production in all 11. Another patient presenting with pulmonary embolus had a thymic mass and was later diagnosed with CS. All patients underwent thymectomy, and nine of 10 tumors exhibited positive ACTH immunochemistry. Median tumor diameter was 5 cm (range, 1-11.5). Six patients recurred 20-28 months after surgery with metastases to mediastinal lymph nodes (n = 5), bone (n = 5), liver (n = 1), parotid gland (n = 1), and breast (n = 1). Four of five patients treated with radiation therapy also received chemotherapy. All recurrent patients received ketoconazole; four later underwent bilateral adrenalectomy. Six recurrent patients died 22-90 months (median, 57) after thymectomy. At last review, six patients were alive 14-90 months (median, 49) after thymectomy. These data are similar to those from the meta-analysis. CONCLUSIONS Thymic ACTH-producing NET is an aggressive disease that should be considered in CS with ectopic ACTH secretion, particularly in younger patients.

Immunohistochemistry analysis of micrometastasis in pretreatment lymph nodes from patients with esophageal cancer.

BACKGROUND With recent advances in neoadjuvant therapy in esophageal cancer, pretreatment lymph node staging has become increasingly important in stratifying patients to appropriate treatment regimens and for prognostication. Immunohistochemical analysis (IHC) using epithelial markers has been shown to identify micrometastases in histologically negative lymph nodes. We performed this study to evaluate if IHC analysis in thoracoscopic/laparoscopic (Ts/Ls) pretreatment staging lymph nodes can reveal additional diagnostic information to routine histopathology. METHODS Specimens of 106 patients with esophageal cancer who had pretreatment Ts/Ls staging were retrospectively studied. Lymph node biopsies were obtained for IHC staining using cytokeratin (CK) of AE1/AE3. IHC staining for p53, an apoptosis protein associated with poor prognosis in esophageal cancer, was also performed. RESULTS 331 Ts/Ls staging lymph node biopsies were collected from 106 patients. A total of 15.4% (51/331) of the lymph nodes or 34.9% (37/106) of patients were found to have metastatic deposits by routine histology. All the histologically positive lymph nodes were CK positive. Among the remaining 280 histologically negative lymph nodes, 11(3.9%) were found to have micrometastasis by CK staining. Three patients (4.3%, 3/69) were upstaged from N0 to N1. They died of early recurrences after treatment. A total of 67.6% (25/37) of the patients with histologically positive lymph node were p53 positive. No histologically negative lymph node was found to be p53 positive in this series. CONCLUSIONS Immunohistochemical analysis for CK can detect micrometastatic involvement of lymph nodes that are missed on routine pathologic examination, and, therefore, can improve lymph node staging. Its clinical significance in esophageal cancer warrants further study.

Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of cancer cell internalization in vivo

The cell membrane is a critical barrier to effective delivery for many therapeutics, including those which are nanoparticle-based. Improving nanoparticle transport across the cell membrane remains a fundamental challenge. Cancer cells preferentially internalized pegylated calcium phosphate nanoparticles over normal epithelial cells. Furthermore, non-cytotoxic levels of doxorubicin markedly amplified this difference by increasing free unbound caveolin-1 and resulted in enhanced caveolin-mediated nanoparticle endocytosis in cancer cells. Engineered pegylated siRNA-loaded triple-shell calcium phosphate nanoconstructs incorporating ultra-low levels of doxorubicin recapitulated these effects and delivered increased numbers of siRNA into cancer cells with target-specific results. Systemic administration of nanoparticles in vivo demonstrated highly preferential entry into tumors, little bystander organ biodistribution, and significant tumor growth arrest. In conclusion, siRNA-loaded calcium phosphate nanoparticles incorporating non-cytotoxic amounts of doxorubicin markedly enhances nanoparticle internalization and results in increased payload delivery with concomitant on-target effects.

Characterization and Management of Cardiac Involvement of Thymic Epithelial Tumors

Introduction: Although thymic epithelial tumors (TETs) commonly infiltrate mediastinal structures, cardiac involvement is uncommon and has not been systematically studied. The purpose of this study was to describe our single-institution experience of the clinical presentation, treatment, and follow-up of cardiac involvement in patients with TETs. Methods: A single-institution retrospective review of cardiac involvement among patients with TETs from 2008 to 2012. Results: The frequency of cardiac involvement was 4%. All five patients with confirmed cardiac disease had left heart involvement. Only one patient was symptomatic. Myocardial invasion was the most common mode of involvement followed by transvenous spread. Surgical resection of the involved area was attempted in three patients: in one, surgery was aborted because of extensive myocardial involvement; in the other two patients, resection was incomplete. Surgery averted a potentially catastrophic hemodynamic complication in one patient. However, cardiac tumor recurred in both patients who underwent incomplete resection. One patient underwent radiation therapy resulting in complete regression of an aortic root mass. Conclusions: This study represents the most comprehensive review of cardiac involvement in patients with TETs. In contrast to previous single-case reports, we found a preponderance of asymptomatic presentation, left heart involvement, and myocardial invasion. Dynamic cardiovascular magnetic resonance imaging should be considered in cases when cardiac involvement is suspected. Although immediate surgical resection is indicated for impending hemodynamic compromise, long-term palliation with surgery for myocardial involvement seems poor, especially when complete resection cannot be performed. Radiation therapy should be considered in selected patients.