Two clinical trials of an intraocular steroid delivery system for cataract surgery
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Publications and source records attributed to D Chang.
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BACKGROUND: Retroperitoneal or visceral sarcoma may recur with disease limited to the abdomen and pelvis. In this clinical situation, further surgical treatments in an attempt to control the disease may be appropriate. CT is used to help select patients for additional surgical interventions. STUDY DESIGN: Preoperative abdominal and pelvic CT scans of 33 patients with recurrent sarcoma were reviewed retrospectively. All patients underwent reoperative surgery and, when appropriate, perioperative intraperitoneal chemotherapy. Patients were divided into two groups according to survival and disease status: alive with no evidence of disease (n = 7) and alive with disease or dead of disease (n = 26). Twenty-two CT indices were studied retrospectively for each patient and evaluated statistically. RESULTS: The presence of large (greater than 5 cm) tumor volume in 3 of the 13 abdominopelvic regions resulted in a significant difference in the prognosis between the groups of patients. These findings included tumor in the left lower quadrant (p = 0.032), tumor in the pelvis (p = 0.008), and tumor in the distal jejunum (p = 0.032). Two other CT indices that showed a significant difference in survival between the groups were involvement of five abdominopelvic regions or fewer (p = 0.008) and a peritoneal cancer index of 15 or less (p = 0.03). A statistical approach using a tree-structured diagram showed that patients with tumor diameter greater than 5 cm in the pelvis accompanied by tumor involvement of more than one segment of small bowel had a 0% probability of postoperative disease-free survival. In contrast, patients with tumor diameter less than 5 cm in the pelvis on CT had an 86% probability of disease-free survival. CONCLUSIONS: For patients with recurrent sarcoma, selection criteria were generated by a preoperative CT of the abdomen and pelvis. In this disease, CT was a reliable diagnostic test for predicting benefit from further surgical interventions and should be used in the future to help select patients for an aggressive versus a palliative approach.
AIMS: Long-term survival after surgery for pancreatic cancer remains very low and it is particularly important that minimal surgery-related morbidity and mortality rates are achieved. It has been stated that centres performing small numbers of proximal pancreaticoduodenectomies are likely to have high morbidity and mortality rates. The results of pancreatic surgery in a district general hospital are reported. METHODS: This was a retrospective analysis of all pancreaticoduodenectomies over 4 years. RESULTS: Twenty-one selected patients underwent proximal pancreaticoduodenectomy and two patients total pancreatectomy over a 4-year period from 1995 to 1999. The operations were performed by two surgeons with a special interest in upper gastrointestinal surgery. The median age was 62 (38-83) years. There were 14 men and nine women. Fifteen patients had adenocarcinoma of the head of the pancreas, five had ampullary carcinoma, one duodenal carcinoma and there was one case of chronic pancreatitis. Six patients had pylorus-preserving pancreaticoduodenectomy (PPPD) and 15 had a standard Whipple procedure. The median stay in hospital was 20 (13-26) days. Two patients had a pancreatic leak, one of whom developed an intra-abdominal abscess which was treated successfully by percutaneous drainage. Six patients experienced delayed gastric emptying, two of whom had PPPD. Both the 30-day and in-hospital mortality rates were zero. The median number of lymph nodes dissected was 12 and in 11 patients no nodal metastasis was found. CONCLUSIONS: It is possible to perform pancreatic surgery in a district general hospital and achieve results that are comparable to those of specialist centres.
BACKGROUND: Peritoneal mesothelioma is a rare peritoneal malignancy, representing approximately one-third of all mesotheliomas. It is regarded as a universally fatal cancer with few treatment options. METHODS: Records of 33 patients with peritoneal mesothelioma were reviewed retrospectively. Demographic, clinical and quantitative prognostic indicators were evaluated and analysed statistically using survival as endpoint. Patients were treated by a uniform strategy involving cytoreductive surgery with peritonectomy procedures and perioperative intraperitoneal chemotherapy (cisplatin, doxorubicin). RESULTS: There were ten women and 23 men; mean age was 53.0 years. Asbestos exposure was recorded in five patients and a family history of cancer in 13. Presentation was mainly abdominal distension and pain. Median survival was 31.0 months; overall projected survival at 3 years was 56 per cent. The most significant positive predictive factors of survival were: female sex (P= 0.003), low prior surgical score (P=0.002), completeness of cytoreduction (P=0.0002) and second-look surgery (P=0.019). The morbidity rate for this combined treatment was 33 per cent and the perioperative mortality rate was 3 per cent. CONCLUSION: Although peritoneal mesothelioma is rare, progress in its management has occurred. Survival has been extended and selection factors by which patients may be allocated to aggressive management strategies have been defined.
AIM: To assess possible improvements in drug delivery to unresectable liver tumours we investigated the pharmacokinetics of intrahepatic doxorubicin in the dog liver with and without inflow occlusion. METHODS: Using a lattice template, doxorubicin was injected into 16 sites (over a 9 cm2 area) in each of three lobes of the liver for a total of 48 sites. The total doses of doxorubicin used were 4.8 mg and 96 mg (0.1 and 2 mg/site). Dogs with intravenous and intra-arterial delivery of the same total doses of doxorubicin were used as controls. Experiments using intrahepatic injection were performed with and without a 30 min occlusion of the hepatic artery, common bile duct and portal vein (inflow occlusion). The studies with vascular stasis were performed to determine if drug clearance from the injection sites and their plasma levels were reduced. Also, it was observed that blood and drug loss along the needle tract was reduced when inflow occlusion was used. Plasma and liver samples were harvested over a 90-min period and analysed by high pressure liquid chromatography (HPLC). RESULTS: In plasma mean peak levels and mean area under the curve (AUC) were significantly lower with intrahepatic doxorubicin (P<0.05) than with intravenous or intra-atrial delivery. In the liver AUCintrahepatic/AUCintravenous ratios were 3.45 and 3.6 with 4.8 mg and 96 mg of doxorubicin respectively. The AUCintrahepatic/AUCintraarterial ratios were 1.97 and 1.65 respectively. The liver extraction ratio (AUCliver/AUCplasma) after intravenous administration with 4.8 mg and 96 mg of doxorubicin was 31.9 with both doses of doxorubicin. The corresponding extraction ratios were 107.6 and 51 for intra-arterial administration and 425.2 and 237.7 for intrahepatic administration for the two doses of doxorubicin. Intrahepatic injection with inflow occlusion minimized the leakage back along the needle-tracts. The liver visibly retained the injected drug more completely. However, there was a decrease in systemic clearance resulting in a reduction of the pharmacological advantage. CONCLUSION: These results indicate that lattice-intrahepatic administration of doxorubicin into the liver using a lattice template was associated with a significant increase in local and decrease in systemic exposure as compared to intravenous or intra-arterial administration of the same doses. Simultaneous occlusion of arterial and portal venous inflow was not shown to improve regional drug delivery. These pharmacokinetic studies may constitute a basis for palliative treatment of liver tumours by lattice intralesional injection when these cancers are found to be unresectable at the time of exploratory surgery.
We report a case of ruptured abdominal aortic aneurysm (AAA) in a patient receiving chemotherapy for pancreatic cancer. We reviewed the literature on the effects of corticosteroids and chemotherapy on aaa formation and discuss possible mechanisms for drug action to promote aneurysm expansion and rupture. If cancer and AAA coincide and curative chemotherapy is possible, a potential impact of chemotherapy on AAA expansion should be considered.
OBJECTIVES: Endovascular aortoiliac aneurysm (EAIA) repair uses substantial fluoroscopic guidance that requires considerable radiation exposure. Doses were determined for a team of three vascular surgeons performing 47 consecutive EAIA repairs over a 1-year period to determine whether this exposure constitutes a radiation hazard. METHODS: Twenty-nine surgeon-made aortounifemoral devices and 18 bifurcated devices were used. Three surgeons wore dosimeters (1) on the waist, under a lead apron; (2) on the waist, outside a lead apron; (3) on the collar; and (4) on the left ring finger. Dosimeters were also placed around the operating table and room to evaluate the patient, other personnel, and ambient doses. Exposures were compared with standards of the International Commission on Radiological Protection (ICRP). RESULTS: Total fluoroscopy time was 30.9 hours (1852 minutes; mean, 39.4 minutes per case). Yearly total effective body doses for all surgeons (under lead) were below the 20 mSv/y occupational exposure limit of the ICRP. Outside lead doses for two surgeons approximated recommended limits. Lead aprons attenuated 85% to 91% of the dose. Ring doses and calculated eye doses were within the ICRP exposure limits. Patient skin doses averaged 360 mSv per case (range, 120-860 mSv). The ambient (> 3 m from the source) operating room dose was 1.06 mSv/y. CONCLUSIONS: Although the total effective body doses under lead fell within established ICRP occupational exposure limits, they are not negligible. Because radiation exposure is cumulative and endovascular procedures are becoming more common, individuals performing these procedures must carefully monitor their exposure. Our results indicate that a team of surgeons can perform 386 hours of fluoroscopy per year or 587 EAIA repairs per year and remain within occupational exposure limits. Individuals who perform these procedures should actively monitor their effective doses and educate personnel in methods for reducing exposure.
The objectives of this study were to evaluate reconstructive methods for patients receiving brachytherapy after cancer ablation. This retrospective review evaluated 19 patients who received brachytherapy and reconstruction between 1991 and 1998. The average age of the patient was 61.9 years and the average follow-up was 2.9 years. Lesions were located in the upper extremity (N = 6), trunk (N = 2), and lower extremity (N = 11). In all patients, early postoperative brachytherapy was initiated 5 days after wound closure. The average radiation dose was 47 Gy (range, 45-50 Gy) and was delivered over a 3 to 5-day period. In each case, varying numbers of catheters were employed (average, 8 +/- 5 catheters). Free flap coverage was performed in 8 patients, and the latissimus dorsi was used most often. Pedicled regional flaps were employed in 11 patients (58%). Sixteen patients (84%) had additional external beam irradiation, and 10 patients (52%) underwent preoperative chemotherapy. All flaps survived with a demonstrated low complication rate (10%). In 2 patients, partial flap necrosis and infection occurred. Three donor site complications were observed and included wound dehiscence in 2 patients and hematoma in 1 patient. Cumulative effects of external beam radiation and brachytherapy did not affect the complication rate. Location of the defect did not alter the incidence of complications. Wound complications did not delay functional rehabilitation in these patients; however, hospital stay was longer. In 8 patients local recurrence occurred (42%) between 6 and 36 months after surgery whereas in 6 patients (32%) distant metastasis was observed. Ten patients are currently alive without evidence of disease. One of the most important concerns about early postoperative brachytherapy is wound healing. With careful planning and precise reconstructive techniques, the use of brachytherapy as a part of salvage or primary surgery does not lead to increased wound morbidity. Reconstructive procedures and a multidisciplinary approach have allowed the delivery of brachytherapy in these complicated patients with low morbidity.
We previously demonstrated that bovine serum conglutinin has markedly greater ability to inhibit influenza A virus (IAV) infectivity than other collectins. We now show that recombinant conglutinin and a chimeric protein containing the NH(2) terminus and collagen domain of rat pulmonary surfactant protein D (rSP-D) fused to the neck region and carbohydrate recognition domain (CRD) of conglutinin (termed SP-D/Cong(neck+CRD)) have markedly greater ability to inhibit infectivity of IAV than wild-type recombinant rSP-D, confirming that the potent IAV-neutralizing activity of conglutinin resides in its neck region and CRD. Furthermore, by virtue of incorporation of the NH(2) terminus and collagen domain of SP-D, SP-D/Cong(neck+CRD) caused substantially greater aggregation of IAV particles and enhancement of neutrophil binding of, and H(2)O(2) responses to, IAV than recombinant conglutinin or recombinant rSP-D. Hence, SP-D/Cong(neck+CRD) combined favorable antiviral and opsonic properties of conglutinin and SP-D. This study demonstrates an association of specific structural domains of SP-D and conglutinin with specific functional properties and illustrates that antimicrobial activities of wild-type collectins can be enhanced through recombinant strategies.
OBJECTIVE: The purpose of our study was to determine the findings of portal hypertensive gastropathy on barium studies in eight patients and whether there are useful radiographic criteria for diagnosing this condition. CONCLUSION: Our experience suggests that portal hypertensive gastropathy may manifest on barium studies as thickened nodular folds in the gastric fundus. Although varices or various forms of gastritis can also produce thickened gastric folds, portal hypertensive gastropathy should be suspected when this finding is detected in patients with known portal hypertension.
In this study, we explored what effect inhibitors of the 26S proteasome have on cell cycle distribution and induction of apoptosis in human skin fibroblasts and colon cancer cells differing in their p53 status. We found that proteasome inhibition resulted in nuclear accumulation of p53. This was surprising because it is thought that the degradation of p53 is mediated by cytoplasmic 26S proteasomes. Nuclear accumulation of p53 was accompanied by the induction of both p21WAF1 mRNA and protein as well as a decrease in cells entering S phase. Interestingly, cells with compromised p53 function showed a marked increase in the proportion of cells in the G2-M phase of the cell cycle and an attenuated induction of apoptosis after proteasome inhibition. Taken together, our results suggest that proteasome inhibition results in nuclear accumulation of p53 and a p53-stimulated induction of both G1 arrest and apoptosis.
T-cell activation requires co-stimulation through receptors such as CD28 and antigen-specific signalling through the T-cell antigen receptor. Here we describe a new murine costimulatory receptor-ligand pair. The receptor, which is related to CD28 and is the homologue of the human protein ICOS, is expressed on activated T cells and resting memory T cells. The ligand, which has homology to B7 molecules and is called B7-related protein-1 (B7RP-1), is expressed on B cells and macrophages. ICOS and B7RP-I do not interact with proteins in the CD28-B7 pathway, and B7RP-1 co-stimulates T cells in vitro independently of CD28. Transgenic mice expressing a B7RP-1-Fc fusion protein show lymphoid hyperplasia in the spleen, lymph nodes and Peyer's patches. Presensitized mice treated with B7RP-1-Fc during antigen challenge show enhanced hypersensitivity. Therefore, B7RP-1 exhibits co-stimulatory activities in vitro and in vivo. ICOS and B7RP-1 define a new and distinct receptor-ligand pair that is structurally related to CD28-B7 and is involved in the adaptive immune response.
Variable regulatory subunits of protein phosphatase 2A (PP2A) modulate activity, substrate selectivity and subcellular targeting of the enzyme. We have cloned a novel member of the B type regulatory subunit family, B delta, which is most highly related to B alpha. B delta shares with B alpha epitopes previously used to generate subunit-specific antibodies. Like B alpha, but unlike B beta and B gamma which are highly brain-enriched, B delta mRNA and protein expression in tissues is widespread. B delta is a cytosolic subunit of PP2A with a subcellular localization different from B alpha and may therefore target a pool of PP2A holoenzymes to specific substrates.
Canine rapid ventricular pacing produces a low output cardiomyopathic state which is similar to dilated cardiomyopathy. In this study dogs were paced at 245 beats per minute (bpm) for 3-4 weeks until signs of heart failure were apparent. Unpaced dogs were used as controls. A previous study identified myocardial protein changes in the pH region 4-7 following ventricular pacing by using two-dimensional electrophoresis (2-DE) (Heinke et al., Electrophoresis 1998 19, 2021-2030). Many of these proteins were associated with mitochondria, energy metabolism within the cardiomyocyte, the cytoskeleton and calcium cycling. The present study aimed to examine the proteins migrating in the more basic region of the 2-DE pattern using immobilised pH gradient 3-10 strips to separate myocardial proteins. The expression of 31 proteins was altered in the paced myocardium: 21 were decreased and 10 increased. Following the identification of 23 of these spots by either amino acid compositional analysis or peptide mass fingerprinting or a combination of both, we confirm that many of the proteins whose expression is altered following ventricular pacing are associated with the mitochondria and energy production within the cardiomyocyte, including creatine kinase M, triosephosphate isomerase, phosphoglycerate mutase, cytochrome c oxidase, cytochrome b5, hydroxymethyl glutaryl CoA synthase, myoglobin, and 3,2-trans-enoyl-CoA transferase. Additionally, the cytoskeletal protein actin was increased in the paced hearts. These results strongly support the notion that energy production is impaired and mitochondrial dysfunction is involved in the development of heart failure in the paced dog.
Assuming that peritoneal carcinomatosis is a local/regional dissemination of disease, a treatment strategy utilizing cytoreductive surgery and intraperitoneal chemotherapy was developed to treat colon cancer. In an attempt to improve knowledge of the mechanisms controlling abdominal and pelvic recurrences and for better selection of patients for reoperation, we studied those patients who had a second-look surgery following cytoreduction for peritoneal carcinomatosis from colorectal cancer. A group of 18 patients with symptoms and signs of recurrent peritoneal carcinomatosis were treated with reoperative surgery after definitive cytoreduction and intraperitoneal chemotherapy. An analysis of clinical features of these patients was performed using survival as an endpoint for evaluation of prognosis. The data suggest that the clinical features to be used to select patients for a second-look procedure after prior cytoreduction were the completeness of resection at the time of initial cytoreduction (p = 0.04) and the completeness of resection at the time of the second look (p = 0.066). In addition, a limited extent of peritoneal carcinomatosis distribution found at the time of the second look predicted a favorable result. A new objective assessment of peritoneal carcinomatosis, the peritoneal cancer index, was found to be of help during patient selection (p = 0.066). We concluded that second-look surgery with potential curative intent should be considered in patients who had a complete initial cytoreduction and those in whom total removal of the recurrence is judged possible at the time of the second look. At the time of abdominal exploration, a limited distribution and volume of peritoneal carcinomatosis as defined by the peritoneal cancer index should be considered. Palliative debulking procedures should be used to alleviate symptoms in other patients.
The origin of Taiwanese aborigines remains obscure; it has been speculated that they may be from either mainland China or southeastern Asia. We used the JCV genotyping method to elucidate the origin of Bunun aborigines who now live in central mountain areas of Taiwan. We found that Bunun aborigines carried two major (B1-a2 and CY) and two minor JCV genotypes (B1-a1 and SC). This was contrasted with the JCV genotype profile in modern Taiwanese: one major (SC) and two minor genotypes (CY and B1-a1). It thus appears that B1-a2 and CY are indigenous to the Bunun tribe. B1-a2 was first identified in this study as a discrete cluster that contained only Bunun and Philippine JCV isolates and that was closely related to B1-a1, one of the three common JCV genotypes in China. CY predominates in North China, while SC predominates in South China and southeastern Asia. The present findings suggest that the Bunun tribe is an admixture of two ethnic groups, one carrying B1-a2 and the other carrying CY. In other words, it is likely that the Bunun tribe was established by two waves of immigrations from mainland Asia, predating those by southern Chinese which began in the 17th century.
INTRODUCTION: In the past, peritoneal carcinomatosis, regardless of primary tumor type, has always been a lethal condition. Recently, special treatments using cytoreductive surgery with peritonectomy procedures combined with perioperative intraperitoneal chemotherapy have resulted in long-term survival. Appendiceal malignancy with a low incidence of liver and lymph node metastases may be especially appropriate for these aggressive local regional treatments. METHODS: All patients treated with surgery before January 1999 are included. Patients left with gross residual disease after surgery were not given intraperitoneal chemotherapy, but were later treated with intravenous chemotherapy. The intraperitoneal chemotherapy was given in the perioperative period, starting with mitomycin C at 12.5 mg/m2 for males and 10 mg/m2 for females. For patients whose pathology showed adenomucinosis, intraperitoneal chemotherapy was limited to treatment in the operating theater with heated mitomycin C. Patients with mucinous adenocarcinoma or pseudomyxoma/adenocarcinoma hybrid had, in addition to mitomycin C, five consecutive days of intraperitoneal 5-fluorouracil at 650 mg/m2 instilled in 1-1.5 liters of 1.5% dextrose peritoneal dialysis solution. A complete cytoreduction was defined as tumor nodules <2.5 mm in diameter remaining after surgery. The histopathology categorized the patients as having adenomucinosis, adenomucinosis/carcinomatosis hybrid, or mucinous carcinomatosis. A previous surgical score was used to estimate the extent of previous surgical procedures. RESULTS: The morbidity of treated patients was 27% and the mortality was 2.7%. In a multivariate analysis, prognostic factors for survival included the completeness of cytoreduction (P < .0001), the histopathological character of the appendix malignancy (P < .0001), and the extent of previous surgical interventions (P = .001). Patients with a complete cytoreduction and adenomucinosis by pathology had a 5-year survival of 86%; with hybrid pathology, survival at 5 years was 50%. Incomplete cytoreduction had a 5-year survival of 20% and 0% at 10 years. CONCLUSIONS: Cytoreductive surgery and perioperative intraperitoneal chemotherapy can be used to salvage selected patients with peritoneal surface spread of appendiceal primary tumors. Similar strategies for other patients with peritoneal surface malignancy such as peritoneal carcinomatosis from colon or gastric cancer, peritoneal sarcomatosis, or peritoneal mesothelioma should be pursued.
BACKGROUND: Peritoneal carcinomatosis from gastrointestinal cancers is a fatal diagnosis without special combined surgical and chemotherapy interventions. Guidelines for cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) by using the Coliseum technique have been developed to treat patients with peritoneal carcinomatosis and other peritoneal surface malignancies. The purpose of this study was to analyze the morbidity and mortality of patients undergoing cytoreductive surgery and HIIC by using mitomycin C. METHODS: Data were prospectively recorded on 183 patients who underwent 200 cytoreductive surgeries with HIIC between November 1994 and June 1998. Seventeen of the 183 patients returned for a second-look surgery plus HIIC. All HIIC administrations occurred after cytoreduction and used continuous manual separation of intra-abdominal structures to optimize drug and heat distribution. Origins of the tumors were as follows: appendix (150 patients), colon (20 patients), stomach (7 patients), pancreas (2 patients), small bowel (1 patient), rectum (1 patient), gallbladder (1 patient), and peritoneal papillary serous carcinoma (1 patient). Morbidity was organized into 20 categories that were graded 0 to IV by the National Cancer Institute's Common Toxicity Criteria. In an attempt to identify patient characteristics that may predispose to complications, each morbidity variable was analyzed for an association with the 25 clinical variables recorded. RESULTS: Combined grade III/IV morbidity was 27.0%. Complications observed included the following: peripancreatitis (6.0%), fistula (4.5%), postoperative bleeding (4.5%), and hematological toxicity (4.0%). Morbidity was statistically linked with the following clinical variables: duration of surgery (P < .0001), the number of peritonectomy procedures and resections (P < .0001), and the number of suture lines (P = .0078). No HIIC variables were statistically associated with the presence of grade III or grade IV morbidity. Treatment-related mortality was 1.5%. CONCLUSIONS: HIIC may be applied to select patients with peritoneal carcinomatosis from gastrointestinal malignancies with 27.0% major morbidity and 1.5% treatment-related mortality. The frequency of complications was associated with the extent of the surgical procedure and not with variables associated with the delivery of heated intraoperative intraperitoneal chemotherapy. The technique has shown an acceptable frequency of adverse events to be tested in phase III adjuvant trials.