Search PubMed⌕ Search

Biomedical subjects

H R Alexander

Publications and source records attributed to H R Alexander.

135 records · Page 8Linked to original sources
PubMedDate not supplied

Endothelial monocyte-activating polypeptide II, a tumor-derived cytokine that plays an important role in inflammation, apoptosis, and angiogenesis.

The interactions between a tumor and its surrounding environment are complex and characterized by a variety of factors. Tumors produce a number of proteins that enable them to recruit a vascular supply, invade into surrounding tissues, and metastasize to distant sites. The host, in turn, responds to these signals by producing its own repertoire of molecules that may either assist or prevent the actions of the tumor. A thorough understanding of this relationship is critical to the development of novel anti-cancer therapies. The tumor-derived cytokine endothelial monocyte-activating polypeptide II (EMAP-II) has profound effects on the tumor as well as on host response. These effects target the inflammatory cascade as well as the processes involved in angiogenesis. In this review the authors describe the current understanding of the role of EMAP-II in inflammation, apoptosis, and angiogenesis and use this molecule to illustrate the complex interactions that occur in the tumor microenvironment.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Gadolinium-enhanced 3D MRA prior to isolated hepatic perfusion for metastases.

PURPOSE: Isolated hepatic perfusion (IHP) is a new treatment for patients with isolated unresectable liver metastases, which can result in a partial or complete response in approximately 75% of patients. Preoperative knowledge of hepatic arterial anatomy is important to adequately perfuse the liver. Digital subtraction angiography (DSA) is currently used to identify the hepatic arterial anatomy. The purpose of this study was to determine if MR angiography (MRA) could replace DSA prior to IHP. METHOD: Twenty-seven patients scheduled to undergo IHP underwent MRA with a contrast-enhanced 3D time-of-flight gradient echo sequence. Both maximal intensity projections (MIPs) and source coronal images were used to evaluate the images. The results of the MRA were interpreted by two readers who were blinded to the surgical results. The first 17 patients also underwent DSA, and a separate comparison was made with those results. Anatomy was characterized as either normal hepatic arteries (NHAs), normal vasculature with an accessory left hepatic artery (aLHA), or a replaced right hepatic artery (rRHA). RESULTS: MRA correctly detected all 22 patients with NHAs but also identified 6 aLHAs, of which only 2 were confirmed surgically. MRA correctly detected all five rRHAs. MIP images alone accurately depicted the hepatic arterial anatomy in only 9 of 27 (33%), usually because significant vessels were not visualized or their origin could not be determined. Source coronal images were required to accurately determine the anatomy in all patients. Among the 17 patients who underwent DSA, MRA detected 14 of 14 with NHA and 3 of 3 with rRHA. Six aLHAs were identified by MRA and five were confirmed by DSA. CONCLUSION: Enhanced 3D MRA is an accurate method of depicting the hepatic arterial supply. In comparison to surgery, MRA overestimates the number of aLHAs, but this may be because these small vessels are not detected at surgery. Based on the results of this study, DSA has been replaced by MRA in the planning of IHP at our institution. A better display of MRA images is needed as MIP images were usually insensitive for the small caliber arteries supplying the liver.

Angiography, Digital Subtraction↗
PubMedDate not supplied

Cytokines and their role in the pathophysiology of cancer cachexia.

Cancer cachexia describes a syndrome that consists of weight loss, and abnormalities in carbohydrate, protein, and lipid metabolism, which result in a state of persistent net negative energy balance. Patients suffering from cancer cachexia have a significantly shortened survival after cancer treatment. Recent experimental studies have focused on the belief that the mechanisms of cancer cachexia involve the host's production of inflammatory cytokines, which through broad physiologic actions ultimately lead to a chronic state of wasting, malnourishment, and death. Cytokines that have been thought to play a role in the pathophysiology of cachexia include tumor necrosis factor, interleukin-1, interleukin-6, interferon-gamma and differentiation factor. It has become clear that these cytokines have overlapping physiologic activities, which makes it likely that no single substance is the sole cause of cachexia in most cancer patients. Only further investigation may make it possible to more clearly define the role of cytokines in the pathophysiology of cancer cachexia. Specific strategies to reverse the cachectic effects of these substances may then be developed to ultimately improve cancer treatment.

Animals↗
PubMedDate not supplied

Continuous hyperthermic peritoneal perfusion with cisplatin for the treatment of peritoneal mesothelioma.

PURPOSE: Peritoneal mesothelioma remains a difficult therapeutic challenge. Aggressive debulking combined with continuous hyperthermic peritoneal perfusion (CHPP) using cisplatin (CDDP) is a novel strategy for the treatment of peritoneal mesothelioma, allowing high regional delivery of chemotherapeutics and hyperthermia while minimizing systemic toxicity. PATIENTS AND METHODS: From June 1993 to May 1996, 10 patients with peritoneal mesothelioma (six men, four women; mean age 40 years, range 15-57) underwent tumor debulking followed by a 90-minute CHPP. CHPP parameters included mean initial CDDP of 120 micrograms/mL (range 81-166), perfusate volume 5.2 L (range 4-7), flow 1.5 L/min, intraperitoneal temperature at three locations-41.5 degrees C, 40.5 degrees C, 41.1 degrees C, and core temperature 38.4 degrees C (range 37.2 degrees C-39.5 degrees C). Nine of 10 patients had malignant peritoneal mesothelioma, eight with associated ascites, while the tenth had a symptomatic, multiply recurrent benign peritoneal mesothelioma. Nine of 10 patients were optimally debulked. Pharmacokinetics were performed on blood and perfusate samples on nine patients; CDDP levels were quantitated by atomic absorption spectroscopy. RESULTS: Total perfusate cisplatin AUC was a mean of 21-fold higher (range 2- to 116-fold) than total serum cisplatin AUC, and serum CDDP behaved similarly to systemically administered CDDP. Median follow-up after CHPP is 10 months (range 2-32), with no treatment-related mortality. In eight optimally debulked patients there is no evidence of recurrent disease clinically or by CT or MRI. Seven patients with symptomatic ascites have been completely palliated. CONCLUSIONS: CHPP with CDDP is well tolerated with no significant regional toxicity. Because favorable CDDP pharmacokinetics suggest the potential for enhanced CDDP tumoricidal effect during CHPP, tumor debulking and CHPP may represent an effective strategy for the treatment of peritoneal mesothelioma.

Adolescent↗
PubMedDate not supplied

Thymidylate synthase protein expression: Association with response to neoadjuvant chemotherapy and resection for locally advanced gastric and gastroesophageal adenocarcinoma.

PURPOSE: A phase II study of neoadjuvant fluorouracil, leucovorin, and interferon alpha-2a was conducted to determine the feasibility of this regimen's use and the response rates in patients undergoing resection for locally advanced gastric or gastroesophageal adenocarcinoma. Also, tumor protein expression of free, total, or bound thymidylate synthase before and after initial exposure to fluorouracil was quantitated to determine if thymidylate synthase expression is associated with response in this treatment setting. PATIENTS AND METHODS: Twenty-two patients with T3-4N0-2M0 gastric or gastroesophageal adenocarcinoma were treated with three cycles of neoadjuvant fluorouracil (370 mg/m2 intravenously on days 2 through 6), leucovorin (500 mg/m2 intravenously on days 2 through 6), and interferon alpha-2a (5x106 U/m2 subcutaneously days 1 through 7), followed by resection and three cycles of consolidation therapy. Endoscopic tumor biopsies were done in 13 patients before therapy and during cycle 2 of the 5-fluorouracil/leucovorin/interferon regimen, and total thymidylate synthase, free thymidylate synthase, bound thymidylate synthase, and percent complexed thymidylate synthase were quantitated by Western blot. Tumor protein expression was evaluated for its association with response to neoadjuvant therapy and patient survival. RESULTS: Eight of 21 (38%) evaluable patients had a partial response, and another 5 of 21 (24%) had a minor response (25% to 49% tumor reduction) after three cycles of neoadjuvant fluorouracil/leucovorin/interferon. The pretreatment total thymidylate synthase level was significantly higher in five nonresponders than in eight responders. After exposure to fluorouracil, levels of free thymidylate synthase were significantly lower and the percent bound thymidylate synthase was higher in responders than in nonresponders. The median potential follow-up period is 24 months, and 11 of 21 patients have died from disease. CONCLUSIONS: These preliminary results indicate that a response to neoadjuvant fluorouracil-based therapy may be associated with decreased levels of total thymidylate synthase before therapy and free thymidylate synthase after exposure to fluorouracil in patients with locally advanced gastric cancer. Quantification of thymidylate synthase protein expression before and after exposure to fluorouracil may provide a method to select patients for fluorouracil therapy in the neoadjuvant, adjuvant, or advanced-disease setting based upon the fundamental sensitivity of the tumor.

Adenocarcinoma↗
PubMedDate not supplied

Palliation of regional symptoms of advanced extremity melanoma by isolated limb perfusion with melphalan and high-dose tumor necrosis factor.

PURPOSE: Bulky, symptomatic melanoma of the extremity is a difficult management problem. In some patients, slowly progressive yet extensive regional disease can produce pain, edema, bleeding, and immobility. The use of hyperthermic isolated limb perfusion may provide good regional palliation even in the presence of distant metastatic disease. This study evaluates the ability of isolated limb perfusion using melphalan and high-dose tumor necrosis factor to palliate regional symptoms of locally advanced extremity melanoma. METHODS: Fifteen patients with symptomatic extremity melanoma were treated for 90 minutes with isolated limb perfusion using mild hyperthermia, tumor necrosis factor at a dose of 4 mg (n = 8) or 6 mg (n = 7) given at the initiation of perfusion, and melphalan, 10 mg/L limb volume, given at 30 minutes into the perfusion. Eleven patients also received three courses of low-dose gamma-interferon, 0.2 mg subcutaneously, once a day for the 2 days preceding surgery and at the initiation of perfusion. RESULTS: Symptomatic improvement was achieved in 9 of 11 patients who had pain, 6 of 6 patients with edema, 5 of 6 patients with decreased extremity mobility, and 5 of 6 with bleeding or severe ulceration. The objective response rate in 14 evaluable patients was 100%, with a complete response rate in 5 of 14. Twelve of 15 patients achieved local control of advanced extremity melanoma after isolated limb perfusion. Treatment-related systemic toxicities were minimal and short lived. CONCLUSIONS: Isolated limb perfusion with melphalan and tumor necrosis factor is an effective and safe palliative treatment of locally advanced symptomatic melanoma of the extremity.

Adult↗