Biomedical subjects

H R Alexander

Publications and source records attributed to H R Alexander.

At least 19 recordsLinked to original sources

PubMed1997

Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia.

Several inflammatory cytokines, most notably tumor necrosis factor (TNF) and IL-1, induce anorexia and loss of lean body mass, common manifestations of acute and chronic inflammatory conditions. In C57BL/6 female mice, the administration of TNF, IL-1, and, to a lesser extent, leukemia inhibitory factor (LIF), produced a prompt and dose-dependent increase in serum leptin levels and leptin mRNA expression in fat. IL-10, IL-4, ciliary neurotrophic factor, and IL-2, cytokines not known to induce anorexia or decrease food intake, had no effect on leptin gene expression or serum leptin levels. After administration of Escherichia coli lipopolysaccharide (LPS), leptin gene expression and leptin levels were increased. These findings suggest that leptin levels may be one mechanism by which anorexia is induced during acute inflammatory conditions.

Adipose Tissue↗

PubMed1997

Bilateral adrenalectomy for Cushing's syndrome. Anterior versus posterior surgical approach.

OBJECTIVE: This study evaluates the intraoperative and postoperative complications in patients with Cushing's syndrome who underwent bilateral adrenalectomy comparing the posterior or anterior operative approach. BACKGROUND: The posterior approach for bilateral adrenalectomy has been advocated over the anterior approach because of rapid recovery and decreased morbidity, but the long-term complications associated with each procedure are not well described. METHODS: The intraoperative profiles and morbidity in 48 patients undergoing bilateral adrenalectomy for Cushing's disease through either the anterior or posterior approach from 1985 to the present were reviewed comparing the intraoperative complication and early and late postoperative complication rate and morbidity. RESULTS: Twenty-seven patients underwent an anterior transabdominal procedure, whereas 21 underwent a posterior retroperitoneal procedure via bilateral incisions. Age, weight, and diagnostic categories of Cushing's syndrome were similar between the two groups as well as serum cortisol and 24-hour urinary cortisol levels. Operative time, estimated blood loss, and transfusion requirements were not different between the groups, even though adrenal glands excised through the anterior approach were significantly larger. Acute morbidity was similar between the groups. However, 17 (81%) of 21 patients who underwent posterior bilateral adrenalectomy suffered from chronic back pain, compared with 2 (7%) of 27 via the anterior approach. Five of these patients in the posterior group considered the pain incapacitating, and the mean time to return to work was significantly longer in the posterior group because of back pain. CONCLUSIONS: The anterior approach to bilateral adrenalectomy has comparable intraoperative complications and early morbidity compared to the posterior approach. The posterior approach has a very high incidence of chronic incision-related back pain. The anterior approach is the preferred open surgical technique in most patients undergoing bilateral adrenalectomy for Cushing's syndrome without other contraindications for undergoing laparotomy.

Adrenalectomy↗

PubMed1997

Fibrinolytic and coagulant responses to regional limb perfusions of tumor necrosis factor, interferon-gamma, and/or melphalan.

Regional limb perfusion with antineoplastic agents stresses the local vasculature in a variety of ways. However, by monitoring the perfusates from limbs treated with melphalan alone or with melphalan plus tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma), we were able to distinguish the effect of the cytokines on the observed coagulant and fibrinolytic responses. We collected samples of effluent from a series of lower extremities that were perfused with the cytokines and/or melphalan as treatment for localized melanoma. Both regimens produced statistically significant evidence of coagulant and fibrinolytic activation. However, limbs receiving cytokines in addition to the melphalan responded with a sharper rise in tissue plasminogen activator (tPA) and plasmin (plasmin-antiplasmin complexes [PAP]) than limbs treated with melphalan alone. Evidence of thrombin formation (prothrombin fragment 1 + 2 [F1 + 2], thrombin-antithrombin complexes [TAT]) was also greater when the cytokines were included, although the response was delayed and less consistent than the fibrinolytic activation.

Adult↗

PubMed1996

Treatment of peritoneal carcinomatosis by continuous hyperthermic peritoneal perfusion with cisplatin.

There is considerable clinical and experimental evidence to suggest that the intraperitoneal administration of cisplatin via continuous hyperthermic peritoneal perfusion (CHPP) has potential clinical efficacy. The treatment is ideally suited for patients with small-volume peritoneal implants but technically appears to provide the best method of uniformly distributing hyperthermia and chemotherapy to the entire peritoneal cavity. In addition, preclinical data suggest that clinically attainable temperatures and a relatively brief exposure are sufficient for significant cell killing. Further work exploring the possibility of combining biologic agents with chemotherapy in this setting or the use of systemic agents used in combination with CHPP is needed. The technique is also attractive because of the relative technical ease with which it can be administered. If initial phase I and phase II studies demonstrate a therapeutic effect using this approach, then clearly large-scale multiinstitutional phase III studies will be required to established its therapeutic potential.

Antineoplastic Agents↗

PubMed1996

Role of endogenous interferon gamma in murine tumor growth and tumor necrosis factor alpha antitumor efficacy.

BACKGROUND: The anticancer role of tumor necrosis factor-alpha (TNF-alpha) has been limited by toxicity. These experiments evaluate blocking endogenous interferon-gamma (IFN-gamma) activity to abrogate TNF-alpha toxicity. METHODS: C57B1/6 mice bearing MCA 105 tumor were treated with TNF-alpha and anti-IFN-gamma antibody (Ab) to evaluate the effect on the acute lethality of TNF-alpha and their efficacy as evaluated by tumor growth rate, tumor histology, and survival. RESULTS: Anti-IFN-gamma Ab decreased TNF-alpha lethality. Anti-IFN-gamma Ab alone increased tumor growth significantly more than did nonimmune IgG (p2 < 0.0001). Tumor-bearing mice that received nonimmune IgG and TNF-alpha had slower tumor growth (p2 < 0.02) and a trend toward improved survival (p = 0.07) compared with saline-treated controls. Anti-IFN-gamma Ab abrogated the antitumor effect of TNF-alpha, prevented acute tumor necrosis histologically, and resulted in tumor growth rate and host survival similar to that of controls. The findings in mice that received anti-IFN-gamma Ab and high-dose TNF-alpha were comparable with those in mice that received a lower, equitoxic dose of TNF-alpha alone. CONCLUSIONS: Blocking endogenous IFN-gamma accelerates tumor growth in this model and partially abrogates the toxic and antitumor activity of exogenous TNF-alpha equally. This suggests that blocking endogenous IFN-gamma activity is not a useful strategy for limiting TNF-alpha treatment toxicity.

Animals↗

PubMed1996

Macrophage-derived tumor necrosis factor and tumor-derived of leukemia inhibitory factor and interleukin-6: possible cellular mechanisms of cancer cachexia.

BACKGROUND: The cellular basis for augmented cytokine production in the tumor-bearing host is not known. Recently leukemia inhibitory factor (LIF) and interleukin (IL)-6, produced by a variety of tumors, have been implicated as mediators of cachexia. METHODS: Five murine tumor cell lines were tested for the production of these cytokines. 4JK tumor was further tested to determine if IL-1, tumor necrosis factor (TNF), or cocultivation with RAW 264 cells augmented IL-6 or LIF production. RESULTS: 4JK from in vivo tumors produced significantly more IL-6 than did 4JK from culture, indicating that tumor production of IL-6 and LIF is potentially augmented by infiltrating macrophages. When 4JK was cocultured with RAW 264 cells, TNF, or IL-1 in vitro, a three- to 15-fold increase in tumor production of LIF and IL-6 was noted (p2 < or = 0.03). Conversely, in coculture experiments performed with a neutralizing TNF antibody, a 50% reduction in tumor production of LIF ad IL-6 was noted (p2 < 0.04). Resting RAW cells produced only minimal quantities of TNF; however, when RAW cells were exposed to tumor-conditioned supernatant from 4JK, their TNF production was markedly increased. CONCLUSIONS: In the tumor microenvironment, host macrophages may be activated and produce inflammatory cytokines such as TNF. Local TNF then appears to act on tumor cells to stimulate production of IL-6 and LIF. Enhanced tumor production of cytokine mediators may contribute to deleterious effects of neoplastic growth on the host.

Animals↗

PubMed1996

Is reoperation for gastrinoma excision indicated in Zollinger-Ellison syndrome?

BACKGROUND: Surgical excision of gastrinomas in patients with Zollinger-Ellison syndrome (ZES) decreases the incidence of hepatic metastases, but long-term biochemical cures are achieved in fewer than 30% of cases. A growing number of patients have persistent or recurrent disease after initial operation. The effect of reoperation in these patients has not been previously reported. METHODS: From December 1982 to August 1995, 120 patients with ZES underwent operation for gastrinoma resection. Seventy-eight patients had recurrent or persistent ZES after operation; 17 patients underwent 18 reoperations. After initial operation all patients underwent yearly functional and imaging studies. If a tumor was unequivocally imaged, reexploration was done. RESULTS: Five patients, all with sporadic disease, were disease free after operation, with a median follow-up of 28 months. Tumor was found in all 18 reoperations and resected in 17. In patients with continuing disease-free intervals, locations of gastrinomas included pancreatic head lymph nodes (three), liver metastasis (one), and pancreatic tail lymph node (one). There were no deaths in the cured group; two patients in the group with persistent disease have died (median follow-up, 34 months). CONCLUSIONS: Reoperation for gastrinoma excision resulted in elimination of disease in 30% of patients and should be considered for patients with imageable disease.

Adult↗

PubMed1996

A prospective trial evaluating a standard approach to reoperation for missed parathyroid adenoma.

OBJECTIVES: The authors evaluate the results of preoperative imaging protocols and surgical re-exploration in a series of patients with missed parathyroid adenomas after failed procedures for primary hyperparathyroidism. BACKGROUND: The success rate is lower and the complication rate is increased in patients undergoing reoperation for primary hyperparathyroidism compared with initial procedures. Scarring and distortion of tissue planes plus the potential for ectopic gland location leads to this worsened outcome. METHODS: Two hundred eighty-eight consecutive patients with persistent/recurrent hyperparathyroidism were treated at a single institution after a failed procedure or procedures at outside institutions. Two hundred twenty-two of these patients (77%) were believed to have a missed single adenoma, and these patients underwent 228 operations and 227 preoperative work-ups. Preoperative evaluation consisted of a combination of four noninvasive imaging studies--neck ultrasound, nuclear medicine scan, neck and mediastinal computed tomography scan, and neck and mediastinal magnetic resonance imaging. Based on the noninvasive testing alone, 27% patients underwent surgery whereas the other patients underwent invasive studies, including selective angiography (58%), selective venous sampling for parathyroid hormone (43%), or percutaneous aspiration of suspicious lesions (15%). RESULTS: Abnormal parathyroid adenomas were found in 209 of 222 initial procedures and 6 of 6 second procedures, with an overall success rate in terms of resolution of hypercalcemia in 97% (215/222) of patients. The single most common site of missed adenoma glands was in the tracheal-esophageal groove in the posterior superior mediastinum (27%). The most common ectopic sites for parathyroid adenomas are thymus (17%), intrathyroidal (10%), undescended glands (8.6%), carotid sheath (3.6%), and the retroesophageal space (3.2%). The most sensitive and specific noninvasive imaging test is the sestamibi subtraction scan, with 67% true-positive and no false-positive results. The rate of true-positive and false-positive results for ultrasound, computed tomography, magnetic resonance imaging, and technetium thallium scans were 48%/21%, 52%/16%, 48%/14% and 42%/8%, respectively. The incidence of injury to the recurrent laryngeal nerve was 1.3%. CONCLUSIONS: A single missed parathyroid adenoma is the most common cause for a failed initial parathyroid operation. Appropriate use of preoperative imaging tests and knowledge of the potential location or parathyroid adenomas can lead to very high cure rates with minimal morbidity.

Adenoma↗

PubMed1996

Parathyroid adenomas in the aortopulmonary window.

PURPOSE: To describe localization studies in nine patients with ectopic parathyroid adenomas in the aortopulmonary window. MATERIALS AND METHODS: Nine patients with ectopic parathyroid tissue (eight adenomas, one hyperplastic gland) in the aortopulmonary window were examined with ultrasound (US), computed tomography (CT), magnetic resonance (MR) imaging, and scintigraphy. Diagnostic arteriography (n = 4) and venous sampling (n = 3) were performed in the first four patients; arteriography for the purpose of staining was attempted in the last five patients. RESULTS: The results of CT and MR imaging studies were positive in eight of nine patients (89%) and five of eight patients (63%), respectively. The results of thallium/technetium scintigraphy were negative in three patients scanned (0%), but the results of a repeat study in one patient were positive (33%). Sestamibi scans were positive in six of six patients (100%). Single photon emission CT was performed in all six patients and enabled distinction between adenomas in the aortopulmonary window and those in the thymus. CONCLUSION: Ectopic parathyroid glands in the aortopulmonary window are usually detected at sestamibi scintigraphy, and SPECT is helpful in distinguishing these adenomas from more common adenomas in the anterior mediastinum. CT and MR imaging studies can also enable this distinction, but imaging must extend below the aortic arch.

Adenoma↗

PubMed1996

Treatment of patients with melanoma of the extremity using hyperthermic isolated limb perfusion with melphalan, tumor necrosis factor, and interferon gamma: results of a tumor necrosis factor dose-escalation study.

PURPOSE: To evaluate response rates and systemic and regional toxicity of hyperthermic isolated limb perfusion (ILP) for treatment of in-transit metastases of extremity melanoma using escalating-dose tumor necrosis factor (TNF) in conjunction with melphalan and interferon gamma (IFN). PATIENTS AND METHODS: All patients received IFN 0.2 mg2 for 2 days followed by a 90-minute ILP with TNF and IFN (0.2 mg) given at time 0 and melphalan (10 mg/L limb volume) given at 30 minutes. Twenty-six patients were treated with 4 mg of TNF and 12 patients received 6 mg of TNF. All patients had assessable disease in the perfusion field and all but two patients were assessable for response at 1 month after treatment. RESULTS: Mean peak perfusate TNF levels in the 4-mg group were 4.8 micrograms/mL, compared with 7.4 micrograms/mL for the 6-mg group (P = .03). The complete response rate in the 4-mg TNF group was 76%, with an overall objective response rate of 92%, compared with 36% and 100% for the 6-mg group. Subgroup analyses showed that the lower complete response rate in the 6-mg TNF group was not explained by differences in disease burden or prior regional therapy. Systemic drug toxicity was short-lived, easily managed, and related to perfusate leak more than to TNF perfusate dose. Regional toxicity, particularly painful myopathy and neuropathy, was greater with the 6-mg dose level and was considered dose-limiting. CONCLUSION: ILP with 4 mg TNF, IFN, and melphalan can lead to complete local responses in the majority of patients with extremity melanoma. Escalating the TNF dose to 6 mg did not increase the complete response rate and increased regional toxicity.

Adult↗

PubMed1996

False-positive iodine-131 whole-body scans due to cholecystitis and sebaceous cyst.

False-positive whole-body 131I scans are not frequent but have serious consequences in the management of patients with thyroid cancer. They can be classified in four main groups: elimination of iodine in body fluids, infection or inflammation, cysts or transudates and nonthyroid tumors. We report on two patients with false-positive post-therapy 131I scans. The first patient had uptake projected in the right pelvic area which was later proven to be a large gluteal sebaceous cyst. The second patient had uptake in the gallbladder area that did not disappear after 131I treatment; she underwent exploratory laparotomy which revealed extensive chronic cholecystitis. These cases illustrate two new causes of false-positive 131I whole-body scans (sebaceous cyst and cholecystitis), which highlights two mechanisms (elimination in body fluid and inflammation).

Adenocarcinoma, Follicular↗

PubMed1995

Endogenous D-factor activity partially mediates the toxic but not the therapeutic effects of tumor necrosis factor.

We have earlier shown that passive immunization against differentiation-inducing factor/leukemia-inhibitory factor (D factor) activity improves the survival of endotoxemic mice, suggesting that D factor may contribute to the systemic toxicity associated with tumor necrosis factor (TNF). In the current experiments, TNF induced D-factor gene expression in various tissues of non-tumor-bearing female C57BI/6 mice. Passive immunization against D-factor significantly improved survival after a lethal TNF challenge in both non-tumor-bearing (p2 < 0.02) and tumor-bearing mice (p2 < 0.01). In mice bearing 10-day s.c. MCA 105 sarcomas, D-factor antibody alone had no effect on tumor growth as compared with control IgG. Tumor regression and regrowth in mice treated i.v. with TNF was not affected by pre-treatment with D-factor antibody, as compared with pre-treatment with IgG. However, TNF-treatment-related mortality was abrogated by pre-treatment with D-factor antibody (0% vs. 36% for IgG-pre-treated controls). These results indicate that endogenous D-factor activity contributes to the toxicity but not to the anti-tumor effects of TNF therapy. With renewed interest in the use of TNF for the treatment of patients with cancer, improved understanding of the role of D factor in mediating the effects of TNF may have important clinical benefits.

Animals↗

PubMed1995

Reductions in tissue plasminogen activator and thrombomodulin in blood draining veins damaged by venous access devices.

A frequent complication of venous access devices (VADs) is axillary-subclavian venous thrombosis. To study this problem we have compared blood drawn through VADs with peripheral blood samples in a group of oncology patients with venographically demonstrated venous damage (N = 14) and a group with normal venograms (N = 21). The samples were assayed for a battery of proteins believed to be involved in thrombogenesis. After approximately six weeks of catheterization the venographically abnormal patients had significantly less thrombomodulin (P = 0.0055) and significantly higher PAI:tPA (P = 0.022) in catheter-drawn samples as compared with the venographically normal group. Although the data are inconclusive, it is hypothesized that these changes resulted from local endothelial injury.

Adult↗

PubMed1995

Localization of insulinomas to regions of the pancreas by intra-arterial stimulation with calcium.

OBJECTIVE: To determine the sensitivity of calcium injected into pancreatic arteries in localizing insulin-secreting tumors to regions of the pancreas. DESIGN AND PATIENTS: To stimulate the release of insulin, 25 patients with surgically proven insulinomas (average diameter, 15 mm) had calcium gluconate (0.025 mEq Ca++/kg body weight) injected before surgery into the arteries supplying the pancreatic head (gastroduodenal and superior mesenteric arteries) and the body and tail (splenic artery) of the pancreas. SETTING: Tertiary referral hospital. MEASUREMENTS: Insulin levels were measured in samples taken from the right and left hepatic veins before and 30, 60, and 120 seconds after calcium injection. A twofold increase in insulin level in the sample taken from the right hepatic vein 30 or 60 seconds after injection localized the insulinoma to the segment of the pancreas supplied by the selectively injected artery. Localization done using calcium stimulation was compared with localization done using transcutaneous ultrasonography (n = 22), computed tomography (n = 23), magnetic resonance imaging (n = 21), arteriography (n = 25), and portal venous sampling (n = 9). RESULTS: Calcium stimulation localized 22 of 25 insulinomas (sensitivity, 88% [95% CI, 68% to 97%]) to the correct region of the pancreas. The sensitivities of the other imaging methods were 9% for ultrasonography (CI, 1% to 23%), 17% for computed tomography (CI, 5% to 39%), 43% for magnetic resonance imaging (CI, 22% to 66%), 36% for arteriography (CI, 18% to 57%), and 67% for portal venous sampling (CI, 30% to 93%). Calcium stimulation added only a few minutes to the time needed for pancreatic arteriography and caused no morbid conditions. CONCLUSION: Intra-arterial calcium stimulation with right hepatic vein sampling for insulin gradients is the most sensitive preoperative test for localizing insulinomas.

Adult↗

PubMed1995

Potential involvement of IL-10 in suppressing tumor-associated macrophages. Colon-26-derived prostaglandin E2 inhibits TNF-alpha release via a mechanism involving IL-10.

The administration of murine TNF-alpha to colon (C)-26 bearing mice, significantly protects the host against the catabolic effects of the tumor. This effect of exogenous TNF-alpha can be primarily attributed to tumor lysis rather than to a direct anticachectic action. Murine peritoneal macrophages cultured with the C-26 line or with C-26 culture supernatant do not release TNF-alpha in response to LPS stimulation. The reduction in TNF-alpha levels is associated with a significant increase in IL-10 levels. Single cell suspension of freshly disaggregated C-26 tumor (which contains host macrophages), do not produce TNF-alpha but contain significant levels of PGE2 and IL-10. In contrast, PGE2 but not TNF-alpha or IL-10 can be detected in the C-26.IVX cell line that is used to generate tumors in vivo. Neutralizing anti IL-10 Ab but not isotype-matched Ab, significantly reverses the inhibitory effect of the tumor cells and their culture supernatant on macrophage TNF-alpha release. Additional evidence is presented to indicate that the C-26-derived inhibitory activity is related to PGE2. Taken together, these results support the hypothesis that tumor-derived PGE2 prevents tumor-infiltrating macrophages from producing TNF-alpha, in part by augmenting macrophage IL-10 synthesis.

Animals↗

PubMed1995

Continuous intraoperative external monitoring of perfusate leak using iodine-131 human serum albumin during isolated perfusion of the liver and limbs.

Regional isolated perfusion using tumor necrosis factor (TNF) shows significant promise for treatment of cancer which is limited to limbs or organs. The high toxicity of TNF requires very sensitive real time monitoring of leakage in order to avoid serious patient complications. Human serum albumin labeled with iodine-131 is used with an externally mounted and collimated NaI(Tl) detector to track the leakage of blood from the isolated perfusion blood circuit into the general systemic vascular space. Blood activity levels measured using the monitor demonstrated a very good correlation with blood serum samples taken concurrently with external monitoring. External monitoring can reduce the risks of perfusion leakage intraoperatively with the precision necessary to safely perform isolated perfusion using TNF.

Chemotherapy, Cancer, Regional Perfusion↗

PubMed1995

Venographic surveillance of tunneled venous access devices in adult oncology patients.

BACKGROUND: Tunneled venous access devices (VADs) are often essential in the care of patients with advanced malignancies, but they carry an uncertain risk of thrombosis. METHODS: To determine the incidence of venoocclusion related to silicone VADs in a population of adult oncology patients, we prospectively studied 50 individuals with upper extremity venograms approximately 6 weeks after their VADs had been implanted. Twenty-one of these patients were reevaluated with venograms approximately 12 weeks after catheterization. In addition, venograms were performed on a separate group of 24 patients who needed catheterization of axillary-subclavian veins that had been catheterized in the past. RESULTS: The 6-week venograms in the prospective study showed partial venous obstruction in 15 patients (30%), whereas three (6%) had developed symptomatic total venoocclusion by this time. The 12-week venograms showed two additional complete occlusions. Venograms of 30 previously catheterized veins showed complete venoocclusion in nine (30%), although only two had a history of thrombosis. CONCLUSIONS: Our observations indicate that VADs frequently cause partial venoocclusion within the first 6 weeks of catheterization and that permanent venous damage from VADs is common, even without a history of VAD-related thrombosis.

Adult↗

PubMed1995

Cachexia-anorexia-asthenia.

The National Cancer Institute (Canada) sponsored a workshop on symptom control in Banff, Alberta, in October 1993. This article reports on the workshop recommendations for research on one symptom complex, the cachexia-anorexia-asthenia syndrome. In addition to encouraging study generation, the recommendations provide a baseline for assessing the scope and strength of future Canadian research initiatives on cachexia-anorexia-asthenia.

Anorexia↗