Biomedical subjects

G M Doherty

Publications and source records attributed to G M Doherty.

At least 37 records · Page 2Linked to original sources

PubMed1998

Lethality of multiple endocrine neoplasia type I.

The lethality of the endocrine tumors associated with multiple endocrine neoplasia type I (MEN-I), particularly the pancreatic islet cell tumors, has been controversial. We evaluated the cause and age of death in MEN-I kindreds. Our database contains 34 distinct kindreds with 1838 members. Reliable death data are available for 103 people (excluding accidents and age < 18 years). We compared survival curves of MEN-I patients who died from causes related to MEN-I with those from MEN-I carriers who died from a nonendocrine cause and unaffected kindred members. We also compared ages of death between affected and unaffected members of MEN-I kindreds. Of 59 MEN-I-affected patients, 27 died directly of MEN-I-specific illness and 32 of non-MEN-I causes. The MEN-I-specific deaths occurred at a younger age (median 47 years) than either MEN-I patients whose death was from some nonendocrine cause (median 60 years, p < 0.02) or than all kindred members who did not die of MEN-I disease (median 55 years, p < 0.05). The causes of death of the MEN-I patients included islet cell tumor (n = 12), ulcer disease (n = 6), hypercalcemia/uremia (n = 3), carcinoid tumor (n = 6), and nonendocrine malignancies (n = 9). There was no difference in survival between MEN-I carriers and unaffected kindred members. Of our MEN-I patients, 46% died from causes related to their endocrine tumors after a median age of 47 years, which was younger than family members who did not die from these tumors. Pancreatic islet cell tumors were the most common cause of death of MEN-I patients. Management of kindreds with MEN-I should include an aggressive screening program with early therapeutic intervention when a tumor is identified.

Adult↗

PubMed1998

Prospective study of the utility of somatostatin-receptor scintigraphy in the evaluation of patients with multiple endocrine neoplasia type 1.

BACKGROUND: Neuroendocrine tumors (NETs) are a potentially lethal component of multiple endocrine neoplasia type 1 (MEN 1). Somatostatin receptor scintigraphy (SRS) can be used to localize NETs and evaluate patients for extraduodenopancreatic disease; its utility in managing MEN 1 is undefined. METHODS: All patients with MEN 1 evaluated by SRS from April 1994 to November 1997 are reported. SRS findings were correlated with other imaging studies and operative findings. RESULTS: Thirty-seven SRS studies were performed in 29 patients with MEN 1. SRS identified occult tumor in 36% (4/11) of patients with only biochemical evidence of NET; 2 patients went on to resection. SRS showed tumor in 79% (15/19) of patients with computed tomography (CT)-demonstrated tumor; 30% (6/20) of the SRS lesions were occult on CT. Conversely, 55% (16/29) of CT-identified lesions were occult on SRS. SRS found distant disease in 21% (6/29) of patients. In patients who had previous operations, SRS found tumor in 40% (4/10) of patients, again with both new positive and false-negative results compared with other imaging. SRS also had 3 important false-positive results, including 1 patient who had laparotomy with no tumor identified. CONCLUSIONS: SRS is useful in identifying otherwise occult NETs in patients with MEN 1 and can substantially alter management. However, SRS also has significant false-positive and false-negative results that demand correlation with other studies.

Adult↗

PubMed1998

Pancreatic islet cell tumor metastasis in multiple endocrine neoplasia type 1: correlation with primary tumor size.

BACKGROUND: Islet cell tumor (ICT) metastasis is one of the potentially lethal outcomes of multiple endocrine neoplasia type 1 (MEN 1). Management of ICT in patients with MEN 1 is controversial; some advocate resection based on biochemical evidence of progression, whereas others use tumor size to predict the risk of metastasis and the need for resection. This study correlates the size of primary ICT with the presence of metastases. METHODS: Forty-eight patients with MEN 1 with ICT, from 34 kindreds followed up in our multiple endocrine neoplasia program, were evaluated; 43 of the 48 have been explored for ICT. Metastases to the lymph nodes and liver were documented. RESULTS: Thirty-three percent of patients with pancreatic tumors less than 1 cm in greatest diameter had metastatic disease at surgery and in follow-up, whereas 34.8% of patients with tumors greater than 2 cm in diameter had metastases to lymph nodes or liver. The 2 patients with liver metastases each had primary tumors greater than 2 cm. Follow-up revealed subsequent metastasis in 1 patient. CONCLUSIONS: The size of primary tumors in MEN 1 does not correlate with metastatic potential. This is not a good criterion for exploration. Continued follow-up of these patients will be necessary to define the effect of operation on the course of ICT in MEN 1.

Adenoma, Islet Cell↗

PubMed1998

Surgical treatment of localized gastrinoma within the liver: a prospective study.

BACKGROUND: Studies demonstrate that liver metastases of gastrinoma significantly reduce survival. METHODS: Since 1982 we have prospectively studied 213 patients with Zollinger-Ellison syndrome. For this report the results of surgery for localized liver gastrinoma were analyzed. RESULTS: Zollinger-Ellison syndrome was diagnosed biochemically in all patients and acid output was controlled with medications. Imaging studies demonstrated liver gastrinoma in 69 patients (32%). Fifty-two had diffuse unresectable disease, whereas 17 (10%) had localized disease. All patients with localized liver gastrinoma and 2 patients with diffuse disease who needed surgery are the subject of this report. Major hepatic lobectomy was performed in 10 patients and wedge resections in 9. Three patients had apparent liver primary gastrinomas and 16 had metastatic disease. Seventeen of 19 patients were able to have all identifiable gastrinoma resected. Extrahepatic tumor was also removed at the same procedure. Extirpation of liver gastrinoma required hepatic lobectomy in 10 patients and wedge resections in the others. Five-year survival was 85%. Five of 17 completely resected patients (29%) remained disease free. CONCLUSIONS: Resectable localized liver gastrinoma is rare. Primary liver gastrinomas can occur. Surgical resection of localized liver gastrinoma provides a cure rate similar to that of extrahepatic gastrinoma and an excellent long-term survival.

Female↗

PubMed1997

IFN regulatory factor-1 gene transfer into an aggressive, nonimmunogenic sarcoma suppresses the malignant phenotype and enhances immunogenicity in syngeneic mice.

IFN-gamma has a direct antitumor effect on many tumor cell lines mediated through the IFN-gammaR. One effect of IFN-gamma is to induce the nuclear transcription factor IFN regulatory factor-1 (IRF-1), which may function as a tumor suppressor. In this study, mouse IRF-1 cDNA under a high constitutive expression promoter was transfected into the highly aggressive, nonimmunogenic MCA 101 murine sarcoma. Clones were obtained by G418 selection and screened for IRF-1 mRNA expression by reverse transcriptase-PCR (RT-PCR). High expression clones had high levels of two MHC class I proteins (H-2Kb and H-2Db) on the cell surface that correlated with increased levels of class I mRNA by RT-PCR. Furthermore, these clones also had increased levels of MHC class II protein (I-Ab), which correlated with increased levels of one subunit of class II mRNA by RT-PCR. IRF-1-expressing clones had markedly diminished cell growth in vitro and decreased anchorage-independent growth in a soft agar assay. These clones also demonstrated markedly prolonged tumor latency and slowed growth in syngeneic C57BL/6 mice. IRF-1 gene-transfected cells had shortened tumor latency and formed faster growing tumors in gamma-irradiated immunodeficient mice compared with results in immunocompetent mice. Mice immunized with IRF-1-transfected cells were protected against subsequent challenge with IRF-1 transfected cells and also demonstrated greater tumor latency and slower tumor growth against subsequent challenge with untransfected cells compared with mice immunized with empty vector-transfected cells. These studies demonstrate a tumor suppressor effect of IRF-1, which acts in vivo through both partial reversion of the malignant phenotype and enhanced immune recognition and may play a role in the antitumor effects of IFN-gamma.

Animals↗

PubMed1997

Underlying pathology in mammary Paget's disease.

BACKGROUND: Management of patients with mammary Paget's disease is controversial; recent recommendations range from primary radiotherapy to modified radical mastectomy. This review correlates associated breast findings with disease stage and outcome to help guide evaluation and treatment. METHODS: Retrospective review of clinical, mammographic and pathologic data from 38 women with mammary Paget's disease treated between 1979 and 1995 was performed. Mastectomies were performed on all but two patients with the entire breast and lymph nodes evaluated for histopathologic evidence of carcinoma. RESULTS: Underlying carcinoma (ductal carcinoma in situ and/or invasive ductal cancer) was found in most patients (92%) even when no palpable mass was evident (85%); this carcinoma is often multifocal (73%). Mammography fails to identify the underlying disease in many patients with no palpable mass and multifocal underlying disease (64%). Patients with Paget's disease and a palpable mass have a much greater incidence of invasive cancer, multifocal lesions, and positive lymph nodes, and have worse survival. CONCLUSIONS: Although some patients with Paget's disease might be well treated by breast conservation therapy, many patients have underlying multifocal carcinoma (including invasive cancer), which can be inapparent by examination and mammography. Selecting candidates with disease amenable to complete excision without mastectomy is problematic.

Adult↗

PubMed1997

Pancreatic polypeptide is a useful plasma marker for radiographically evident pancreatic islet cell tumors in patients with multiple endocrine neoplasia type 1.

BACKGROUND: The usefulness of human pancreatic polypeptide (hPP) as a plasma marker for islet cell neoplasms is controversial. We sought to determine the relation between fasting plasma hPP levels and radiographically detectable pancreatic islet cell tumors in patients with multiple endocrine neoplasia type 1 (MEN 1). METHODS: Fasting plasma hPP levels were measured prospectively in 202 individuals from 31 independent kindreds with MEN 1. Plasma levels greater than 3.0 times the normal age-specific values were defined as elevated. Patients with elevated plasma hPP levels were evaluated with computed tomographic scanning and magnetic resonance imaging, octreotide scanning, or selective angiography. RESULTS: Twenty-two patients had elevated fasting plasma hPP levels, and 20 of these patients were evaluated radiographically. Pancreatic lesions were detected in 19 patients. A group of eight patients with normal basal fasting plasma hPP levels were evaluated with computed tomography, magnetic resonance imaging, octreotide scanning, or selective angiography based on clinical presentation. One patient in this group had an imaging study that was positive for a pancreatic lesion. CONCLUSIONS: The presence of a markedly elevated fasting plasma hPP level in patients with MEN 1 is 95% sensitive and 88% specific for the presence of radiographically detectable pancreatic islet cell tumors.

Adenoma, Islet Cell↗

PubMed1997

Prospective study of provocative angiograms to localize functional islet cell tumors of the pancreas.

BACKGROUND: Controversy exists concerning the use of preoperative imaging studies in patients with islet cell tumors. Since 1993 we have evaluated the use of provocative angiography in patients with insulinoma or Zollinger-Ellison syndrome (ZES). METHODS: Twelve patients with a working diagnosis of insulinoma (n = 4) or ZES (n = 8) were studied. Of the eight patients with ZES, four were known to have multiple endocrine neoplasia type 1. All patients underwent conventional imaging studies followed by provocative angiography. Angiograms were graded based on the ability to detect tumor and regionalize it within the pancreas. RESULTS: Of the three patients with a working diagnosis of ZES but equivocal results of biochemical studies, none had arteriographic imaging of an islet cell tumor or a positive provocative study result (true negative result). Of the nine patients with documented islet cell tumor, seven (78%) underwent arteriographic imaging of the tumor and eight (89%) had correct regional localization by provocative angiography. Sensitivity and specificity for imaging were 78% and 100%, respectively, and for regional localization 89% and 100%, respectively. CONCLUSIONS: Provocative angiography is the localization study of choice for both gastrinoma and insulinoma. Having few false-negative results, it can be used to corroborate the diagnosis and, having few false-positive results, it detects tumor and biochemically confirms localization in nearly every patient.

Adenoma, Islet Cell↗

PubMed1997

Staging laparoscopy with laparoscopic ultrasonography: optimizing resectability in hepatobiliary and pancreatic malignancy.

BACKGROUND: Open laparotomy has traditionally been required to stage hepatobiliary and pancreatic (HBP) cancers accurately. For unresectable patients, costs and morbidity have been high. Today, laparoscopy alone or combined with laparoscopic ultrasonography (LUS) is being examined for its value in defining the extent of malignancy. STUDY DESIGN: We have analyzed the effect of routine implementation of this new staging technique in our HBP center. Staging laparoscopy (SL) with LUS was performed in 50 consecutive patients with HBP malignancies. All patients were considered to have resectable tumors as determined by traditional preoperative staging modalities. Primary tumors were located in the liver (n = 7), biliary tract (n = 11), or pancreas (n = 32). An average of 2.7 preoperative studies per patient were performed prior to SL-LUS. RESULTS: Staging laparoscopy with laparoscopic ultrasonography predicted resectable tumors in 28 patients (56%). At laparotomy, 26 of 28 were actually resectable: the false-negative rate was 4%. Staging laparoscopy with laparoscopic ultrasonography indicated unresectability in 22 patients (44%). Staging laparoscopy alone demonstrated previously unrecognized occult metastases in 11 patients (22%). In 11 other patients (22%) in whom SL alone was negative, LUS established unresectability from vascular invasion (n = 5), lymph node metastases (n = 5), or intraparenchymal hepatic tumor (n = 1). All cases of unresectability due to vascular invasion were validated by laparotomy. Five of six lymph node or hepatic metastases were proved histologically by LUS-guided needle biopsy rather than laparotomy. CONCLUSIONS: Unnecessary laparotomy can be safely avoided by SL-LUS in many patients with HPB malignancies, reducing costs and morbidity.

Adult↗

PubMed1996

Endogenous interferon-gamma acts directly on tumor cells in vivo to suppress growth.

BACKGROUND: Recent evidence implicates endogenous interferon-gamma (IFN-gamma) in the host response to an immunogenic tumor (MCA105); antibody blockade of host IFN-gamma increased tumor growth rate (Doherty et al., Ann. Surg. Oncol. 3: 198-203, 1996). Those experiments did not attempt to determine the site of IFN-gamma activity (the host, the tumor, or both). MATERIALS AND METHODS: MCA101 murine tumor cells were transfected with a plasmid expression vector containing an antisense construct to the IFN-gamma receptor (IFN-gamma R) or a control construct. Clones were isolated and tested for IFN-gamma stimulation of MHC I expression, sensitivity to IFN-gamma growth effects in vitro, and specific [125I]IFN-gamma binding. RESULTS: The antisense strategy was successful in decreasing the number of cell-surface IFN-gamma binding sites and in vitro response to IFN-gamma. Finally, in vivo experiments demonstrated significantly increased untransfected tumor growth rate in animals after blockade of endogenous IFN-gamma by a single dose of anti-IFN-gamma antibody and more rapid growth of the IFN-gamma R-deficient cells compared to controls. CONCLUSION: endogenous IFN-gamma has a direct effect on this less immunogenic tumor in vivo, which serves to slow growth and which is, at least partially, mediated through interferon-gamma receptors on the tumor cell.

Animals↗

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

Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A.

BACKGROUND: The surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A (MEN 2A) is controversial. We report the long-term follow-up, mutational analysis, and surgical outcome in a large group of patients with MEN 2A and hyperparathyroidism. METHODS: Clinical and genetic data for MEN 2A patients with biochemically and pathologically confirmed hyperparathyroidism and a minimum of 5 years of follow-up were analyzed retrospectively, and outcomes after surgical management were compared. RESULTS: Thirty-five (29%) of 119 patients from 14 MEN 2A kindreds had biochemical and pathologic evidence of hyperparathyroidism, with a mean follow-up of 14.7 years. The phenotypic expression of hyperparathyroidism was associated with germline mutations of the RET protooncogene at codons 634 and 618. At initial operation, 21 (62%) patients had a selective resection, eight (24%) had a subtotal resection, five (14%) had total parathyroidectomy with autotransplantation, and one had an inadvertent total parathyroidectomy. Twenty-seven (77%) patients were cured by the first operation. Persistent hyperparathyroidism occurred in three (8.6%) patients, and recurrent hyperparathyroidism occurred in five (14.3%) patients; both occurred only in patients treated with selective or subtotal resection. Permanent postoperative hypoparathyroidism occurred in six (21%) of 29 patients after selective or subtotal resection, in the one patient with inadvertent total parathyroidectomy, and in one (20%) of 5 patients treated with total parathyroidectomy and autotransplantation. CONCLUSIONS: Recurrent or persistent hyperparathyroidism occurs after selective or subtotal parathyroidectomy, as a result of either missed glands or interval development of neoplasia in previously normal parathyroid glands left in situ. Therefore we advocate total parathyroidectomy and heterotopic autotransplantation for patients with hyperparathyroidism and MEN 2A.

Adolescent↗

PubMed1996

Evaluation of somatostatin-receptor scintigraphy for detecting neuroendocrine tumors.

BACKGROUND: Somatostatin-receptor scintigraphy (SRS) has gained attention as an imaging modality for neuroendocrine tumors (NETs). The purpose of this study was to present one of the first American series evaluating the ability of SRS to detect local and distant disease caused by NETs. METHODS: Medical records were reviewed from 35 patients who underwent a total of 38 studies using 111In-pentetreotide between 1993 and 1995. Twenty-two patients had islet cell tumors, seven had carcinoid tumors, and six had other NETs. RESULTS: The overall sensitivity of SRS was 74% for detecting local disease (primary tumor +/- regional lymph node metastases) in all NETs, excluding insulinoma, 75% in gastrinoma, 0% in insulinoma, 78% in other islet cell tumors, and 50% in carcinoids. For detecting distant disease, the overall sensitivity of SRS was 67% for all NETs, excluding insulinoma, 100% for gastrinoma, 50% for other islet cell tumors, and 80% for carcinoids. Specificity and positive predictive value were 100% for all tumors. Negative predictive value ranged from 33% to 100%. CONCLUSIONS: A positive SRS study strongly predicts the presence of tumor (100% positive predictive value in our study). However, unlike the European reports of very high sensitivity (80% to 88%), we found that SRS had a lower sensitivity (67% for all NETs excluding insulinoma and 71% for noninsulinoma gastroenteropancreatic NETs). Thus negative SRS in patients with NETs must be viewed cautiously, because the false-negative rate is high, and this limits the use of this method in the most difficult patients.

Adenoma, Islet Cell↗

PubMed1996

Mammographically detected breast cancer. Benefits of stereotactic core versus wire localization biopsy.

OBJECTIVE: The authors evaluated the differences between stereotactic core needle biopsy (SCNBx) and needle localization surgical biopsy (NLBx) in cost and treatment course for patients with mammographically detected breast cancer. SUMMARY BACKGROUND DATA: Stereotactic core needle breast biopsy is a reproducible and reliable alternative to surgical biopsy for histologic diagnosis of mammographic lesions. METHODS: Records from 52 consecutive patients with invasive breast cancer diagnosed by SCNBx (n = 21) or NLBx (n = 31) over 2 years were reviewed. Episode-of-care costs were extracted from the Barnes Hospital billing system database. RESULTS: At the time of excision, surgical margins were statistically more frequently positive in patients treated with NLBx (55%) than patients treated with SCNBx (0%, p < 0.0001). Furthermore, patients in the NLBx group undergoing breast conservation surgery required re-excision more frequently (74%) than those in the SCNBx group (0%, p = 0.001). There were no complications in either group after the diagnostic procedure. All SCNBx results were correct in the diagnosis of invasive breast cancer. The median cost of SCNBx was approximately $1000 less than the median cost of NLBx. This cost difference was carried through the definitive procedure, whether it was breast conservation or mastectomy. CONCLUSIONS: This study shows the advantage of SCNBx to diagnose breast cancer and definitive operative care at a single procedure. The preoperative diagnosis of breast cancer eliminated positive operative margins and procedures to re-excise breast tissue. The use of SCNBx also saved approximately $1000 per patient compared with the use of NLBx. Our data suggest that SCNBx is the diagnostic procedure of choice for mammographically detected cancers.

Adenocarcinoma↗

PubMed1996

Laparoscopic adrenalectomy compared to open adrenalectomy for benign adrenal neoplasms.

BACKGROUND: Laparoscopic adrenalectomy has recently been used for removing a variety of adrenal neoplasms. The purpose of the present study was to compare results and outcomes in patients who underwent either laparoscopic or open adrenalectomy at our institution from 1988 to the present. STUDY DESIGN: The records of 66 consecutive patients with benign adrenal neoplasms who underwent adrenalectomy from 1988 through 1995 were retrospectively reviewed. Patients were divided into three groups based on the operative approach: group I (n = 25), open anterior transabdominal approach; group II (n = 17), open posterior retroperitoneal approach; and group III (n = 24), laparoscopic transabdominal flank approach. Various parameters were compared and statistical analyses were performed. RESULTS: The three groups were similar in age, gender, American Society of Anesthesiologists class, and distribution of unilateral compared with bilateral adrenalectomy. Mean tumor size was slightly larger in group I (3.4 +/- 1.4 cm) than in group II (2.4 +/- 1.4 cm) or group III (2.7 +/- 1.4 cm) (p = NS). Mean operative times for unilateral adrenalectomy were 142 +/- 38 minutes in group I, 136 +/- 34 minutes in group II, and 183 +/- 35 minutes in group III (p < 0.001, groups I and II compared with group III). For bilateral adrenalectomy, mean operative times were 205 +/- 71 minutes (group I), 328 +/- 11 minutes (group II), and 422 +/- 77 minutes (group III). Patients who underwent laparoscopic adrenalectomy had significantly less operative blood loss (mean, 104 mL compared to 408 mL in group I and 366 mL in group II, p < 0.001) and a lower incidence of perioperative blood transfusion. Laparoscopic adrenalectomy was also associated with significantly reduced parenteral pain medication requirements (p < or = 0.001) and more rapid resumption of a regular diet (p < or = 0.01) compared to open adrenalectomy. Postoperative length of stay was significantly longer in group I (8.7 +/- 4.5 days) and in group II (6.2 +/- 3.9 days) after open adrenalectomy than after laparoscopic adrenalectomy (3.2 +/- 0.9 days) (p < 0.01). Total hospital charges were similar for groups II and III but somewhat higher for group I. Patients were able to resume 100 percent activity an average of 10.6 +/- 4.9 days after laparoscopic adrenalectomy and returned to work a mean of 16.0 +/- 6.1 days postoperatively. CONCLUSIONS: Laparoscopic adrenalectomy is a safe and effective procedure and has several advantages over open adrenalectomy. Laparoscopic adrenalectomy should become the preferred operative approach for the treatment of patients with small, benign adrenal neoplasms.

Adrenal Gland Neoplasms↗

PubMed1995

Prolongation of skin allografts by recombinant tumor necrosis factor and interleukin-1.

OBJECTIVE: The hypothesis is that systemic administration of recombinant tumor necrosis factor-alpha (TNF-alpha) and/or recombinant interleukin-1 alpha (IL-1 alpha) can decrease the rejection of a skin allograft. SUMMARY BACKGROUND DATA: Tumor necrosis factor and IL-1 are pluripotent cytokine hormones that are central to the host immunologic response to foreign substances. Cytokine effects and toxicity may be reduced by systemic administration of recombinant cytokines. The authors previously have demonstrated that pretreatment with cytokines such as IL-1 or TNF can reduce the lethality of endotoxin (lipopolysaccharide), gram-negative sepsis, cancer cachexia, and oxygen toxicity. METHODS: Skin grafts from the tails of Balb/c mice were placed on the backs of C57Bl/6 mice. Mice were treated with daily intraperitoneal saline, recombinant m-TNF (Genentech, South San Francisco, CA) or h-IL-1 (Hoffman LaRoche, Nutley, NJ) from postgraft day 1 to postgraft day 28. Tumor necrosis factor and IL-1 high doses were chosen because they protected mice from the lethality of lipopolysaccharide. Animals were examined daily for toxicity and graft rejection. Graft survival was plotted in a Kaplan-Meier plot and analyzed by the log-rank test. Comparison of proportions was done using the Fisher's exact test. RESULTS: Either TNF or IL-1 alone significantly prolonged skin graft survival compared with saline control. Furthermore, the combination of TNF and IL-1 prolonged skin graft survival longer than either cytokine alone. Mice on the highest dose TNF and IL-1 combination did not reject skin grafts during the 28-day treatment period. Significant toxicity was associated with cytokine treatment. Similar significant proportions of death occurred with IL-1 alone and the highest combination of TNF and IL-1. CONCLUSION: Both TNF and IL-1 can be effective as suppressors of skin allograft rejection in mice.

Animals↗

PubMed1994

Cost of unsuccessful surgery for primary hyperparathyroidism.

BACKGROUND: Surgery for primary hyperparathyroidism demands skill and experience. The monetary and personal costs of unsuccessful surgery are investigated here. METHODS: We reviewed 47 consecutive patients operated on by one surgeon during a period of 16 months, including their clinical data and medical costs of their treatment. RESULTS: All 39 patients without previous operation were normocalcemic after operation, with no recurrent nerve injury nor hypoparathyroidism. Of the eight who had undergone previous operation elsewhere, seven had abnormal glands that should have been resected at the initial operation, and hypoparathyroidism developed in two patients. Total costs of reoperative parathyroid surgery were more than twice the cost of an initial operation (median, $8383 versus $3948, p < 0.001) because of the cost of radiologic studies (median, $3378 versus $43, p < 0.001). CONCLUSIONS: (1) An experienced parathyroid surgeon can consistently cure hyperparathyroidism at the initial operation. (2) The majority of patients referred for hyperparathyroidism not cured by previous operation have glands in usual anatomic locations. (3) The cost to the patient of an inadequate initial operation includes the physical effects of remaining hyperparathyroid, additional time off work, potentially invasive localization testing, reoperative surgery with increased risk of complications, and substantial expense. Initial parathyroid surgery should be performed by surgeons experienced and proficient in its practice.

Adult↗

PubMed1993

13C-n.m.r. of the cyanylated apoflavodoxin and flavodoxin from Clostridium pasteurianum.

The thiol group of the flavodoxin from Clostridium pasteurianum has been cyanylated in a single step using [cyanato-13C]2-nitro-5-thiocyanatobenzoic acid. This chemical modification increases the dissociation constant of the apoflavodoxin-FMN complex 10-fold from 0.33 +/- 0.15 nM to 2.9 +/- 1.3 nM. The thiocyanate carbons of the cyanylated cysteine residue of apoflavodoxin and flavodoxin had chemical shift values of 114.7 and 112.3 p.p.m. respectively. From these chemical shifts we conclude that the binding of FMN by the cyanylated apoflavodoxin causes a decrease in the polarity and/or hydrogen bonding capacity of the environment of the thiocyanate group. We compare these results with those obtained from similar studies on the cyanylated apoflavodoxin and flavodoxin from Megasphaera elsdenii and we discuss how FMN binding and cyanylation perturb the structures of apoflavodoxins from Megasphaera elsdenii and Clostridium pasteurianum.

Apoproteins↗