bluuebunny/crossref_metadata_2025 huggingface dataset:
Thyroid Cancer Detected by Ultrasound‐Guided Fine‐Needle Aspiration Biopsy
Authors: Yokozawa Tamotsu , Fukata Shuji , Kuma Kanji , Matsuzuka Fumio , Kobayashi Akira , Hirai Keisuke , Miyauchi Akira , Sugawara Masahiro
Published: August 2002

A greater percentage of thyroid cancers can be detected by ultrasound‐guided fine‐needle aspiration biopsy (UG‐FNAB) than by ordinary FNAB. A group of 678 patients were selected sequentially as having been diagnosed with benign nodules by the conventional FNAB method. We reexamined these patients by UG‐FNAB and investigated the types of thyroid cancer that were missed by the conventional FNAB. Of the 678 patients diagnosed with benign nodules (using conventional FNAB), 571 (84.2%) demonstrated the same diagnosis when UG‐FNAB was used. The remaining 107 patients (15.8%) studied were suspected of having a malignancy after UG‐FNAB had been performed. Surgical specimen histology proved thyroid cancer in 99 of the 107 patients: 93 had papillary carcinoma, 4 had follicular carcinoma, 1 had medullary carcinoma and 1 had anaplastic carcinoma. Two drawbacks were noted when conventional FNAB was used: (1) cancer lesions difficult to palpate (n= 55) (e.g., small cancers with or without benign lesions or cancers associated with Hashimoto's thyroiditis or Graves’ disease); and (2) palpable cancers with insufficient cell material for analysis (n= 44) (e.g., cystic carcinoma and cancers with calcified lesions. UG‐FNAB is a powerful technique for detecting microcancers, cystic carcinomas, cancers associated with benign nodules, Hashimoto's thyroiditis, or coarse calcifications.
Islet Cell Carcinoma of the Pancreas
Authors: Lo Chung Yau , van Heerden Jon A. , Thompson Geoffrey B. , Grant Clive S. , Söreide Jon Arne , Harmsen William S.
Published: August 2002

Islet cell carcinoma (ICC) of the pancreas is a rare, indolent malignancy associated with higher resectability rate and better survival than ductal carcinoma. This retrospective study presents results of surgical treatment from a single institution. From 1985 through 1993 a total of 64 patients (36 men, 28 women) were surgically treated for ICC. Ages ranged from 22 to 80 years (median 55 years) with a median postoperative follow‐up of 39 months (range 10–97 months). Of the 64 patients, 30 (47%) had functioning and 34 (53%) nonfunctioning tumors. Gastrinoma (n= 11) followed by glucagonoma (n= 6) and insulinoma (n= 4) were the most common functioning tumors. In the patients undergoing a laboratory study, 67% of the nonfunctioning tumors had elevated peptide hormone levels. Potentially curative resections were performed in 17 patients (26%), palliative procedures in 35 (55%), and exploratory laparotomy alone in 12 (19%). One patient (2%) died within 30 days after operation. Symptomatic improvement was achieved in 96% of patients with a mean duration of 22 months. Three‐ and five‐year survivals were 66% and 49%, respectively. In patients with curative resection, the disease‐free survival at 3 years was 53% (95% CI: 32–86%). The presence of diffuse hepatic metastases was a predictor of poor survival at 3 years (74% versus 58%;p= 0.05); there was no statistically significant difference in survival between functioning and nonfunctioning groups (p> 0.1). Although curative resection for ICC is rare, meaningful palliation can be achieved in most patients with rare mortality and acceptable morbidity.
Gastric Smooth Muscle Tumors: Diagnostic Dilemmas and Factors Affecting Outcome
Authors: Sanders Laura , Silverman Mark , Rossi Ricardo , Braasch John , Munson Lawrence
Published: August 2002

We reviewed the 46 gastric stromal tumors that were treated at our institution between 1958 and 1992. The most common presenting symptoms were gastrointestinal bleeding, pain, and fatigue or malaise. The tumors ranged from 4 to 150 mm, with surgery most often being a wedge excision or partial gastrectomy. Abdominal computed tomography was the most specific diagnostic test obtained preoperatively. Factors associated with decreased survival included size ≥ 8 cm (p= 0.02), more than 0–3 mitoses per 10 HPF (p< 0.001), positive margins or unresectability (p= 0.008), and tumor pathologic grade II or more (p= 0.004). These tumors have an unpredictable behavior. Surgical resection with negative margins remains the best therapy, but resection for palliation is sometimes indicated as it can be associated with prolonged survival.
Recurrence after resection for ductal adenocarcinoma of the pancreas
Authors: Sperti Cosimo , Pasquali Claudio , Piccoli Antonio , Pedrazzoli Sergio
Published: August 2002

We analyzed the pattern of failure and clinicopathologic factors influencing the disease‐free survival of 78 patients who died after macroscopic curative resection for pancreatic cancer. Local recurrence was a component of failure in 56 patients (71.8%) and hepatic recurrence in 48 (61.5%), both accounting for 97% of the total recurrence rate. About 95% of recurrences occurred by 24 months after operation. Median disease‐free survival time was 8 months, and cumulative 1‐, 3‐, and 5‐year actuarial disease‐free survival rates were 66%, 7%, and 3%, respectively. Multivariate analysis showed that tumor grade (p = 0.04), microscopic radicality of resection (p = 0.04), lymph node status (p = 0.01), and size of the tumor (p = 0.005) were independent predictors of disease‐free survival. Patterns of failure and disease‐free survival were not statistically influenced by the type of surgical procedure performed. Median survival time from the detection of recurrence until death was 7 months for local recurrence versus 3 months for hepatic or local plus hepatic recurrence (p < 0.05). From our experience and the data collected from the literature, it appears that surgery alone is an inadequate treatment for cure in patients with pancreatic carcinoma. Effective adjuvant therapies are needed to improve locoregional control of pancreatic cancer after surgical resection.
Accuracy of Current Educational Literature on the Staging of Gastric Carcinoma
Authors: Fung Anthony S.Y.
Published: August 2002

Staging of gastric adenocarcinoma is important for comparing aspects of the disease in Asia and in the Western countries, and it may be used to direct the treatment strategy. A survey of 13 popular current surgical textbooks and review journals found a high level of inaccuracy. Two texts (15%) did not mention any staging systems, and one (8%) described a nonstandard system. Three (23%) described staging systems that were out of date, and six descriptions (46%) were inaccurate. Only 40% of the cited staging systems was reliable. This level of inaccuracy leads to confusion for the reader and to difficulty interpreting other relevant literature.
Appraisal of Ten‐Year Survival following Esophagectomy for Carcinoma of the Esophagus with Emphasis on Quality of Life
Authors: Baba Masamichi , Aikou Takashi , Natsugoe Shoji , Kusano Chikara , Shimada Mario , Kimura Shigeto , Fukumoto Toshitaka
Published: August 2002

Characteristics of 10‐year survival after esophagectomy for carcinoma were studied retrospectively in 161 patients who underwent curative operation between 1973 and 1984. Of the 161 patients, 44 (27.3%) survived for 10 years after operation (right transthoracic approach with cervical anastomosis in 36 patients and left thoracoabdominal approach with jejunoesophagostomy in 8 patients). Females survived significantly longer than males; 10‐year survival was observed in 10 (50%) of 20 females and 34 (24.1%) of 141 males. TNM factors were significantly linked to the 10‐year survival for 25 patients (56.8%) whose tumors invaded the adventitia and 20 patients (45.5%) who had lymph node metastases, where the total number of involved nodes was less than eight. A questionnaire mailed 10 years after operation revealed that about one‐fifth of the 10‐year survivors could not go up one flight of stairs without taking a rest, and that the daily activity significantly deteriorated if the patient's age at the time of surgery was more than 66 years. One‐third of the 10‐year survivors were not satisfied with the daily quantity of food intake, resulting in no gain of body weight after discharge from the hospital. This complaint was significantly correlated with either weekly reflux or heartburn, resulting in the increasing number of nonmalignancy deaths. Of 13 ten‐year survivors who were alive at 10 years but died after that, 11 (84.6%) died of pneumonia or malnutrition. Duodenogastroesophageal reflux may eventually cause nonmalignancy death 10 years after esophagectomy for carcinoma.
Lack of Benefit of Combined Pancreaticosplenectomy in D2 Resection for Proximal‐Third Gastric Carcinoma
Authors: Kodera Yasuhiro , Yamamura Yoshitaka , Shimizu Yasuhiro , Torii Akihito , Hirai Takashi , Yasui Kenzo , Morimoto Takeshi , Kato Tomoyuki , Kito Tsuyoshi
Published: August 2002

Of the 2790 patients with gastric carcinoma who underwent surgery between January 1978 and December 1993, there were 224 who underwent a D2 resection for cancer of the proximal third of the stomach. Survival in these patients was retrospectively analyzed with special reference to the survival benefit of pancreaticosplenectomy (PS). The D2 resection involved a splenectomy in
129 patients, a PS in 38 patients, and neither in 57 patients, with
5‐year survivals of 74%, 59%, and 91%, respectively. Although these differences in survival were attributable to the apparent deviation in the incidence of prognostic variables, no significant survival benefit of PS was observed for patients with the same clinical stage disease
(stages II and III) or the same nodal status (n1 and n2). Because PS was associated with a significant increase in the incidence of anastomotic dehiscence and length of hospital stay, the dismal survival benefit implies that it should not be performed routinely with the D2 resection but should be employed only for lesions with direct invasion of the pancreas.
Comparison of Pancreatogastrostomy and Pancreatojejunostomy after Pancreatoduodenectomy Performed by One Surgeon
Authors: Kim Sun Whe , Youk Eui Gon , Park Yong Hyun
Published: August 2002

Pancreatogastrostomy (PG) for restoring pancreaticoenteric continuity after pancreatoduodenectomy (PD) has been recommended by a few surgeons on the basis of certain theoretic and practical advantages of this procedure over pancreatojejunostomy (PJ). The purpose of this study was to determine whether PG can be a safe alternative to PJ. Eighty‐six PDs performed by the same surgeon for periampullary carcinoma were analyzed to compare early and late postoperative results of PJ (
n= 38) and PG
(n= 48). The two groups were comparable for age, sex, diagnosis, stage, and operation time. PJ leakage developed in six patients (15.8%) and PG leakage in one (2.1%) (p <
0.05). Overall rates of morbidity/hospital mortality were 34.2/7.9%
and 18.8/4.2% in the PJ and PG groups, respectively. In conclusion, PG showed a more favorable early outcome than PJ. PG is recommended for surgeons who encounter difficulties with PJ for reconstruction after PD.
Bullets and Their Role in Sepsis after Colon Wounds
Authors: Sarmiento Juan M. , Yugueros Patricia , Garcia Alberto F. , Wolff Bruce G.
Published: August 2002

The objective of this study was to determine the relation between the presence of a bullet (gunshot) after injury to the colon and the incidence of sepsis in its track and the soft tissue where it is retained. A retrospective review was carried out of the charts of consecutive patients admitted for abdominal gunshot wounds with proved colon injury during laparotomy where the bullet was either retained in the soft tissue or exited the body. The review covered a period of 4 years beginning January 1, 1990. Three groups were identified for analysis: (1) patients from whom the bullet was surgically removed, with additional cleansing and débridement of the area (
n= 21); (2) patients who did not undergo surgical removal of the bullet (n= 81); and (3)
patients in whom the bullet exited spontaneously and in whom only débridement of the skin was carried out (n=
83). Similar risk factors were noted among the groups (age, ATI score, colostomy rate), except for a higher incidence of shock in group 3
(p= 0.003). The incidence of sepsis in soft tissue was least in group 1. It was five and seven times greater in groups 2 and 3, respectively. After an abdominal gunshot with colon injury, the missile should be removed if feasible and the local tissue débrided. If the bullet has exited spontaneously, its internal track must be débrided and lavaged extensively.
Nonparasitic Cysts of the Liver: Results and Options of Surgical Treatment
Authors: Koperna Thomas , Vogl Sonja , Satzinger Ulli , Schulz Franz
Published: August 2002

Nonparasitic cysts of the liver (NPHC) are highly variable in respect to appearance and therapeutic approach. The treatment of these cysts varies according to the nature and appearance of the disease. Based on the variable nature of disease and the various therapeutic options, all of which were attempted in our patients, the most suitable mode of treatment for different forms of NPHC are discussed. Ninety‐one patients with NPHC who had been treated surgically from 1977 through 1995 were examined retrospectively. Asymptomatic peripheral cysts measuring up to 10 cm do not require further treatment. Computed tomography (CT)‐guided aspiration (n= 9) should be regarded as a palliative measure. Within a short period, CT‐guided aspiration led to recurrence of symptoms in seven of our patients. Standard treatment of NPHC is fenestration with widest possible excision of the cystic wall, which can be performed laparoscopically (n= 10) or by the conventional surgical mode (n= 54). One patient was initially operated by the laparoscopic technique but developed bleeding, which necessitated conversion to the open mode. Three patients underwent synchronous laparoscopic cholecystectomy. Recurrence rates were similar: 11% in the laparoscopically treated group and 13% in the group that underwent conventional open surgery. Conventional surgical treatment was always successful in cases of solitary cysts. However, in cases of multiple cysts measuring more than 5 cm, conventional surgery was followed by recurrence of symptoms in 26% of patients (7/27), who then had to undergo a second operation. Partial resection of the liver (n= 9) was successfully performed in cases of polycystic disease (n= 5) with concomitant enlargement of the organ as well as in cases of large solitary cysts of the left lobe of the liver (n= 4). In patients in whom we found that the cysts communicated with the ductal system (n= 3), we performed a cystojejunostomy to drain the bile. The complication rate was low. In addition to frequent postoperative ascites, which necessitated no further intervention, we observed infectious complications in four patients. Twenty patients (22%) expired during a mean follow‐up period of 6.2 years. Interestingly, deaths were frequently associated with malignancy (11/20). After fenestration of multiple cysts measuring > 5 cm, the patients are at high risk for recurrence. Hence partial resection of the liver is an excellent therapeutic alternative in selected patients with polycystic disease and massive enlargement of the organ in whom the disease could not be controlled by simple fenestration. The results of this study show that laparoscopic fenestration should replace the conventional surgical technique as the gold standard in cases of NPHC because the laparoscopic technique is less stressful for the patient and is associated with a rate of success similar to that of the conventional technique.
Prophylactic Thyroidectomy in 75 Children and Adolescents with Hereditary Medullary Thyroid Carcinoma: German and Austrian Experience
Authors: Dralle Henning , Gimm Oliver , Simon Dietmar , Frank‐Raue Karin , Görtz Günter , Niederle Bruno , Wahl Robert A. , Koch Bernd , Walgenbach Siegfried , Hampel Rainer , Ritter Michael M. , Spelsberg Fritz , Heiss A. , Hinze Raoul , Höppner Wolfgang
Published: August 2002

When mutations of the RETproto‐oncogene were found in 1993 to account for hereditary medullary thyroid carcinoma (MTC), surgeons obtained the opportunity to operate on patients prophylactically (i.e., at a clinically asymptomatic stage). Whether this approach is justified, and, if so, when and to which extent surgery should be performed remained to be clarified. A questionnaire was sent to all surgical departments in Germany and Austria. All of the patients who fulfilled the following criteria were enrolled: (1) preoperatively proved RET mutation; (2) age ≤ 20 years, (3) clinically asymptomatic thyroid C cell disease; and (4) TNM classification pT0–1/pNX/pN0–1/M0. Seventy‐five patients were identified, and fifteen mutations were detected in six codons. Two adolescents had unilateral pheochromocytomas as part of the multiple endocrine neoplasia II (MEN‐II) syndrome. No hyperparathyroidism was noted. All patients underwent total thyroidectomy, and 57 patients went on to have lymph node dissection. Parathyroid glands were removed in 34 patients and autografted in 11. Histopathology revealed MTC in 46 patients (61%, youngest 4 years); C cell hyperplasia (CCH) only was detected in the other 29 patients. Three patients had lymph node metastases (LNMs) the youngest being age 14 years. Calcitonin levels were not useful for differentiating between CCH and MTC, but in all patients with LNMs at least the stimulated calcitonin levels were assayed. After surgery, five patients (6.7%) sustained permanent hypoparathyroidism, and one patient (1.3%) had a permanent unilateral recurrent nerve palsy. All but three patients (96%) were biochemically cured. In conclusion, prophylactic total thyroidectomy can be performed safely in experienced centers. We recommend prophylactic total thyroidectomy at age 6. Cervicocentral lymph node dissection should be included when calcitonin levels are elevated or if patients are older than 10 years. Bilateral lymph node dissection should be performed if LNMs are suspected or when patients with elevated calcitonin are older than 15 years.
Gastric Bypass Operation for Obesity
Authors: Fobi Mathias A.L. , Lee Hoil , Holness Ronald , Cabinda DeGaulle
Published: August 2002

Gastric bypass is considered by many to be the gold standard for surgical treatment of obesity. Gastric bypass was a natural evolution from gastric operations that were used for the treatment of peptic ulcer disease. Gastric bypass, first described in 1967, has undergone many modifications. It presently exists as a hybrid operation. Gastric bypass operation has been extensively scrutinized and evaluated against other operations for the treatment of obesity. Co‐morbidities due to severe obesity are usually ameliorated or arrested after the weight loss from gastric bypass. Gastric bypass operation is now being performed with a perioperative morbidity of less than 10%. The average percentage excess weight loss with gastric bypass is 70%. The success rate, defined as 50% excess weight loss after at least 2 years of follow‐up, is 85%. The metabolic deficiencies of gastric bypass are controllable with supplemental intake. This report with special references to the Fobi pouch operation, a modification of gastric bypass done by the author, presents the evolution, modifications, risks, outcome, and future trends of gastric bypass for treatment of obesity.
Evaluation of Retinoblastoma and Ki‐67 Immunostaining as Diagnostic Markers of Benign and Malignant Parathyroid Disease
Authors: Farnebo Filip , Auer Gert , Farnebo Lars‐Ove , Teh Bin Tean , Twigg Stephen , Aspenblad Ulla , Thompson Norman W. , Grimelius Lars , Larsson Catharina , Sandelin Kerstin
Published: August 2002

Assessment of the malignant potential of parathyroid tumors in the absence of metastases can be difficult using morphologic criteria alone. In this study we have examined a total of
58 parathyroid tumors (31 benign, 15 malignant, and 12 equivocal) from
54 patients using immunohistochemistry with monoclonal antibodies directed against the retinoblastoma (RB) protein and the cell cycle‐associated antigen Ki‐67 to evaluate their role as diagnostic markers. RB protein immunoreactivity was not useful for distinguishing between benign and malignant parathyroid tumors. Analysis of the proliferation marker Ki‐67 showed that there was a trend toward more intense staining in the malignant cases. The Ki‐67 labeling index was highest in the parathyroid cancers (median 33) and lowest in the sporadic primary adenomas (median 2). An observation that might have clinical implications is that tumors from patients with familial hyperparathyroidism linked to chromosome 1q showed a high Ki‐67 index, indicating strong proliferative activity (median 25). This correlates well with the clinical observation of tumors with malignant potential in this syndrome. Because of the considerable overlap between groups of tumors, Ki‐67 is not suitable for definitive differentiation between benign and malignant tumors. However, Ki‐67 may give valuable information about which patients should be followed more closely.
Anterior Transhepatic Approach for Isolated Resection of the Caudate Lobe of the Liver
Authors: Yamamoto Junji , Kosuge Tomoo , Shimada Kazuaki , Yamasaki Susumu , Takayama Tadatoshi , Makuuchi Masatoshi
Published: August 2002

We have devised a new technique for isolated caudate lobe resection in which we access the caudate lobe by separating the liver parenchyma along the interlobar plane. The safety and radicality of the procedure were evaluated in five patients: four with hepatocellular carcinoma (HCC) and one with metastatic rectal cancer. All of the tumors were located mainly in the paracaval portion of the caudate lobe. The patients with HCC (three of four) underwent an anatomic caudate lobe resection by identification of the right margin of the caudate lobe. Two patients required red blood cell transfusion, and one showed bile leakage after surgery. All of the patients are alive without recurrence more than 4 years after surgery, except one with rectal carcinoma who developed lung metastases. The anterior transhepatic approach is a safe and potentially curative surgical option for a tumor in the paracaval portion of the caudate lobe.
Muscular Performance and Fatigue in Primary Hyperparathyroidism
Authors: Deutch Søren R. , Jensen Martin B. , Christiansen Peer M. , Hessov Ib
Published: August 2002

The purpose of this study was to evaluate changes in muscular strength and endurance, work capacity, and subjective fatigue following surgical treatment of primary hyperparathyroidism (pHPT), and to assess whether changes in muscular function were due to changes in activation of the muscles. A prospective consecutive study design was used, and patients surgically treated for nontoxic goiter served as controls. Nineteen female patients with mild to moderate pHPT and 20 controls were included. Maximal isometric handgrip and quadriceps strength, quadriceps endurance (intermittent stimulation), and quadriceps activation (superimposed twitch technique) were used for evaluation of muscular function. All patients were operated on successfully. Knee extension strength increased by 17 ± 17% (mean ± SD; p= 0.0004) in the patients, whereas no change was observed in the controls. The relative strength increase correlated positively to patient age at operation (r= 0.52, p= 0.02). Handgrip strength, quadriceps endurance, and general work capacity did not change in any group after operation. Subjective fatigue was preoperatively higher in patients than in controls (p= 0.01), and decreased postoperatively to the level of controls. In conclusion, women with pHPT increase knee extension force after parathyroidectomy as a result of increased force generation capacity of the muscle. If change in physical performance is a determinant for change in subjective fatigue in pHPT after operation, then change in strength of the quadriceps muscle seems to be of primary importance, whereas handgrip strength, muscular endurance, and work capacity do not seem to be important. The cause of the increasing strength benefit with increasing age at operation as found in this study needs further investigation.
Parietal Cell Vagotomy versus Vagotomy‐antrectomy: Ulcer Surgery in the Modern Era
Authors: Donahue Philip E.
Published: August 2002

Patients with peptic ulcer occasionally develop complications that require surgical intervention, despite the advances in medical treatment and changes in the natural history of disease. The clinical surgeon must make a decision about performing “selective vagotomy antrectomy versus highly selective vagotomy,” based on the information discussed herein. The goals for operative treatment remain safe correction of the presenting problem, avoidance of perioperative morbidity and mortality, and freedom from disabling postoperative side effects. This paper addresses broad aspects of the details of surgical interventions; because most operative procedures are performed in urgent circumstances in patients who often have a variety of conditions, it is not surprising that there is no best operation suited to every complication of ulcer.
Tumors of the Oral Cavity and Pharynx
Authors: Wertheimer‐Hatch Laura , Hatch George F. , Hatch Kathryn F. , Davis Gregory B. , Blanchard D. Kay , Foster Roger S. , Skandalakis John E.
Published: August 2002

We have compiled all the reported cases of smooth muscle (stromal) tumors of the oral cavity and pharynx from 1884 through 1996. Our collective data included 139 leiomyomas (LM) and 68 leiomyosarcomas (LMS); but because we did not have sufficient information for 13 cases of LM, we report on only 126; and we report on only 66 of 68 cases of LMS. The peak age of incidence was 40 to 49 years for benign tumors and 50 to 59 years for malignant lesions, with the incidence in men slightly predominating over that in women. The most common sites of LM of the oral cavity and pharynx were the lips, tongue, and hard and soft palate. The most common sites of LMS included the maxilla and mandible. More than 40% of LMs presented as an intraoral mass, and more than half were known to be present for longer than 1 year. About 10% presented with pain, difficulty chewing or swallowing, swelling, toothache or loose teeth, or a combination of these symptoms. Patients with LMS were much more likely to have obvious symptoms of shorter duration, and one‐third presented with pain or swelling (or both). Other relatively common symptoms of LMS included tenderness, interference with dentures, or an intraoral mass. In this review, there were almost twice as many LMs as LMSs, which was consistent with smooth muscle tumors found in other areas of the gastrointestinal tract.
Limits of Infrapopliteal Bypass Surgery for Critical Leg Ischemia: When Not to Reconstruct
Authors: Biancari Fausto , Kantonen Ilkka , Albäck Anders , Mätzke Sorjo , Luther Michael , Lepäntalo Mauri
Published: August 2002

The aim of this study was to identify the risk factors affecting the immediate 30‐day postoperative outcome of infrapopliteal bypass grafts. A series of 511 revascularization procedures to the infrapopliteal arteries have been performed in 439 patients with critical leg ischemia. There were 306 crural bypasses and 205 pedal bypasses. The 30‐day postoperative primary and secondary patency rates were 77.5% and 83.4%, respectively; the leg salvage rate was 89.8%; the survival rate was 94.7%; and 85.1% of patients were alive with a salvaged leg. A history of myocardial infarction, angina pectoris, or stroke had a great impact on the postoperative cardiac and cerebrovascular fatal and nonfatal complications. C‐reactive protein arose as an important predictor of the length of hospital stay (p= 0.03), postoperative cardiac complications (p= 0.02), leg salvage (p= 0.009), amputation with patent graft (p= 0.009), and patients who survived with a salvaged leg (p= 0.006). Poor results were achieved in patients on long‐term dialysis. Surgical experience had an influence on leg salvage (p= 0.02) and on patients alive with salvaged leg rates (p= 0.009). Infrapopliteal bypass surgery is a demanding procedure requiring high surgical skill and experience. Revascularization may be contraindicated when severe coronary disease, previous stroke, renal failure requiring long‐term dialysis, diabetes, or high serum concentration of C‐reactive protein coexist with critical leg ischemia, as these patients are at high risk for early postoperative leg or life loss.
Reconstitution of Liver Mass Via Cellular Hypertrophy in the Rat
Authors: Nagy Peter , Teramoto Tadahisa , Factor Valentina M. , Sanchez Aranzazu , Schnur Janos , Paku Sandor , Thorgeirsson Snorri S.
Published: August 2002

The liver has an extremely effective regenerative capacity. When 70% of a rat liver is removed by surgery, the liver mass regrows in 7 to 10 days by the compensatory hyperplasia of the remnant part. In case of damage to the surviving hepatocytes, the facultative stem–cell compartment is activated and the liver regenerates by means of oval–cell proliferation/differentiation. In the present study, we demonstrate that when both hepatocyte proliferation and stem–cell activation were prevented by dexamethasone (Dex) administration, the liver mass was restored in the absence of DNA synthesis. The restoration of the liver was accomplished by the preferential enlargement/hypertrophy of the periportal hepatocytes. A similar response was observed when cell proliferation was arrested by 5–fluorouracil (FU) following partial hepatectomy. Therefore, the hepatocytic hypertrophy appears to provide an alternative mechanism of liver–mass restoration. This hypertrophic condition of the liver is not stable, because following the withdrawal of Dex, the enlarged hepatocytes entered in the cell cycle and the normal liver structure and DNA content was re–established.
The Vascular Endothelial Growth Factor Receptor Kdr/Flk–1 Is A Major Regulator of Malignant Ascites Formation in the Mouse Hepatocellular Carcinoma Model
Authors: Yoshiji Hitoshi , Kuriyama Shigeki , Hicklin Daniel J. , Huber James , Yoshii Junichi , Ikenaka Yasuhide , Noguchi Ryuichi , Nakatani Toshiya , Tsujinoue Hirohisa , Fukui Hiroshi
Published: August 2002

The vascular endothelial growth factor–A (VEGF–A), also known as the vascular permeability factor (VPF), has been shown to play an important role in malignant ascites formation. The effects of VEGF–A are mediated through flt–1 and kinase insert domain-containing receptor/fetal liver kinase (KDR/Flk–1) receptors. It has been shown that KDR/Flk–1 is a predominant receptor in solid hepatocellular carcinoma (HCC) development, but the role of this receptor in hepatic ascites formation has not yet been elucidated. In this study, we examined the role of KDR/Flk–1 in the murine MH134 hepatic malignant ascites formation by means of VEGF–A- and KDR/Flk–1-specific neutralizing antibodies (VEGF–A nAb and KDR/Flk–1 nAb, respectively). The mean volume of ascites, number of tumor cells in ascites, and the peritoneal capillary permeability were significantly suppressed by VEGF–A nAb and KDR/Flk–1 nAb treatment. These inhibitory effects of KDR/Flk–1 nAb were more potent than those of VEGF–A nAb. The autophosphorylation of KDR/ Flk–1 in the peritoneal wall was almost completely abolished by KDR/ Flk–1 nAb, whereas a certain level of activation was still shown by VEGF–A nAb treatment. Another VEGF–family, VEGF–C, which also binds KDR/Flk–1, was detected in the ascites. Furthermore, in the therapeutic experiment, although both VEGF–A nAb and KDR/Flk–1 nAb prolonged the survival rate of ascites–bearing mice, the latter showed a more significant impact on the survival of animals. These results suggest that KDR/Flk–1 is a major regulator of malignant hepatic ascites formation, and that in addition to VEGF–A, VEGF–C may also be involved in the malignant ascites formation via KDR/ Flk–1 activation.
Repopulation of Mouse Liver With Human Hepatocytes And In Vivo Infection With Hepatitis B Virus
Authors: Dandri Maura , Burda Martin R. , Török Eva , Pollok Joerg M. , Iwanska Alicja , Sommer Gunhild , Rogiers Xavier , Rogler Charles E. , Gupta Sanjeev , Will Hans , Greten Heiner , Petersen Joerg
Published: August 2002

Mice containing livers repopulated with human hepatocytes would provide excellent in vivo models for studies on human liver diseases and hepatotropic viruses, for which no permissive cell lines exist. Here, we report partial repopulation of the liver of immunodeficient urokinase–type plasminogen activator (uPA)/recombinant activation gene–2 (RAG–2) mice with normal human hepatocytes isolated from the adult liver. In the transplanted mice, the production of human albumin was demonstrated, indicating that human hepatocytes remained functional in the mouse liver for at least 2 months after transplantation. Inoculation of transplanted mice with human hepatitis B virus (HBV) led to the establishment of productive HBV infection. According to human–specific genomic DNA analysis and immunostaining of cryostat liver sections, human hepatocytes were estimated to constitute up to 15% of the uPA/RAG–2 mouse liver. This is proof that normal human hepatocytes can integrate into the mouse hepatic parenchyma, undergo multiple cell divisions, and remain permissive for a human hepatotropic virus in a xenogenic liver. This system will provide new opportunities for studies on etiology and therapy of viral and nonviral human liver diseases, as well as on hepatocyte biology and hepatocellular transplantation. (Hepatology 2001;33:981–988.)
Involvement of P21Waf1/Cip1, P27Kip1, and P18Ink4c in Troglitazone–Induced Cell–Cycle Arrest in Human Hepatoma Cell Lines
Authors: Koga Hironori , Sakisaka Shotaro , Harada Masaru , Takagi Toshiyuki , Hanada Shinichiro , Taniguchi Eitaro , Kawaguchi Takumi , Sasatomi Kurumi , Kimura Rina , Hashimoto Osamu , Ueno Takato , Yano Hirohisa , Kojiro Masamichi , Sata Michio
Published: August 2002

Peroxisome proliferator-activated receptor γ (PPARγ) regulates cell growth and differentiation. Recent evidence has suggested that PPARγ ligands had anti–tumor effects through inhibiting cell growth and inducing cell differentiation in several types of malignant neoplasm. In the present study, we investigated: 1) the expression of PPARγ in both human hepatoma cell lines and 5 resected human hepatocellular carcinoma (HCC) tissues; 2) the growth–inhibitory effect of troglitazone, a PPARγ ligand, on those hepatoma cells; and 3) the molecular mechanisms of troglitazone–induced cell–cycle arrest. Five hepatoma cell lines, HLF, HuH–7, HAK–1A, HAK–1B, and HAK–5, were used. The mRNA expression levels of PPARγ, p21WAF1/Cip1, and p27Kip1 were determined by real–time quantitative reverse transcription–polymerase chain reaction. The expression of cell cycle-regulating proteins, such as p21, p27, p18INK4c, cyclin E, and pRb, was examined using Western blotting. PPARγ was constitutively expressed in all the cell lines and the HCC tissues used in this study. A cytostatic effect of troglitazone was found in those cell lines, and this inhibition of cell growth was dosage–dependent. G0/G1 arrest was apparently demonstrated in flow cytometric analysis in HLF, HAK–1A, HAK–1B, and HAK–5, all of which showed an increased expression of p21 protein. However, HuH–7, lacking p21 protein expression, did not demonstrate clear arrest in the cell–cycle analysis. HLF, which was deficient in the protein product of the retinoblastoma tumor–suppressor gene (pRb), responded most profoundly to troglitazone, showing an increased expression in not only p21, but also in p27 and in p18. These findings suggested that p21, p27, and p18 might be involved in troglitazone–induced cell–cycle arrest in human hepatoma cells.
Protracted, But Not Acute, Hepatitis A Virus Infection Is Strongly Associated With Hla–Drb1*1301, A Marker for Pediatric Autoimmune Hepatitis
Authors: Fainboim Leonardo , Cañero Velasco Maria Cristina , Marcos Cintia Y. , Ciocca Mirta , Roy Adriana , Theiler Graciela , Capucchio Monica , Nuncifora Silvia , Sala Livio , Zelazko Marta
Published: August 2002

HLA alleles are known to be associated with susceptibility to develop autoimmune hepatitis (AH), and hepatitis A virus (HAV) infection is postulated as a putative trigger for AH. We investigated whether HLA may influence the outcome of the HAV infection by studying 67 children with self–limited and 39 children with protracted forms of this infection. HLA typing of the uncomplicated forms showed no significant increase of any HLA class I or II alleles. In contrast, DRB1*1301 was present in 46.1% of the children with protracted forms (vs. 9.8% in healthy controls; relative risk [RR]: 7.6; χ2 = 33.3; P = 2 × 10-9). In uncomplicated hepatitis, 45% developed anti–smooth muscle antibody (SMA)/actin antibodies, but only 1 child had detectable antibodies after 3 months of infection onset. In contrast, after 1 year, 69% of the patients suffering protracted forms had titers of anti–SMA/actin antibodies that ranged between 1:40 and 1:160. Within their follow–up, 2 patients developed a Hashimoto's thyroiditis, but the remaining patients showed no signs of developing autoimmune hepatitis. We conclude that the DRB1*1301 haplotype is strongly associated with the protracted forms of HAV infection and suggest that the infection allows a sustained release of liver self–antigens. However, other still–unknown susceptibility genes are required for the full development of pediatric AH.
Expression of Hepatitis C Virus Ns5a Natural Mutants in A Hepatocytic Cell Line Inhibits the Antiviral Effect of Interferon in A Pkr–Independent Manner
Authors: Podevin Philippe , Sabile Abdelmajid , Gajardo Rodrigo , Delhem Nadira , Abadie Annie , Lozach Pierre-Yves , Beretta Laura , Bréchot Christian
Published: August 2002

The impact of hepatitis C virus NS5A protein mutations on interferon alfa (IFN–α) signaling pathway, cell proliferation, and viability is an important issue that is still under debate. We have therefore combined transient and stable expression in a human hepatocytic cell line (Huh7) of 3 full–length NS5A sequences, isolated from patients with or without response to IFN–α therapy. Expression of all 3 NS5A–reduced IFN–α global antiviral activity on both vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV) replication. We did not show, however, an effect of these 3 NS5A proteins on double–stranded RNA-dependent kinase (PKR) expression and activity as well as colocalization and coimmunoprecipitation between NS5A and PKR. We also failed to show an effect of the 3 NS5A mutants tested on cell proliferation and viability. Overall, our results support an important role of NS5A in controlling IFN–α antiviral activity; they show, however, that PKR–independent mechanisms are implicated, at least in liver–derived cells.
An Early Lesion in Hepatic Carcinogenesis: Loss of Heterozygosity in Human Cirrhotic Livers and Dysplastic Nodules At the 1P36–P34 Region
Authors: Sun Min , Eshleman James R. , Ferrell Linda D. , Jacobs Gretta , Sudilovsky Eulalia C. , Tuthill Ralph , Hussein Mahmoud R. , Sudilovsky Oscar
Published: August 2002

Loss of heterozygosity (LOH) of chromosome 1 has been suggested, by karyotyping, to be an initial episode in human hepatocarcinogenesis. However, this alteration has not yet been investigated in cirrhotic nodules (CNs) or dysplastic nodules (DNs). In an initial study from explanted or resected cirrhotic livers, LOH in 1p36–p32 was examined in 31 hepatocellular carcinomas (HCCs), 25 low–grade dysplastic nodules (LGDNs), and 24 high–grade dysplastic nodules (HGDNs). In HCCs, LOH was detected most frequently at loci D1S2843 (1p36.1) (28.6%), D1S513 (1p34.3) (29.2%), and MYCL1 (1p34.1) (28.6%). In HGDN and LGDN, LOH incidences at D1S513 were 11.1% and 13.6%, respectively. To further refine those results and to determine sequential relationships among CN, DN, and HCC, LOH was next studied in an additional 53 HCCs, 56 HGDNs, 30 LGDNs, and 215 CNs from 11 explanted human cirrhotic livers, including 30 “nodule–in–nodule” lesions. Seven markers between D1S2843 (1p36.12) and MYCL1 (1p34.1), and 1 each at D1S484 (1q24.1), IGF2R–3 (6q26), and TP53 (17p13.1) were used. LOH at D1S2843 and D1S513 was detected in HCCs (20.4% and 23.5%, respectively), HGDNs (7.7% and 18.5%), LGDNs (13.6% and 6.9%), and CNs surrounding either HCCs or DNs (7.4% and 8.3%). These results demonstrate that LOH at D1S2843 and D1S513 are early events in human liver carcinogenesis. Data from CN surrounding either HCCs or DN, and also nodule–in–nodule lesions, provide evidence supporting a CN→DN→HCC progression. Different deletion patterns from multiple HCCs and DNs suggest independent origins for carcinogenesis in the same individual.
Differential Effects of Microsomal Enzyme-Inducing Chemicals on the Hepatic Expression of Rat Organic Anion Transporters, Oatp1 and Oatp2
Authors: Rausch-Derra Lesley C. , Hartley Dylan P. , Meier Peter J. , Klaassen Curtis D.
Published: August 2002

The organic anion transporting polypeptides, Oatp1 (Slc21a1) and Oatp2 (Slc21a5), mediate hepatic uptake of cardiac glycosides. Previously, we demonstrated that chemicals that increase cytochrome P450s differentially affect hepatic uptake of cardiac glycosides. We postulated that increased uptake of cardiac glycosides observed after pretreatment of animals with phenobarbital (PB) and pregnenolone–16α–carbonitrile (PCN) occurs via increased hepatic expression of Oatp1 and/or Oatp2. Male Sprague–Dawley rats were injected with PB, PCN, 3–methylcholanthrene (3–MC), or vehicle for 4 days. Branched–DNA (bDNA) signal amplification and Western blot analyses were used to assess hepatic Oatp1 and Oatp2 mRNA and protein, respectively. The expression of Oatp1 was not increased by any chemical treatment. Increases in Oatp2 expression were observed from livers of rats treated with PB and PCN, in which PCN caused a robust elevation of Oatp2 mRNA and protein. Oatp2 expression was suppressed in response to 3–MC. To determine the temporal effects of PCN treatment on the expression of Oatp2, rats were administered PCN, livers were extracted at various times, and Oatp2 expression was analyzed. Maximal expression of Oatp2 mRNA was observed at 24 hours and remained elevated, whereas the amount of Oatp2 protein increased throughout the 96–hour interval. The finding that Oatp2 expression increases in response to PB and PCN is consistent with our previous findings that PB and PCN enhance hepatic uptake of cardiac glycosides. These results suggest that Oatp2, but not Oatp1, is inducible by PB and PCN, which imparts the increased capacity of the liver to extract cardiac glycosides from the plasma.
The Integrin, α6β1, Is Necessary for the Matrix–Dependent Activation of Fak and Map Kinase and the Migration of Human Hepatocarcinoma Cells
Authors: Carloni Vinicio , Mazzocca Antonio , Pantaleo Pietro , Cordella Claudia , Laffi Giacomo , Gentilini Paolo
Published: August 2002

Expression of the integrin, α6β1, a receptor for laminins, is associated with the progression of hepatocellular carcinoma (HCC). The approach to investigating the α6β1 integrin signaling in HCC cells was to express a deletion mutant of the β4 integrin cytoplasmic domain (β4–Δcyt) in 2 HCC cell lines, HepG2 and Huh7. Expression of this mutant prevents formation of the α6β1 heterodimer. As expected, adhesion of both the HepG2/β4–Δcyt and Huh7/β4–Δcyt transfectants to laminin, but not to collagen, was reduced compared with the mock transfectants. However, migration of the β4–Δcyt transfectants toward both collagen and laminin was inhibited, suggesting a role for α6β1 in the signaling of migration. Migration of HCC cells requires mitogen–activated protein (MAP) kinase. The adhesion of the β4–Δcyt transfectants to collagen resulted in a substantial reduction in MAP kinase activation in comparison with the mock transfectants, although their ability to activate MAP kinase in response to epidermal growth factor (EGF) stimulation was not impaired. In addition, matrix adhesion of the β4–Δcyt transfectants did not stimulate the tyrosine phosphorylation of focal adhesion kinase (FAK), and this defect correlated with reduced binding of adaptor protein Grb2 to FAK. These results suggest that FAK tyrosine phosphorylation is dependent on α6β1 expression, and that FAK–Grb2 association plays a central role in α6β1–mediated activation of MAP kinase. Moreover, the expression of α6β1 in HCC cells is necessary for FAK/MAP kinase–dependent migration.
A Randomized, Double–Blind Trial Comparing Pegylated Interferon Alfa–2B to Interferon Alfa–2B As Initial Treatment for Chronic Hepatitis C
Authors: Lindsay Karen L. , Trepo Christian , Heintges Tobias , Shiffman Mitchell L. , Gordon Stuart C. , Hoefs John C. , Schiff Eugene R. , Goodman Zachary D. , Laughlin Mark , Yao Ruji , Albrecht Janice K.
Published: August 2002

This international, randomized, active–controlled, parallel–group, double–blind dose–finding study compared peginterferon alfa–2b (PegIntron™) to interferon alfa–2b for the initial treatment of compensated chronic hepatitis C. We randomly assigned 1,219 subjects to receive either the standard three–times–weekly (TIW) interferon alfa–2b dose (3 MIU) or the once–weekly (QW) peginterferon alfa–2b (0.5, 1.0, or 1.5 μg/kg). Subjects were treated for 48 weeks and then followed for an additional 24 weeks. All 3 peginterferon alfa–2b doses significantly (P ≤ .042) improved virologic response rates (loss of detectable serum HCV RNA) after treatment and after follow–up, as compared with interferon alfa–2b. Unlike the end–of–treatment virologic response, the sustained virologic response rate was not dose–related above 1.0 μg/kg peginterferon alfa–2b because of a higher relapse rate among patients treated with 1.5 μg/kg peginterferon alfa–2b, particularly among patients infected with genotype 1. All 3 peginterferon alfa–2b doses decreased liver inflammation to a greater extent than did interferon alfa–2b, particularly in subjects with sustained responses. No new adverse events were reported, and the majority of adverse events and changes in laboratory values were mild or moderate. In conclusion, peginterferon alfa–2b maintained (0.5 μg/kg) or surpassed (1.0, 1.5 μg/kg) the clinical efficacy of interferon alfa–2b while preserving its safety profile. The higher rate of virologic response during treatment with 1.5 μg/kg peginterferon alfa–2b in patients infected with genotype 1 and high viral levels warrants further evaluation.
The Mitochondrial Permeability Transition Contributes to Acute Ethanol–Induced Apoptosis in Rat Hepatocytes
Authors: Higuchi Hajime , Adachi Masayuki , Miura Soichiro , Gores Gregory J. , Ishii Hiromasa
Published: August 2002

Acute ethanol intoxication induces oxidative stress and apoptosis in primary cultured hepatocytes. Oxidative stress can trigger mitochondrial cytochrome c release initiating the mitochondrial pathway of apoptosis. Based on this information, we formulated the hypothesis that ethanolinduced oxidative stress causes mitochondrial dysfunction resulting in apoptosis. In the present study, we found that the mitochondrial membrane permeability transition (MPT) is essential for induction of mitochondrial cytochrome c release and caspase activation of ethanol. The short–term incubation with ethanol (50 mmol/L) induced the MPT, cytochrome c release, caspase activation, and apoptosis of cultured rat hepatocytes. Hepatocyte apoptosis was prevented by caspase inhibitors (i.e., Z–VAD–fmk, DEVD–cho, and DMQD–cho). An MPT inhibitor, cyclosporin A, also prevented ethanol–induced cytochrome c release, caspase activation, and apoptosis, suggesting that acute ethanol–induced apoptosis is MPT dependent. Ethanol–induced MPT was also attenuated by N'N'–dimethylthiourea (DMTU, a scavenger of hydrogen peroxide, 10 mmol/L) and N–acetyl–cysteine (NAC, an antioxidant, 5 mmol/L). Preventing hepatocyte MPT by DMTU or NAC attenuated cytochrome c release as well as caspase activation, suggesting that ethanol–induced oxidative stress mediates the MPT. Thus, acute ethanol induces MPT via oxidative stress, and the MPT mediates mitochondrial pathway of apoptosis in hepatocytes exposed to acute ethanol.