Interleukin-2 improves tumour response to DNP-modified autologous vaccine for the treatment of metastatic malignant melanoma.

This paper is a report of response rate (RR) and survival of 34 metastatic melanoma patients who received a dinitrophenyl (DNP)-modified autologous melanoma cell vaccine. In all, 27 patients started the vaccine as a primary treatment for metastatic melanoma and seven started it as an adjuvant, with no evidence of disease at the time, but had developed new metastases. Interleukin-2 (IL-2) was administered in 24 out of the 34 patients: 19 who progressed on vaccine alone and five who had the combination from start. Interleukin-2 was administered in the intravenous, bolus high-dose regimen (seven patients) or as subcutaneous (s.c.) low-dose treatment (17). Overall response for the entire group was 35% (12 patients out of 34), 12% having a complete response (CR) and 23% a partial response (PR). However, only two patients had tumour responses while on the vaccine alone, whereas the other 10 demonstrated objective tumour regression following the combination with IL-2 (two CR, eight PR), lasting for a median duration of 6 months (range 3-50 months). Of the 12 responding patients, 11 attained strong skin reactivity to the s.c. injection of irradiated, unmodified autologous melanoma cells. None of the patients with a negative reactivity experienced any tumour response. Patients with positive skin reactions survived longer (median survival - 54 months). The results suggest enhanced RRs to the combination of IL-2 and autologous melanoma vaccine. Skin reactivity to unmodified autologous melanoma cells may be a predictor of response and improved survival, and therefore a criterion for further pursuing of immunotherapeutic strategies.

Laparoscopic cholecystectomy in octogenarians.

BACKGROUND: This study aimed to assess the outcome of laparoscopic cholecystectomy (LC) in patients 80 years old or older. METHODS: All consecutive patients 80 years old or older who underwent LC for symptomatic gallstone disease were evaluated. Data analysis included patients' age, gender, indication for surgery, comorbid condition, American Society of Anesthesiology (ASA) score, preoperative endoscopic retrograde cholangio pancreatography (ERCP), intraoperative cholangiogram, operative time, conversion to open surgery, morbidity, mortality, and length of stay. RESULTS: In this study, 67 patients (31 men and 36 women) with a mean age of 84 years (range, 80-90 years) were evaluated. Of these 67 patients, 38 (57%) underwent surgery for complicated diseases including acute cholecystitis in 15 patients (22%), gallstone pancreatitis in 17 patients (25%), cholangitis in 3 patients (4.5%), and obstructive jaundice in 3 patients (4.5%). A total of 38 patients (57%) had a preoperative ASA of 3 or 4; 23 (34%) had a preoperative ERCP; and 6 (9%) had intraoperative cholangiogram. The mean operative time was 94 +/- 20 min. Five patients (7.4%) underwent conversion to open surgery because of unclear anatomy. Complications occurred in 12 patients (18%) including pulmonary edema in 3 patients, myocardial infarction in 1 patient, atelectasis in 2 patients, common bile duct injury in 1 patient, urinary tract infection in 2 patients, wound infection in 2 patients, and intraabdominal infected hematoma in 1 patient. The mean length of stay was 5.3 days. There was no mortality. CONCLUSIONS: In octogenarians LC is safe and associated with acceptable morbidity and mortality. Therefore, it should be considered for this age group. The relatively high incidence of complicated gallstone disease in this age group may be decreased if surgery is offered to them at earlier stage of the disease, leading to further decrease in perioperative morbidity.

Lipopolysaccharide endotoxemia reduces cell proliferation and decreases enterocyte apopotosis during intestinal adaptation in a rat model of short-bowel syndrome.

Sepsis is frequently associated with or complicates short-bowel syndrome (SBS). To investigate the effects of lipopolysaccharide (LPS) endotoxemia on enterocyte proliferation and death via apoptosis in a rat model of SBS, adult male Sprague-Dawley rats were divided into three experimental groups: sham rats underwent bowel transection and reanastomosis; SBS rats underwent 75% small-bowel resection; and SBS-LPS rats underwent 75% bowel resection and were given intraperitoneal injections of LPS 10 mg/kg. Parameters of intestinal adaptation (bowel and mucosal weights, mucosal DNA and protein, villus height, and crypt depth), enterocyte proliferation, and death via apoptosis were determined on day 15 after the operation. Statistical analysis was determined by Student's and ANOVA tests with a P less than 0.05 considered significant. SBS-LPS animals demonstrated a significant decrease (vs SBS rats) in duodenal (20%), jejunal (30%), and ileal (15%) overall weight, duodenal (20%), jejunal (27%), and ileal (18%) mucosal weight, jejunal (20%) and ileal (30%) mucosal DNA, jejunal (29%) and ileal (31%) villus height, and jejunal (14%) and ileal (29%) crypt depth. LPS endotoxemia led to reduced cell proliferation and enterocyte apoptosis compared to untreated SBS animals. Thus, in a rat model of SBS, LPS endotoxemia inhibits intestinal adaptation. A possible mechanism may be decreased cell proliferation. Decreased enterocyte loss via apoptosis may reflect a reduced number of enterocytes. Other mechanisms (necrosis) may be mainly responsible for cell death following LPS injection.

Autologous cell vaccine as a post operative adjuvant treatment for high-risk melanoma patients (AJCC stages III and IV). The new American Joint Committee on Cancer.

This study evaluates the overall survival and disease free survival of melanoma patients that were treated with an autologous melanoma cell vaccine, administered as a post-operative adjuvant. Included are 43 patients with totally resected metastatic melanoma (28-AJCC stage III, 15-AJCC stage IV), with a median follow up of 34 months (6-62). The treatment consisted of eight doses of a vaccine made of 10-25x10(6) autologous melanoma cells either released from the surgical specimen or grown in cell cultures. Tumour cells were conjugated with hapten dinitrophenyl, mixed with Bacille Calmette Guérin and irradiated to 110 Gy. Both disease free survival and overall survival were found to be correlated with intensity of evolving delayed type hypersensitivity to subcutaneous injection of unmodified melanoma cells. Patients with a delayed type hypersensitivity reaction of > or =10 mm had a median disease free survival of 17 months (mean 35 months) and a mean overall survival of 63 months (median not reached). In contrast, patients with a negative or weak delayed type hypersensitivity had a median disease free survival of 9 months (relative risk of recurrence=4.5, P=0.001), and a median overall survival of 16 months (relative risk of death=15, P=0.001). Stage III patients with a positive delayed type hypersensitivity reaction had an improved disease free survival of 16 months and a mean overall survival of 38 months, whereas patients with a negative delayed type hypersensitivity had a median disease free survival of 7 months (relative risk=4.5, P=0.02) and a median overall survival of 16 months (relative risk=9.5, P=0.005). The adjuvant administration of autologous melanoma vaccine was associated with improved disease-free and overall survival to selected patients who successfully attained anti-melanoma reactivity as detected by positive delayed type hypersensitivity reactions to unmodified melanoma cells.

Expression of tyrosinase, MIA and MART-1 in sentinel lymph nodes of patients with malignant melanoma.

BACKGROUND: Regional lymph node status is an important predictor of survival in patients with malignant melanoma. Mapping of sentinel lymph nodes using sensitive molecular techniques has recently been introduced. Malignant melanoma is heterogeneous in terms of its biological, immunological and metastatic properties, and melanoma cells exhibit a polymorphous expression of tumour markers. Thus, assays that include multiple markers appear to be more sensitive than single-marker assays. OBJECTIVES: To characterize the molecular profiles of melanoma cells in sentinel lymph nodes employing the mRNA expression of tyrosinase, MIA and MART-1 as markers. METHODS: Samples of sentinel lymph nodes from 17 melanoma patients and 18 control nodes from non-melanoma patients were assayed by reverse transcriptase-polymerase chain reaction, using specific primers for each marker. RESULTS: We found that both tyrosinase and MIA expression were sensitive indicators of micrometastases in sentinel lymph nodes that were negative on routine histopathological examination, and that the finding of micrometastases expressing MART-1 in sentinel lymph nodes was negatively correlated with overall survival. CONCLUSIONS: Characterization of the molecular profiles of melanoma cells constitutes a valid means of detecting metastatic melanoma cells in sentinel lymph nodes, and of predicting the survival of melanoma patients.

Laparoscopic vs open adrenalectomy for benign adrenal neoplasm.

BACKGROUND: The aim of this study was to compare the outcome of laparoscopic adrenalectomy (LA) performed for benign adrenal neoplasm to the open procedure in a similar group of patients. METHODS: All consecutive patients who underwent LA between June 1996 and February 1999 were evaluated. Data analysis included patient's age and gender, indication for surgery, histological diagnosis, size of specimen, comorbid conditions, length of stay and ileus, postoperative narcotic consumption, and time to return to normal activity. The results were compared retrospectively to a well-matched group of patients who underwent an open adrenalectomy (OA). RESULTS: Twenty-eight LA were performed in 24 patients for the following disorders: adrenocortical adenoma, 16 (four Cushing's syndrome, 12 Conn's syndrome); pheochromocytoma, 10; and nonfunctioning tumor, two. These cases were compared with a well-matched group of 28 patients who underwent OA in the same department. There were two conversions to open surgery (7%) in the laparoscopic group and no deaths in either group. Of all the evaluated parameters, the following statistically significant differences between the two groups were noted: The mean operative time was longer in the LA group (188 vs 139 min, p < 0.001.); however, this became insignificant in the last 10 cases of LA, when the mean length of surgery was reduced to 130 min. The overall morbidity was lower in the LA group (16% vs 39%, p = 0.05), as was the mean time to tolerate a regular diet (2 vs 3.9 days), mean meperidine consumption (mg) (109 vs 209), mean length of stay (4 vs 7.5 days), and mean time to return to normal activity (2.2 vs 5.2 weeks), (p < 0.001 for all). CONCLUSION: LA for benign adrenal disorders is a safe procedure that is associated with significantly lower morbidity, shorter ileus and hospitalization, reduced postoperative pain, and a faster return to normal activity than the open procedure.

Diagnostic dilemmas in parathyroid scintigraphy.

PURPOSE: Tc-99m MIBI scintigraphy can be useful for preoperative localization of parathyroid adenomas, despite its limited sensitivity. To refine interpretation, the authors conducted prospective reviews of the scintigraphic studies of patients with concomitant thyroid nodular disease and revised the false-negative and false-positive results. MATERIALS AND METHODS: Seventy-seven patients with primary hyperparathyroidism, associated with a solitary parathyroid adenoma, underwent dual-phase MIBI scintigraphy with subsequent injection of Tc-99m pertechnetate before surgery. The false-negative and false-positive scintigraphic findings were identified and revised. RESULTS: After surgery, revision of 19 false-negative scans of the total 77 studies led to the demonstration of an adenoma in seven patients. In five of the seven studies, the adenoma had been overlooked as a result of rapid tracer washout. Two additional small focal lesions would have also been identified if subtraction had been used for differences in contour of the MIBI and pertechnetate images. Four studies were interpreted falsely as abnormal, leading to a positive predictive value of 91%; three were associated with thyroid nodular disease. CONCLUSIONS: Differential washout of MIBI from thyroid and parathyroid tissue is not universal. When MIBI is washed out rapidly from parathyroid adenomas, subtraction of a thyroid image should be performed and differences in contour delineated to localize the adenoma accurately. Some, but not all, thyroid lesions account for the false-positive findings.

Primary rectal malignant melanoma: report of two cases.

Primary rectal malignant melanoma is an exceptionally rare neoplasm associated with an extremely poor prognosis despite aggressive surgical treatment. We present two female patients with bulky tumors of the lower rectum that were diagnosed as malignant melanoma, above the squamocolumnar junction. Both patients underwent abdominoperineal resection and postoperatively were treated with autologous melanoma cell vaccine. One patient is considered disease free for months after surgery; the second one developed supraclavicular lymph nodes and right lung metastasis after 7 months.

Synchronous colorectal and renal carcinomas: a noteworthy clinical entity. Report of five cases.

PURPOSE: This study was designed to highlight the incidence of synchronous colorectal and renal carcinomas and to review the literature on that issue. The case reports of five patients who presented with synchronous colorectal and renal cell carcinomas are presented. METHODS: A retrospective study, using systematic medical chart review, analyzed the cases of all patients who underwent large-bowel resection for colorectal cancer in our department between December 1996 and December 1998. RESULTS: Among 103 patients who underwent colorectal surgery during that period, five cases of synchronous colorectal and renal carcinomas were detected (4.85 percent). CONCLUSIONS: Based on our findings, we recommend the routine use of preoperative imaging studies to exclude synchronous asymptomatic renal lesions in patients presenting with colorectal cancer.

[Laparoscopic adrenalectomy].

Constant advances and increasing experience in laparoscopic surgery renders it applicable for adrenal surgery. The wide exposure required for open adrenal surgery makes this minimally invasive procedure an attractive and advantageous alternative. Between 1996-1999, we performed 35 laparoscopic adrenalectomies in 30 patients 20-72-years old. Indications included: Conn's syndrome--14, pheochromocytoma--11, Cushing's syndrome--6, nonfunctioning adenoma--3, and metastatic sarcoma--1. 5 underwent bilateral laparoscopic adrenalectomy. In 3 (8.5%) the procedures were converted to open operations. Overall morbidity was 13% and there was no mortality. Mean operative time was 188 minutes, but only 130 in our last 10 cases. Mean hospital stay was 4 days and they returned to normal activity an average of 2 weeks later. According to our study and previous reports, laparoscopic adrenalectomy is feasible and safe and it may soon become the procedure of choice for adrenal tumors.

Preoperative localization of parathyroid adenoma in patients with concomitant thyroid nodular disease.

We have previously demonstrated the role of high-resolution ultrasonography (US) in preoperative localization of parathyroid adenoma in patients with primary hyperparathyroidism (PHPT) and no thyroid abnormalities. The present study prospectively evaluated the possible additional value of 99mTc-sestamibi (MIBI) in patients with PHPT and concomitant multinodular thyroid disease (MND). Patients with PHPT underwent US and MIBI scintigraphy prior to neck exploration. Imaging data were correlated with the site and pathology of the parathyroid tissue removed and were analyzed separately for patients with MND and those with a normal thyroid gland. Among 77 patients with a solitary parathyroid adenoma at surgery, 40 had concomitant MND, whereas 37 patients had no morphologic changes in the thyroid gland, on US or at surgery. Prior to surgery, MIBI scintigraphy depicted 58 of the 77 adenomas (75%) and US localized 51 (66%): the combined sensitivity was 87% (67/77). Among the 37 patients with no thyroid nodules, MIBI located 29 (78%) and US identified 30 (81%) of the adenomas; the combined sensitivity was 89%. In the 40 patients with MND, MIBI identified 29 adenomas (73%) and US localized only 53% (21/40); the combined sensitivity was 85%. Overall, the positive predictive value (PPV) of MIBI for detecting a solitary parathyroid adenoma was 94%, for US it was 88%, and with the two tests combined it was 97%. In patients with no thyroid abnormalities, the PPV of MIBI and US was 97%, but it decreased to 91% and 78%, respectively, in patients with MND. Two patients with false-positive findings on both MIBI and US had associated thyroid disease. Hence MIBI scintigraphy contributes to localization of a solitary parathyroid adenoma mainly in patients with concomitant MND. The combined MIBI and US modalities result in sparing these patients bilateral neck exploration.

Sulfate transport is not impaired in pendred syndrome thyrocytes.

Pendred syndrome is the most common form of syndromic deafness, characterized by dyshormonogenic goiter associated with sensory-neural deafness. The gene responsible for the disease (PDS) has been cloned, but its function is as yet unknown and the connection between thyroid goiter and sensory-neural deafness remains an enigma. PDS codes for a novel protein, pendrin, which is closely related to a number of sufate transporters. Mechanisms by which abnormal sulfate transport could deleteriously affect iodide organification have been proposed. We tested sulfate transport in thyrocytes obtained from Pendred syndrome patients and found that it was not defective. This suggests that pendrin in fact may not be a sulfate transporter, and emphasizes the importance of functional studies on this novel protein.

Combined endoscopic and surgical management of Mirizzi syndrome.

Mirizzi syndrome is a form of obstructive jaundice caused by a stone impacted in the gallbladder neck or the cystic duct that impinges on the common hepatic duct with or without a cholecystocholedochal fistula. This syndrome is a rare complication of cholelithiasis that accounts for 0.1% of all patients with gallstone disease. Preoperative recognition is necessary to prevent injury to the common duct during surgery. We present a patient with a preoperative diagnosis of type I Mirizzi syndrome that was confirmed and drained by endoscopic retrograde cholangiography (ERC), followed by subtotal cholecystectomy. A review of the literature covering its clinical presentation, diagnosis, and surgical treatment is also presented.

Expression of the insulin-like growth factors and their receptors in adenocarcinoma of the colon.

AIMS: To study changes in the expression of insulin-like growth factors (IGFs) and their receptors, as well as production of the IGF-I and IGF-II polypeptides, in adenocarcinoma of the colon. METHODS: Malignant tissue obtained at operation was used. Total RNA was extracted and specific IGF-I and IGF-II and their receptor mRNAs were measured by a solution hybridisation RNase protection assay. IGF-I and IGF-II polypeptides were measured by specific immunoassays. RESULTS: All normal tissues expressed IGF-II, IGF-I receptor, and IGF-II/mannose-6-phosphate (Man-6-P) receptor. IGF-I mRNA could not be detected but the polypeptide was present in small but equal amounts in normal and malignant tissue. IGF-II was expressed 40 times more abundantly in colonic tumours than in adjacent normal tissue and the concentration of the corresponding polypeptide was twice as high in the malignant tissue. IGF-I receptor expression was increased by a factor of 2.5 and IGF-II/Man-6-P receptor by a factor of 4. CONCLUSIONS: This study confirms that in adenocarcinoma of the human colon there is increased expression of IGF-I receptor and IGF-II. Furthermore, IGF-II/Man-6-P receptor message is increased and the increase in IGF-II message is accompanied by a doubling of the IGF-II protein in the tumour tissue compared with the adjacent normal tissue. These findings suggest that the IGF-II/Man-6-P receptor may also be involved in development of adenocarcinoma of the colon. There is rapidly accumulating evidence implicating the IGF system in the development of malignancy of the large bowel.

Placement of a peritoneal dialysis catheter with routine omentectomy--does it prevent obstruction of the catheter?

OBJECTIVE: To find out if routine omentectomy reduced the incidence of obstruction and other complications of catheters inserted for continuous ambulatory peritoneal dialysis (CAPD). DESIGN: Retrospective study. SETTING: Teaching hospital, Israel. SUBJECTS: 60 patients with end stage renal failure who needed catheters for CAPD. INTERVENTION: Routine omentectomy during insertion of the catheter, usually under local anaesthesia. MAIN OUTCOME MEASURES: Short and long term morbidity, and mortality. RESULTS: No patient died as a result of the procedure. The catheter obstructed in only one patient (2%) during a mean follow-up period of 28 months (range 2-108), and 90% of the catheters survived one year. CONCLUSIONS: Routine omentectomy during insertion of a catheter for CAPD under local anaesthesia is safe and the incidence of obstruction is low. Prospective randomised studies are needed before it can be recommended as the procedure of choice.

Small-bowel pandiverticulosis--a potential source of recurrent gastrointestinal bleeding. Report of a case and review of the literature.

Acquired diverticulae of the jejunum and ileum are uncommon and usually asymptomatic in most patients. Rarely they may cause intestinal obstruction, acute peritonitis due to perforation, or gastrointestinal hemorrhage. In most cases only a few diverticulae are present, and owing to their location diagnosis is often delayed. We herein report an unusual case of extensive panjejunoileal diverticulosis that induced recurrent gastrointestinal bleeding. Although rare, this disorder should be considered in the evaluation of obscure gastrointestinal bleeding.

Salivary gland transplantation: a canine model.

Impaired salivary function with resultant severe dryness of the mouth, or xerostomia, may occur in association with a variety of systemic disorders or therapies. No adequate treatment exists for this debilitating condition, which impedes normal oral function, in particular alimentation and phonation. This study explores the feasibility of salivary gland autotransplantation, using a canine model. A salivary gland with its duct and surrounding blood vessels still attached was excised and reimplanted in the dog's thigh by anastomosing the graft's blood vessels to the femoral artery and vein. The duct was sutured to an artificial orifice cut in the thigh's skin, from which the saliva was collected. Salivary secretion was induced by a single intravenous bolus of pilocarpine (5 mg). Preoperative (normal) salivation was measured by collecting saliva from the gland in situ. Periodic functional studies showed normal saliva production during the first month after grafting, after which the salivary flow was reduced by 35% over the next 2 months. This reduction was interpreted as a sign of disuse atrophy resulting from the lack of autonomic innervation. To overcome this impediment, oral pilocarpine (5 mg/day) was administered to the recipient dog, after which normal levels of saliva were excreted through the graft during the 3-month follow-up period. The quality of the graft saliva was assessed by its protein and electrolyte levels, which showed close to normal values.