Efficacy and tolerability of combination cisplatin and ifosfamide chemotherapy with vaginal cuff brachytherapy in the first line treatment of uterine carcinosarcoma.

PURPOSE OF INVESTIGATION: A retrospective study to evaluate six cycles of cisplatin 40 mg/m2 on day 1 and ifosfamide 1,200 mg/m2 daily on days 1 to 4 with Mesna every four weeks as first line treatment for 29 patients with a diagnosis of uterine carcinosarcoma. MATERIALS AND METHODS: A total of 23 of 29 patients received high dose rate intracavitary vaginal cuff brachytherapy (VCBT) with two fractions of seven Gy each. Median age was 65 years (range 40-82); 13 (44.8%) had Stage I disease, three (10.3%) had Stage II, eight (27.6%) had Stage III, and five (17.2%) patients had Stage IV disease. RESULTS: Most common toxicities were anemia grade 1 (35%)/grade 2 (45%), and neutropenia grade 3 (17%)/grade 4 (6.9%). Eleven dose modifications, four treatment discontinuations, and one patient withdrawal occurred. At a median follow up of 45 months (range 9 to 144), Progression free survival (PFS) was 20% and overall survival (OS) was 40% for Stage IV, PFS 75% and OS 62.5% for Stage III, compared to a PFS 75% and OS 72.2% for Stages I-II. Median OS for the entire group was 12.43 years (95% CI 3.69 to inf); for Stage I-III 12.4 years (6.1 to inf), and for Stage IV 15.6 months (95% CI 9.4 to inf). CONCLUSIONS: Cisplatin and ifosfamide chemotherapy with VCBT was well tolerated and has promising activity in uterine carcinosarcoma.

Downregulation of membrane complement inhibitors CD55 and CD59 by siRNA sensitises uterine serous carcinoma overexpressing Her2/neu to complement and antibody-dependent cell cytotoxicity in vitro: implications for trastuzumab-based immunotherapy.

BACKGROUND: We evaluated the expression of CD46, CD55 and CD59 membrane-bound complement-regulatory proteins (mCRPs) in primary uterine serous carcinoma (USC) and the ability of small interfering RNA (siRNA) against these mCRPs to sensitise USC to complement-dependent cytotoxicity (CDC) and antibody (trastuzumab)-dependent cellular cytotoxicity (ADCC) in vitro. METHODS: Membrane-bound complement-regulatory proteins expression was evaluated using real-time PCR (RT-PCR) and flow cytometry, whereas Her2/neu expression and c-erbB2 gene amplification were assessed using immunohistochemistry, flow cytometry and fluorescent in-situ hybridisation. The biological effect of siRNA-mediated knockdown of mCRPs on HER2/neu-overexpressing USC cell lines was evaluated in CDC and ADCC 4-h chromium-release assays. RESULTS: High expression of mCRPs was found in USC cell lines when compared with normal endometrial cells (P<0.05). RT-PCR and FACS analyses demonstrated that anti-mCRP siRNAs were effective in reducing CD46, CD55 and CD59 expression on USC (P<0.05). Baseline complement-dependent cytotoxicity (CDC) against USC cell lines was low (mean ± s.e.m.=6.8 ± 0.9%) but significantly increased upon CD55 and CD59 knockdown (11.6 ± 0.8% and 10.7 ± 0.9%, respectively, P<0.05). Importantly, in the absence of complement, both CD55 and CD59, but not CD46, knockdowns significantly augmented ADCC against USC overexpressing Her2/neu. CONCLUSION: Uterine serous carcinoma express high levels of the mCRPs CD46, CD55 and CD59. Small interfering RNA inhibition of CD55 and CD59, but not CD46, sensitises USC to both CDC and ADCC in vitro, and if specifically targeted to tumour cells, may significantly increase trastuzumab-mediated therapeutic effect in vivo.

In vitro activity of pertuzumab in combination with trastuzumab in uterine serous papillary adenocarcinoma.

BACKGROUND: Uterine serous papillary adenocarcinoma (USPC) is a rare but highly aggressive variant of endometrial cancer. Pertuzumab is a new humanised monoclonal antibody (mAb) targeting the epidermal growth factor type II receptor (HER2/neu). We evaluated pertuzumab activity separately or in combination with trastuzumab against primary USPC cell lines expressing different levels of HER2/neu. METHODS: Six USPC cell lines were assessed by immunohistochemistry (IHC), flow cytometry, and real-time PCR for HER2/neu expression. c-erbB2 gene amplification was evaluated using fluorescent in situ hybridisation (FISH). Sensitivity to pertuzumab and trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) was evaluated in 5 h chromium release assays. Pertuzumab cytostatic activity was evaluated using proliferation-based assays. RESULTS: Three USPC cell lines stained heavily for HER2/neu by IHC and showed amplification of the c-erbB2 gene by FISH. The remaining FISH-negative USPCs expressed HER2/neu at 0/1+ levels. In cytotoxicity experiments against USPC with a high HER2/neu expression, pertuzumab and trastuzumab were similarly effective in inducing strong ADCC. The addition of complement-containing plasma and interleukin-2 increased the cytotoxic effect induced by both mAbs. In low HER2/neu USPC expressors, trastuzumab was more potent than pertuzumab in inducing ADCC. Importantly, in this setting, the combination of pertuzumab with trastuzumab significantly increased the ADCC effect induced by trastuzumab alone (P=0.02). Finally, pertuzumab induced a significant inhibition in the proliferation of all USPC cell lines tested, regardless of their HER-2/neu expression. CONCLUSION: Pertuzumab and trastuzumab induce equally strong ADCC and CDC in FISH-positive USPC cell lines. Pertuzumab significantly increases tratuzumab-induced ADCC against USPC with a low HER2/neu expression and may represent a new therapeutic agent in patients harbouring advanced/recurrent and/or refractory USPC.

Selective use of perioperative ERCP in patients undergoing laparoscopic cholecystectomy.

BACKGROUND/AIMS: Management of common bile duct stones in the era of laparoscopic surgery is still controversial. The purpose of this study is to investigate the safety, feasibility, success rate and short-term results of the selective use of endoscopic retrograde cholangiopancreatography in patients undergoing laparoscopic cholecystectomy. METHODOLOGY: A prospective study comprising 300 consecutive patients with either symptomatic or complicated gallbladder stones was performed between January 1994 and November 1996. Depending on clinical, laboratory and ultrasonographic criteria, 73 patients (24.3%) underwent endoscopic retrograde cholangiopancreatography with or without endoscopic sphincterotomy. The procedure was successful in 71 patients (97%) either preoperatively in 62 patients (21%) or postoperatively in 9 patients (3%). RESULTS: Endoscopic retrograde cholangiopancreatography was positive in 37 cases (52%), endoscopic sphincterotomy and stone extraction was performed in 35 cases and endoscopic sphincterotomy alone was performed in 2 cases for benign papillary stenosis. The overall predictive value for the presence of common bile duct stone was 52%, the predictive value for patients with jaundice, dilated common bile duct together with elevated liver enzymes was 73.3%. Complications of perioperative endoscopic retrograde cholangiopancreatography were encountered in 4 patients (5.5%) with no mortality. CONCLUSIONS: We conclude that the combination of perioperative endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy is a useful approach for the management of choledochocholelithiasis.

Management of gallbladder stones during pregnancy: conservative treatment or laparoscopic cholecystectomy?

BACKGROUND/AIMS: Safety of laparoscopic cholecystectomy (LC) during pregnancy is still controversial, we report our experience in the management of 42 pregnant patients suffering from symptomatic gallbladder stones. METHODOLOGY: Between June 1993 and July 1998, we performed 1700 LC's. During this period we dealt with 42 pregnant patients who had symptoms of gallbladder stones. Following an initial period of conservative management, only 16 patients underwent LC during pregnancy and 26 patients responded to medical management and were operated upon later on after delivery. RESULTS: Sixteen patients were operated upon successfully during pregnancy, 2 in the 1st trimester, 10 in the 2nd trimester and 4 in the 3rd trimester. No complications occurred and all patients carried on their pregnancies to term and delivered healthy babies. CONCLUSIONS: From our experience and from the review of the literature on this subject, LC during pregnancy is safe, however the indications should be restricted to patients with complications or to those suffering from repeated and persistent symptoms not responding to medical management.

Esophageal foreign bodies.

OBJECTIVE: A retrospective review was performed on 180 patients from 1975 to 1997 to evaluate the diagnosis, and management of esophageal foreign bodies. METHODS: All patients except two were symptomatic and 145 of them were younger than 14 years of age. Plain films were performed in every patient with a suspected esophageal foreign body (EFB). In all patients, rigid esophagoscopy was done under general anesthesia once the diagnosis of impacted EFB is made. RESULTS: Fifty-five percent of the foreign bodies were coins. In children, the majority of impacted esophageal foreign bodies were located at the level of the cricopharyngeus muscle while in adults the site of impaction was the lower esophageal sphincter. The most common symptoms were vomiting and or regurgitation. Of the 180 EFBs encountered, 169 were extracted endoscopically, five were pushed into the stomach, five were not found, and one patient needed cervicotomy. There were no deaths in this series. Predisposing factors were found in 15 patients. Fifteen patients (8.3%) had benign strictures. In ten patients (5.5%), minor complications were encountered, none of which were esophagoscopically related. Alternative diagnostic and therapeutic modalities are discussed. CONCLUSIONS: All patients with a history of suspected foreign body ingestion should have direct endoscopic examination. If the EFB is not detected a thorough radiographic examination, including CT scan, should be performed to detect a possible intra- or extraluminal object. Preservation of the airway is regarded to be the most important consideration in esophageal foreign body management.

Preoperative ultrasonography and prediction of technical difficulties during laparoscopic cholecystectomy.

A prospective study was carried out to investigate the value of preoperative ultrasound findings for predicting difficulties encountered during laparoscopic cholecystectomy (LC). Altogether 160 consecutive patients with symptomatic gallbladder (GB) disease (130 females, 30 males) referred to the Jordan University Hospital were recruited for the purpose of this study. All patients underwent detailed ultrasound examination 24 hours prior to LC. The overall difficulty score (ODS), as a dependent variable, was based on the following operative parameters: duration of surgery, bleeding, dissection of Calot's triangle, dissection of gallbladder wall, adhesions, spillage of bile, spillage of stone, and difficulty of gallbladder extraction. Multiple regression analysis was used to assess the significance of the following preoperative ultrasound variables (independent) for predicting the variation in the ODS: size of the GB, number of GB stones, size of stones, location of GB stones, thickness of GB wall, common bile duct (CBD) diameter, and liver size. Only thickness of GB wall and CBD diameter were found to be significant predictors of the variation in the ODS (adjusted R2 = 0.25). We conclude that the preoperative ultrasound examination is of value for predicting difficulties encountered during LC, but it is not the sole predictor.

Foodhandler-associated Salmonella outbreak in a university hospital despite routine surveillance cultures of kitchen employees.

OBJECTIVE: To describe an outbreak of salmonella food poisoning that probably was due to contamination of mashed potatoes by a foodhandler, which occurred despite a policy for routine surveillance stool cultures of kitchen employees. DESIGN: A case control study of 223 individuals who ate the lunch meal on September 23, 1989, at the Jordan University Hospital (JUH) cafeteria. SETTING: Tertiary care university hospital in Amman, the capital of Jordan. PATIENTS: Individuals who developed loose stool or vomiting 6 to 72 hours after eating the lunch meal of September 23, 1989, at the JUH cafeteria. RESULTS: Of 619 individuals, 183 fit the case definition (attack rate, 19.6%); 150 were employees, 26 were inpatients, and seven were visitors. Twelve other employees became sick 4 to 6 days later and probably were infected secondarily. The incubation period ranged from 16 to 72 hours in 183 instances. Symptoms included diarrhea (88%), fever (71%), abdominal pain (74%), dehydration (34%), and bloody stool (5%). Eighty-four were hospitalized. Cultures of eight food items were negative, but stool culture on 90 of 180 patients and 11 of 61 kitchen employees yielded Salmonella enteritidis group D. A cohort study of 223 individuals revealed a food-specific attack rate of 72% for the steak and potato meal and 18% for the rice and meat meal (RR, 4; CI95, 2.62 to 6.24; P < 0.01). Stratified analysis of the steak and potato meal revealed that the potatoes were implicated most strongly (RR, 1.93; CI95, 1.42 to 2.64; P < 0.01). Cultures were obtained from all kitchen employees, and 11 of 61 grew Salmonella enteritidis group D. One asymptomatic, culture-positive employee prepared the mashed potatoes on September 23. All of these employees had negative stool cultures 3 months earlier. CONCLUSION: This outbreak probably was caused by massive contamination of mashed potatoes by the contaminated hands of the foodhandler. Routine stool culture of foodhandlers is not cost-effective and should not be used as a substitute for health education and proper hygienic practices.

Hereditary thrombophilia among 217 consecutive patients with thromboembolic disease in Jordan.

This is a four-year prospective study on patients admitted or referred with thromboembolic disease to Jordan University Hospital or to the Thrombosis/Haemostasis Laboratory at the University of Jordan. The aim of the study was to find the relative prevalence of hereditary thrombophilia. For the purpose of this work, hereditary thrombophilia was diagnosed in the absence of an acquired cause of thrombophilia in addition to two of the following: 1) positive family history of thrombophilia, 2) confirmed same deficiency in a closely related family member, 3) the deficient protein is constantly below 2 SD of the normal mean on repeated testing. All ages were admitted to the study. Acquired systemic factors or local factors known to cause thrombosis or affect the levels of proteins opposing thrombosis were excluded. There were a total of 217 patients (102 males and 115 females) with confirmed thromboembolic disease. Their mean age was 34 years. A total of 49 patients (26 males and 23 females) fulfilled the criteria of hereditary thrombophilia. There were 17 cases of protein C deficiency (PC), 15 protein S deficiency (PS), 10 antithrombin III deficiency (ATIII), 3 dyfibrinogenemia, 2 heparin cofactor II deficiency, and 2 plasminogen defects. In this group most of the thrombosis was venous. A positive family history was obtained in 65.3% of patients with hereditary thrombophilia. Twenty-seven additional relatives with deficiency were identified upon family studies. The calculated prevalence of hereditary thrombophilia in Jordan is put at 1/25,000. Screening for PC, PS, and ATIII is advocated in young patients who have thromboembolic disease, especially when there is a positive family history of thrombosis.

Lack of effect of certain histamine H2-receptor blockers on the glucuronidation of 7-hydroxy-4-methylcoumarin by human liver microsomes.

Contrary to the general belief that cimetidine and ranitidine spare glucuronidation of drugs, some authors have indicated that both cimetidine and ranitidine could inhibit the glucuronidation of paracetamol (acetaminophen) by cultured rat hepatocytes. Thus, we tested the effect of three histamine H2-receptor blockers (cimetidine, ranitidine and famotidine) on the glucuronidation of 7-hydroxy-4-methylcoumarin (7-OH-4-MC) by human liver microsomes. None of the drugs studied produced significant inhibition of the glucuronidation of 7-OH-4-MC when used at concentrations up to 1.5 mM. Thus, even the new H2-receptor blocker, famotidine, spares glucuronidation. These findings further support the previous reports which suggest that glucuronide conjugation in humans is spared by H2-receptor blockers.

Volvulus of the sigmoid colon in Jordan.

This report discusses 27 patients with sigmoid volvulus treated at Jordan University Hospital (JUH) during a 15-year period. These patients represented 4.7 percent of adult patients treated for intestinal obstruction in the same period. The average age was 54.5 years, and none of the patients was institutionalized. Twenty-five patients presented with acute symptoms, and two had chronic symptoms. Sigmoidoscopic detorsion was achieved in 15 patients. Emergency resection was required in two of these patients: for the development of gangrene a few hours after detorsion in one patient and for recurrence within 24 hours in the other despite the presence of a rectal tube. Early recurrence occurred in two other patients and was managed endoscopically. Emergency surgery was performed in 10 other patients: for a failed endoscopic detorsion in three patients, for ulcerated and bleeding mucosa forecasting gangrene in another, and as a primary treatment in six patients who were either misdiagnosed or suspected to have gangrenous bowel. Elective resection was performed in 13 patients. The mortality rate was 15 percent (4/27) for the whole series and 33.3 percent (1/3) for those with gangrenous bowel.

Adrenal cysts: diagnosis and management.

We present 7 patients (5 adult females and 2 neonate males) with adrenal cysts. The cysts included 1 hydatid, 1 lymphatic and 5 pseudocysts. Three cysts were diagnosed preoperatively and all were resected surgically. The existence of true epithelial cysts of the adrenal gland is doubted by many authors; the present series includes most types of adrenal cyst.

Ketamine hydrochloride as sole anesthetic for open liver biopsy.

We evaluated the use of ketamine as sole anesthetic agent for open liver biopsy, with particular reference to its effect on liver function and hepatotoxicity and its effect on cardiovascular stability and respiration. From 386 patients who underwent liver biopsy at Jordan University Hospital, 12 had open liver biopsy because of contra-indications for closed needle biopsy. The surgical procedure consisted of a small right paramedian incision allowing inspection of the liver surface and a wedge and needle biopsy. Ketamine HCl was used in a dose of 2 mg/kg I.V. with supplemental doses as necessary. No significant fluctuations in cardio-respiratory vital signs were observed. Muscle rigidity and respiratory tagging movements necessitated addition of a muscle relaxant and artificial ventilation in three patients. Six patients reported dreams, two of which were described as nightmares. There was no liver function decompensation, or significant bilirubin or transaminase elevations in the week following the biopsy. Ketamine is a safe anesthetic to use for open liver biopsy in patients with underlying liver disease, although poor muscle relaxation and nightmares may be significant side effects.

Inhibition of ileal and colonic ornithine decarboxylase activity by alpha-difluoromethylornithine in rats: transient atrophic changes and loss of postresectional adaptive growth.

To determine the role of putrescine synthesis in adaptive hyperplasia of the ileum and colon, DL-alpha-difluoromethylornithine (DFMO), an enzyme-activated, irreversible inhibitor of ornithine decarboxylase (ODC), the enzyme controlling putrescine biosynthesis, was fed to rats after excision of the proximal half of the small bowel. A rise in ODC activity (280% in the proximal ileum, 62% in the proximal colon) and a rise in putrescine content (220% in the proximal ileum, 250% in the proximal colon) normally accompanied characteristic cytochemical adaptive increases in the ileum and colon at day 6. Inclusion of 1% DFMO (2.1 gm/kg/day) in drinking water for 12 hours before operation and for 14 days thereafter decreased ODC activity by 85% to 96%, reduced levels of putrescine and spermidine and measurements of the adaptive response by 50% in the ileum, and abolished the adaptive response in the colon. During the first 10 days of DFMO feeding, villous atrophy and other hypoplastic changes occurred in control rats, but by 14 days of DFMO feeding atrophy and hypoplasia were no longer present. Although DFMO inhibits adaptive hyperplasia occurring in the ileum and colon of rats after resection of the proximal half of the small bowel, spontaneous recovery of villous atrophy occurs during further DFMO feeding and may protect the host during chemotherapy.

HLA antigens, blood groups and immunoglobulin levels in idiopathic thrombocytopenic purpura.

Thirty-three patients with idiopathic thrombocytopenic purpura (ITP) were tested for HLA-A, B and C antigens, platelet antibodies, immunoglobulin levels and ABO blood groups. With one exception, ITP proved not to be significantly associated with the HLA antigens studied; an increased frequency of HLA-A28 was found in chronic ITP patients (50 vs. 18.7% in the control population). An increased incidence of blood group A was found in ITP patients (64 vs. 37.98% in the control population), especially in those with acute ITP (84.7%). A significant reduction of IgG levels was noted in patients with chronic ITP, while below-normal levels of IgA were found in both chronic and acute ITP patients. There was no difference in levels of IgM. Circulating platelet isoantibodies were demonstrated in 67.6% of the ITP patients. No correlation was demonstrated between the presence of platelet antibodies, immunoglobulin levels of HLA antigens.

Potentiation of 1,2-dimethylhydrazine-induced anal carcinoma by epidermal growth factor in mice.

Because epidermal growth factor (EGF) can modify cell proliferation in the gastrointestinal tract, effects of EGF were studied on the development of colonic, rectal, and anal neoplasms in male mice treated with 1,2-dimethylhydrazine (DMH) (20 mg/kg/wk for 20 weeks). DMH treatment caused a 13% increase in colonic RNA content, a 16% increase in DNA content, and 28% greater crypt depth. EGF (5 micrograms on alternate days during weeks 20 to 22) administered to DMH-treated mice produced no additional changes in colonic mucosa. At 30 weeks colorectal tumors were present in 13 of 20 mice treated with DMH (mean number of tumors per mouse 2.3 +/- 0.5) and 18 of 24 mice (mean 2.6 +/- 0.7) treated with DMH and EGF. Anal tumors were present in two of 20 DMH-treated mice (mean 0.1 +/- 0.07) but in eight of 24 DMH-EGF-treated mice (mean 0.33 +/- 0.1) (X2 = 4.84; p less than 0.05 for prevalence). Although EGF in this dose has no effect on the frequency of colorectal adenocarcinomas, the frequency of anal squamous cell carcinomas is increased more than three fold.

Therapeutic effect of vincristine, adriamycin and prednisolone (VAP) in angioimmunoblastic lymphadenopathy (AIL).

Five patients, three males and two females, with angioimmunoblastic lymphadenopathy (AIL) are described. The two who received steroids had no response and died 2 and 6 months later. The three patients who received vincristine, adriamycin and prednisolone (VAP) went into remission early and are still in remission with a follow-up of 22-35 months. It is concluded that VAP is effective therapy in AIL.

Laryngocele: an acquired condition.

A 20-year-old female underwent excision of the submandibular gland for chronic sialadenitis and salivary calculus. She developed a wound hematoma which became infected. A wound abscess occurred which discharged spontaneously into the larynx and led to the formation of a combined laryngocele. This was excised, and the patient made a smooth recovery. There is no evidence of recurrence after two years.