Raf kinase inhibitor protein: mechanism of loss of expression and association with genomic instability.

AIMS: Raf kinase inhibitory protein (RKIP; also known as PEBP, for phosphatidylethanolamine-binding protein) is an endogenous inhibitor of the Raf- MAPK kinase (MEK)-MAP kinase pathway. It has emerged as a significant metastasis suppressor in a variety of human cancers including colorectal cancer (CRC) and was recently shown to regulate the spindle checkpoint in cultured cells. This study aims at correlating RKIP expression with chromosomal instability in colorectal cancer samples and identifies possible mechanisms of RKIP loss. METHODS: Chromosomal instability was assessed using metaphase-based comparative genomic hybridisation (CGH) and loss of heterozygosity (LOH) in 65 cases with microsatellite stable CRC and correlated with RKIP expression. Methyl-specific PCR was used on DNA extracted from 82 cases with CRC to determine CpG methylation status at the RKIP promoter and the results correlated with RKIP protein expression. RESULTS: We demonstrate for the first time that in microsatellite stable (MSS) CRC, the number of chromosomal losses is inversely proportional to RKIP expression levels. We also show that methylation of the RKIP promoter is a major mechanism by which RKIP expression is silenced in CRC. CONCLUSIONS: RKIP loss by hypermethylation of its promoter could have a significant influence on colorectal cancer aneuploidy, which might explain its association with metastatic progression.

Pain during mammography: impact of breast pathologies and demographic factors.

OBJECTIVES: The aim of this study was to systematically assess the pain experienced by patients undergoing mammography for various clinical presentations. SUBJECTS AND METHODS: Two hundred and twenty-five patients aged 25-85 years (45.43 +/- 8.25 years) presenting for mammography were included in the study. Presenting symptoms and clinical diagnosis were provided by the referring physicians and demographic information was obtained from self-reported questionnaires. Mammography results were recorded by the radiologist. Two different but reliable and valid measures of pain--Visual Analog Scale (VAS) and Pain/Discomfort Rating Scale (DRS)--were used to assess pain during mammography and data were statistically analyzed to examine the possible predictors of pain. RESULTS: Forty-nine percent of the patients reported pain during mammography when cut-off level of VAS score was 40; however, when the cut-off level was raised to 60 (considering the preexisting pain as presenting symptom in some patients) only 23% reported pain. With DRS, 7% reported pain, 27% discomfort and 66% neither pain nor discomfort. Biserial correlation between the VAS and DRS scores suggested strong positive agreement between the two measures of pain (r = 0.56, d.f. = 90, p < 0.01). Patients presenting with coexisting breast lumps and preexisting breast pain and those diagnosed with inflammatory conditions of the breast and fibrocystic changes experienced more pain during mammography. CONCLUSION: Preexisting breast pathologies and demographic factors such as age and educational level of the patient were important in reporting pain during mammography. This finding indicates that proper assessment of pain using standard measures and its association with breast pathologies and demographic factors is important for planning pain management in women undergoing mammography.

Reference levels of the tumor markers carcinoembryonic antigen, the carbohydrate antigens 19-9 and 72-4, and cytokeratin fragment 19 using the Elecsys Relecsys 1010 analyzer in a normal population in Kuwait. The importance of the determination of local reference levels.

The tumor markers CEA, CA 19-9, CA 72-4 and CYFRA 21-1 were analyzed in a group of apparently healthy subjects (n=232) in Kuwait using the Elecsys Relecsys 1010 analyzer. The distribution of the tumour marker levels was analyzed separately in Kuwaitis (n=103), non-Kuwaitis (n=129), smokers (n=68), non-smokers (n=164), males (n=138) and females (n=94). The distribution of CEA was significantly different in Kuwaitis vs. non-Kuwaitis in the total population (p=0.033) and in non-smokers (p=0.049); in males vs. females in the total population (p<0.0001) and in non-smokers (p=0.0002); and in smokers vs. non-smokers in the total population (p<0.0001) using the non-parametric Mann-Whitney U test. None of the other tumour markers showed significant differences in the subgroups. The upper reference level was defined as the 95th percentile of the normal values in each group. A higher reference level of CEA was observed in smokers (vs. non-smokers) in the total population. Also higher reference levels of CEA were observed in males (vs. females) both in the total population and in non-smokers. In the total population the respective reference levels were: CEA: 4.4 microg/L, CA 19-9: 35 kU/L, CA 72.4: 2.4 kU/L, and CYFRA 21.1: 2.1 microg/L. These results were compared with data in the kit inserts and literature data. The impact of 95th percentiles in a local heterogeneous population is discussed.

Effectiveness of laparoscopic fundoplication for gastro-oesophageal reflux.

BACKGROUND: Gastro-oesophageal reflux (GERD) is a common condition. Many patients respond to conservative therapy. Severe symptomatic cases and those who fail medical treatment are referred to surgery. The long-term results of open fundoplication surgery have been good with a more than 90% response after 10 years of follow-up. The introduction of laparoscopic fundoplication achieved the same results with shorter hospital stay, a better cosmetic result and less cost to the health care providers. PATIENTS AND METHODS: 74 patients who failed medical treatment for GERD were treated by laparoscopic fundoplication. The Toupet procedure was performed in 66 of these patients, the others patients had a Nissen-type fundoplication. The patients were followed up for a mean period (+/- SD) of 14.8 +/- 8.8 months (range 3-33 months). RESULTS: Most of the patients were males (n = 65). The mean age (+/- SD) of all the patients was 36.1 +/- 9.5 years (range 17-60 years). The majority (93.8%) reported disappearance of symptoms and are not using any antireflux medications. Five patients (6.7%) are considered failures of the procedures. Of these, three patients developed recurrence of reflux symptoms during the follow-up period. The other two patients developed complications, i.e. gas bloat, persistent vomiting and dysphagia which warranted taking down the wraps laparoscopically. Two patients developed a small incisional hernia at the site of the 10 mm port. The mean of hospital stay (+/- SD) was 3.1 +/- 1.3 days (range 1-7 days). CONCLUSION: Laparoscopic fundoplication is safe and effectively relieves reflux symptoms in patients who fail medical treatment.

Prognostic significance of CEA and CA 19-9 in colorectal cancer in Kuwait.

Preoperative CEA and CA 19-9 levels have been used in the past as prognostic indicators in colorectal cancer, but Dukes' stage is still considered to be the most important prognostic factor. Recent survival estimates may have been influenced by the fact that in the last decade adjuvant chemotherapy and postoperative irradiation have been included in the routine management of advanced-stage disease. In a heterogeneous Kuwaiti population higher reference levels (95th percentile) of CEA and CA 19-9 have been found than those usually employed. In the present study 62 patients with Dukes' stage B + C could be analyzed for two-year disease-free survival (DFS). Relapse was observed in 19 patients, 28 patients were disease free and 15 patients with censored observations were included. No significant difference in DFS was observed in Dukes' B (69%) versus Dukes' C (48%) patients (p = 0.09). On the other hand, Dukes' stage B + C patients with elevated preoperative levels of CEA or CA 19-9 had a significantly poorer DFS than patients with normal levels. For CEA levels below or above the cutoff the DFS was 74% versus 23% (p = 0.003); for CA 19-9 levels below or above the cutoff the DFS was 71% versus 33% (p = 0.004). In 54 patients with Dukes' stage B + C for whom preoperative levels of both CEA and CA 19-9 were available multivariate analysis revealed a decreasing risk of relapse in the following order: CEA and/or CA 19-9 elevated (chi-square 7.09; p = 0.008), CA 19-9 elevated (chi-square 6.27; p = 0.01), CEA elevated (chi-square 5.47; p = 0.02), and Dukes' C (chi-square 2.08; p = 0.15 n.s.). Hence, novel treatment protocols may have improved the disease-free survival, but the use of adjuvant chemotherapy and/or radiotherapy is of questionable benefit in patients who have elevated levels of CEA and/or CA 19-9 prior to treatment.

Ultrasonographic diagnosis in abdominal tuberculosis.

Sonographic findings were retrospectively analysed in 39 patients with proven abdominal tuberculosis (TB). The patients were treated over 15 years at a major teaching hospital, Mubarak Al-Kabber Hospital, in Kuwait. The findings included clear or complex ascites with fine strands, loculations and debris. The other findings were lymphadenopathy, bowel wall thickening, omental mass, focal lesions in the liver and spleen and psoas abscess. The sonographic findings in abdominal TB are not specific but may give valuable information to prevent unnecessary laparotomy.

Repair of large, multiple, and recurrent ventral hernias: an analysis of 124 cases.

OBJECTIVE: To present our technique for repairing large, multiple, and recurrent ventral hernias, and describe our experience. DESIGN: Retrospective study. SETTING: Teaching hospital, Kuwait. SUBJECTS: 124 patients (4 men and 120 women, age range 25-60) who presented with recurrent (n = 34), multiple (n = 27), or large (n = 63) ventral hernias. INTERVENTION: Abdominoplasty through a bikini crease incision together with a diamond shaped incision to preserve the umbilicus on its vascular pedicle. After wide dissection the hernia was repaired by two layer, tension-free plication using the available lax tissues. Redundant tissue was excised. MAIN OUTCOME MEASURES: Duration of healing, depth of stay in hospital, complications, and recurrence. RESULTS: Most of the hernias (113, 91%) had healed within 12 days, and over the three quarters of patients had left hospital within 10 days (median duration of stay 8 days). There was one severe wound infection, 10 patients developed minimal necrosis of fat or skin (4 of which developed secondary infection), and there were 3 seromas. 3 Hernias (2%). CONCLUSION: We recommend this technique of abdominoplasty for large, multiple, or recurrent hernias, particularly in those patients who have pronounced prolapse of the abdominal wall.

Serial determinations of serum CEA in monitoring management of patients with colorectal carcinoma.

Serum concentrations were determined serially in two groups of patients with colorectal carcinoma: in 123 after curative resection and in 34 with residual cancer. Of the first group, in 98 serum CEA fluctuated within the normal range or with a 2-fold larger amplitude evidencing effective surgery because only 9 had recurrence; in 25 serum CEA rose persistently from a postoperative nadir indicating relapse, mostly liver metastases. Of the 34 patients with relapse, 3 had clinically and 7 CEA-directed second-look laparotomy; although 7 had operation with curative intent, only 3 remained disease-free. In the second group, there were 26 patients after palliative surgery and 8 during nonsurgical treatment. Serum CEA fluctuated within the normal range in 2 patients in remission and in 3 with progressive cancer, and rose in parallel to cancer progression in 29. Thus, serum CEA within or slightly above the normal range was 88% predictive that the patient might be free of disease or in remission; whereas elevated or rising level indicated disease progression. Accordance between serum CEA and clinical status occurred in 145 of 157 (92%) patients.

Successful immunotherapy in a murine metastasizing fibrosarcoma model.

Antigenic differences were demonstrated between the primary murine fibrosarcoma and its metastases. Immunization with irradiated primary tumor cells (TC) protected C57B1/6J mice against subsequent challenge with those cells, but not against challenge with cells from pulmonary metastases (PMC). Mice immunized with irradiated PMC were protected from challenge with those cells, but not against challenge with TC. Mice with fibrosarcomas produced by the injection of 5 X 10(3) cells from the primary tumor were treated by resection of the tumor-bearing limb (Amp), Amp plus cyclophosphamide (Amp + Cy), Amp plus primary TC (Amp + TC), Amp plus primary TC and from its metastatic variant (Amp + TC + PMC), and with combinations of the last two groups with Cy. Although Amp + Cy improved survival, no animal lived 100 days and metastases increased as compared to controls. Immunotherapy significantly improved survival and decreased pulmonary metastases. Antigen combinations from primary and metastatic tumors resulted in significantly better survival than did a single preparation only from TC. Chemotherapy did not enhance the results obtained with immunotherapy and surgery. Immunity conferred in long-term survivors was permanent.