Fascin is involved in the chemotherapeutic resistance of breast cancer cells predominantly via the PI3K/Akt pathway.

BACKGROUND: A major therapeutic challenge for breast cancer is the ability of cancer cells to evade killing of conventional chemotherapeutic agents. We have recently reported the actin-bundling protein (fascin) as a major regulator of breast cancer metastasis and survival. METHODS: Survival of breast cancer patients that received chemotherapy and xenograft tumour model was used to assess the effect of chemotherapy on fascin-positive and -negative breast cancer cells. Molecular and cellular assays were used to gain in-depth understanding of the relationship between fascin and chemoresistance. RESULTS: We showed a significant correlation between fascin expression and shorter survival in breast cancer patients who received chemotherapy. In xenograft experiments, fascin-positive cancer cells displayed significantly more resistance to chemotherapy-mediated apoptotic cell death than fascin-negative counterparts. This increased chemoresistance was at least partially mediated through PI3K/Akt signalling, and was paralleled by increased FAK phosphorylation, enhanced expression of the inhibitor of apoptosis proteins (XIAP and Livin) and suppression of the proapoptotic markers (caspase 9, caspase 3 and PARP). CONCLUSIONS: This is the first report to demonstrate fascin involvement in breast cancer chemotherapeutic resistance, supporting the development of fascin-targeting drugs for better treatment of chemoresistance breast cancer.

S-phase kinase protein 2 is an attractive therapeutic target in a subset of diffuse large B-cell lymphoma.

S-phase kinase protein 2 (SKP2), an F-box protein, targets cell-cycle regulators including cycle-dependent kinase inhibitor p27KiP1 via ubiquitin-mediated degradation. SKP2 is frequently overexpressed in a variety of cancer cells and has been implicated in oncogenesis; however, its role in diffuse large B-cell lymphoma (DLBCL) has not been elucidated. Therefore, we investigated the role of SKP2 and its ubiquitin-proteasome pathway in a large series (301) of DLBCL patient samples and a panel of DLBCL cell lines. Using immunohistochemistry, SKP2 was detected in 41.6% of DLBCL tumours and was inversely associated with p27Kip1 protein level. The DLBCL subset with high SKP2 and low p27Kip1 showed a strong correlation with the proliferating index marker Ki-67 (p < 0.0001) and also with the germinal centre phenotype (p = 0.0147). Treatment of DLBCL cell lines with bortezomib or expression of SKP2-specific siRNA causes down-regulation of SKP2 and accumulation of p27Kip1, leading to suppression of growth by inducing apoptosis. Furthermore, treatment of DLBCL cells with bortezomib causes apoptosis via involving the mitochondrial pathway and activation of caspases. Finally, treatment of DLBCL cells with bortezomib down-regulated the expression of XIAP, cIAP1, and survivin. Altogether, these results suggest that SKP2 and the ubiquitin-proteasome pathway may be a potential target for therapeutic intervention in DLBCL.

Extramedullary myeloid cell tumours localised to the mediastinum: a rare clinicopathological entity with unique karyotypic features.

Extramedullary myeloid cell tumour (EMMT) localised to the mediastinum is a rare manifestation of acute myeloid leukaemia, forming less than 4% of all cases of EMMT. In contrast to other types of EMMT, cytogenetic characteristics of this rare entity are relatively unknown. This report describes a patient with EMMT who had evidence of superior vena cava syndrome and normal peripheral blood counts at diagnosis. The results from an initial biopsy specimen were consistent with a diagnosis of mediastinal large B cell lymphoma. A diagnosis of acute myeloid leukaemia was made three months after initial diagnosis by bone marrow examination. Review of the initial biopsy specimen showed strong positivity for myeloperoxidase, revealing that the patient had been initially misdiagnosed as having large B cell lymphoma. Cytogenetic studies revealed a near triploid and near tetraploid karyotype with structural abnormalities in 12 and three metaphases, respectively. Review of the literature showed that a near tetraploid or triploid karyotype is found in most of the reported cases of mediastinal EMMT. Thus, the presence of a near triploid/tetraploid karyotype and mediastinal EMMT may represent a specific subset of EMMT. The biological relevance of this observation is discussed.

Unusual skin tumors in Langerhans' cell histiocytosis.

A case of Langerhans' cell histiocytosis with unusual skin manifestations in the form of multiple large skin tumors is described. The skin lesions responded partially to chemotherapy with etoposide and prednisone, and residual lesions were excised surgically. The patient developed central diabetes insipidus during treatment.

Spontaneous pneumothorax in metastatic choriocarcinoma.

We report a case of spontaneous bilateral pneumothoraces due to metastatic choriocarcinoma. The patient was successfully treated with tube thoracostomy and chemotherapy. Pneumothorax as a complication of choriocarcinoma has not been reported previously.

Cavitating pneumonia due to Trichosporon beigelii in a patient with acute myeloid leukaemia.

A 21-year-old man with acute myeloid leukaemia developed cavitating pneumonia while neutropenic and on broad spectrum antibiotics following induction chemotherapy. Trichosporon beigelii was isolated from several samples of sputum. He was successfully treated with amphotericin B. Previous reports of lung infection with this organism are reviewed.

Ceftazidime and amikacin as empiric treatment of febrile episodes in neutropenic patients in Saudi Arabia.

Sixty-four consecutive febrile episodes in 50 consecutive patients with malignancy and neutropenia were empirically treated with a combination of ceftazidime and amikacin. Of 52 analysable episodes, the response rate was 59.6% overall and 26.3% of episodes with microbiologically documented infections with septicaemia. Infection-related death occurred in 10 patients (19.2% of episodes). The response rates were similar in patients with acute leukaemia or other malignancies. Poor response is attributed to increased frequency of infections with Gram-positive and fungal organisms. A modified empiric regimen including cover for Gram-positive and fungal organisms is suggested in similar patient populations.

Significant elevation of protein C and protein S levels in thrombotic disorders by low dose danazol.

Six patients (three males and three females), mean age 35.2 years (range 31-43 years), with extensive venous thrombosis were studied. Initial laboratory data indicated that all patients had normal antithrombin III (ATIII), four patients had low protein C (PC), three patients had low protein S (PS) and two patients had low plasminogen. Four patients had high fibrinogen and all patients had reduced tissue-type plasminogen activator activity, elevated tissue plasminogen activator inhibitor and low fibrinolytic activity. All patients were treated with danazol, 5-7 mg/kg orally once daily. In all patients there was significant elevation of ATIII, PC, PS, and plasminogen, reduction in plasma fibrinogen and PAI and enhancement of fibrinolysis. During the 12-36 months period of follow-up, there were no symptoms or signs that suggested recurrence of thrombosis. Apart from weight gain of 5-10 kg and disturbed menstrual cycle in two women, no major side effects were seen. These data suggest that danazol is potentially useful therapy that may increase levels of natural anticoagulants in patients with thrombotic illnesses in which ATIII, PC and PS are low or normal. Further studies are needed to confirm these observations.

Primary thyroid lymphoma: a retrospective analysis of prognostic factors and treatment outcome for localized intermediate and high grade lymphoma.

Non-Hodgkin's lymphoma presenting in the thyroid gland is uncommon. A review of the King Faisal Specialist Hospital and Research Centre (KFSH & RC) experience was performed to assess treatment outcome and prognostic factors in this rare extranodal presentation of localized lymphoma. Sixty patients treated at KFSH & RC between 1975 and 1995 were identified, and their records were reviewed retrospectively. Eight patients who had stage III or IV disease, low grade, or did not complete their prescribed treatment were excluded from the study. There were 38 female and 14 male patients with a median age of 59.5 years at the time of diagnosis (range: 10-87 years). Thirty-five of the 52 patients underwent diagnostic partial or total thyroidectomy at other institutions based on a preoperative assumption of thyroid carcinoma. All 52 patients had non-Hodgkin's lymphoma of intermediate (94%) or high (6%) grade. Detailed staging was carried out in all patients; 16 patients (31%) had disease confined to the thyroid gland (stage IE), whereas 36 (69%) had associated disease in cervical lymph nodes and/or the mediastinum (stage IIE) disease. All patients were treated with curative intent. A total of 18 patients (35%) were treated with a single-modality treatment--radiotherapy alone in 2, chemotherapy alone in 13, and surgery alone in the remaining 3 patients. The majority of patients (34/52; 65%) were treated with a combined-modality approach. The overall relapse-free survival (RFS) and overall survival (OS) at 5 years were 72% and 88%, respectively. There were no significant differences in outcome between those treated with single-modality and those with combined-modality therapy. A univariate analysis showed that the presence of mediastinal lymph node involvement was the most important prognostic factor affecting both RFS and OS. Patients with Hashimoto thyroiditis and without "B" symptoms were found to have a significantly higher RFS without influence on the OS. However, patients who had a good performance status (PS) of 0, 1, and 2 were found to have a significantly higher overall survival in comparison to those with poor performance status. Age, sex, stage, histology, lactic acid dehydrogenase level, tumor bulk, and the treatment modality were not found to correlate with RFS or OS. Mediastinal involvement and PS were found to be the most important independent prognostic factors influencing RFS and OS.

Adding high-dose tamoxifen to CHOP does not influence response or survival in aggressive non-Hodgkin's lymphoma: an interim analysis of a randomized phase III trial.

PURPOSE: CHOP is the standard regimen currently used in the management of the majority of patients with aggressive non-Hodgkin's lymphoma (NHL). However, CHOP only produces 30-35% long-term survival. We hypothesized that adding high-dose tamoxifen, which is known to have multiple drug resistance-modulatory effects, to the CHOP regimen could increase the response rate, and consequently enhance the survival of patients with NHL. PATIENTS AND METHODS: In a prospective, controlled, and randomized study, eligible adult patients with aggressive NHL were randomized between CHOP only (Group I), or CHOP plus high-dose tamoxifen (Group II). The primary aim was to assess the effect of tamoxifen on complete response (CR) rate, with the secondary evaluation of tamoxifen potential impact on survival. The interim analysis of this study is presented. RESULTS: Fifty-one and forty-seven evaluable patients were randomized to Group I and Group II, respectively. The median age of all patients was 53 y (range 18-78 y). The two groups had comparable distributions of the pretreatment prognostic variables. The CR for patients in Group I was 80% (41 patients) as compared with 74% (35 patients) in Group II (P=0.48). Likewise, there was no apparent difference in the partial remission rates between the two groups (6% vs 15%, respectively). Of patients who initially attained CR, 15 (37%) and 10 (29%) subsequently relapsed in Groups II and I respectively (P = 0.45). The NHL International Prognostic Index (IPI) was the only factor that predicted attaining CR. At the time of this interim analysis, the actuarial-estimated overall survival (OS) probability (+/-S.E.) for the entire population at 5 y was 58% (+/-6) with no survival difference between the two groups (P=0.51). Only attaining CR and the IPI predicted OS probability. The probability of remaining event-free at 5 y (+/-SE) for those achieving CR was 72% (+/-9), and there was no significant difference between the two treatment groups (P=0.68). Toxicity profile was similar in the two groups. CONCLUSION: Based on this interim analysis, combining high-dose tamoxifen, as used in this study, with the CHOP regimen has failed to have any favorable effect on the outcome of patients with aggressive NHL, and therefore cannot be recommended for future trials.

Breast cancer in the eastern province of Saudi Arabia.

In the Kingdom of Saudi Arabia (KSA), hospital and population based statistics have shown that breast cancer has the highest crude frequency rate among Saudi women. The scarcity of reports about the disease in the KSA has been the impetus to this analysis about breast cancer in the eastern province of KSA. Data on female patients with invasive breast carcinoma seen at King Fahd Hospital of the University in the eastern province of KSA, were retrospectively reviewed. The analysis intended to examine the pattern of the disease and the outcome for patients. Between 1985 and 1995, 292 patients were identified. Their median age +/- SD (standard deviation) was 42 +/- 10.5 years. Most patients were younger than 50 years (78%) and were predominantly premenopausals (79%). Only 25 (9%) of patients had stage I cancer, whilst 130 (44%), 90 (30%), and 47 (16%) had stage II, III, and IV, respectively. Among patients with known axillary nodal status (242 patients), only 37% were node-negative whilst 32% and 31% had 1-3, and > or = 4 positive nodes, respectively. Adjuvant chemotherapy and tamoxifen were commonly offered; nonetheless, other adjuvant modalities were rarely utilised. The median follow-up +/- SD of all patients was 62.3 +/- 8.9 months: 152 patients (52%) were alive with no evidence of disease, 25 (9%) were alive with evidence of disease, and 115 (39%) were dead from breast cancer or its related complications. The median survival of the entire group was not obtained, but the 10-year projected survival was 55%. For stage I and II patients, 118 (76%) were alive with a projected 10-year actuarial survival of 64%. On the other hand, only 51 (57%) of patients with stage III disease were alive with a median survival of 41.5 months (95% Confidence interval (CI), 18.9 to 51.3). Patients with stage IV disease demonstrated a poor outcome with a median survival of 23.5 (95%, CI 12.2 to 31.4). Multivariate analyses were performed to explore the influence of independent variables on overall survival (OS) for patients with non-metastatic disease. Besides the expected adverse effect of disease progression, the favourable influence of adjuvant chemotherapy and tamoxifen prevailed. The amount of benefit gained from tamoxifen, however, was small. Similar analyses were undertaken to determine the influence of independent variables on progression-free survival (PFS). These analyses ascertained the adverse effects of advanced stage and the favourable impact of adjuvant chemotherapy. Breast cancer in the KSA has features that are distinctive from those of industrialised countries. Survival data, however, were comparable. The favourable influence of adjuvant chemotherapy was evident on both OS and PFS. Adjuvant tamoxifen, however, had little effect. Due to its infrequent use, the role of other adjuvant modalities could not be asserted.

Correlation of fundus lesions and hematologic findings in leukemic retinopathy.

This prospective study evaluated the relationship between the fundus findings in leukemic retinopathy and hematologic parameters. Seventy-four newly diagnosed consecutive patients with acute leukemia were included, 49 with acute myelocytic leukemia (AML), and 25 acute lymphocytic leukemia (ALL). Blood parameters were based on data obtained before starting any therapeutic modalities. Leukemic retinopathy was detected in 32 patients (43%). Patients with ALL and retinal hemorrhages had significantly lower hemoglobin and hematocrit levels than those without hemorrhages (p = 0.004 and 0.018 respectively). AML patients with white-centered hemorrhages had a significantly higher leukocyte count than those without (p = 0.0002). ALL patients with cotton-wool spots had significantly lower hemoglobin levels and hematocrit than patients without such lesions (p = 0.044 and 0.05 respectively). AML patients with cotton wool spots had significantly lower leukocyte and platelet counts than those without (p = 0.019 and 0.003 respectively). Our results suggest that anemia is related to the findings of retinal hemorrhage and cotton-wool spots in ALL patients, that high leukocyte count is associated with white centered hemorrhage in AML patients, and that thrombocytopenia is not associated with retinal hemorrhage in this group of patients.

Turcot syndrome: report of a case and review of the literature.

We report a case of Turcot's syndrome in a 20-year old man with multiple adenomatous polyps of the colon and glioblastoma multiforme. Detailed histopathological study of all 25 polyps removed from his colon confirmed the distinct morphological and numerical features of the colonic polyposis in Turcot's syndrome. Moreover, 45% of the total polyps and all polyps with a diameter exceeding 2 cm showed malignant transformation, indicating the precancerous nature of these polyps. These findings are discussed together with data obtained from a literature review of 32 histopathologically confirmed cases of Turcot's syndrome with reference to the possible heterogeneous nature of the syndrome at the present time. The current views on the relationship of Turcot's syndrome to other polyposis coli syndromes are presented.

Primary gastrointestinal cancers in the Western Region of Saudi Arabia. Is the pattern changing?

OBJECTIVE: To determine the age, sex and relative frequencies of various gastrointestinal malignancies in patients registered with the National Cancer Registry from the Western Region of Saudi Arabia from January 1994 till December 1997, and compare this data with previous hospital based studies about the pattern of these malignancies in Saudi Arabia. METHODS: A National Cancer Registry was established in Saudi Arabia in 1992, and since 1st January 1994 all cancer cases in Saudi Arabia have been registered with the National Cancer Registry. All National Cancer Registry data on patients with primary gastrointestinal cancers from the Western Region of Saudi Arabia from January 1994 till December 1997 was retrieved and analyzed according to ethnic origin, site, age, sex and relative frequencies of various tumors. RESULTS: Out of a total of 1833 cases with primary gastrointestinal malignancies 1207 (66%) were Saudis, while the rest were Non-Saudis. Colorectal cancer was the the most common malignancy found in both population groups accounting for 28.5% of cases in Saudis and 36% in Non-Saudis. Malignancies of liver, stomach and esophagus followed in decreasing frequencies. The mean age of the Saudi population was 58+16 years (standard deviation) with male to female ratio of 1.67:1. About 80% of the patients were above 40 years of age and the peak of onset for most of the tumors was between 50 and 70 years of age. CONCLUSIONS: This study highlights that colorectal cancer is the most common gastrointestinal malignancy seen in the Western Region of Saudi Arabia followed by hepatocellular carcinoma. This is in sharp contrast to the previous hospital based studies from Saudi Arabia and national trends as seen in the cancer incidence report from the National Cancer Registry of Saudi Arabia. The factors for this changing pattern of gastrointestinal malignancy remain to the determined.

Superior vena caval obstrution: King Khalid University Hospital experience.

A five year experience in 21 patients with superior vena caval obstruction (SVCO) was reviwed. SVCO was due to benign conditions in four patients (19%) and malignant tumors in 17 patients (81%). Lymphoma and lung cancer were the most common causes encountered. The most common symptoms and signs were facial swelling, shortness of breath, jugular venous distention, swelling of face and arms, and engorgement of thoracic veins. Benign disorders had a longer duration of symptoms before presentation and required longer time to make the diagnosis than in malignant disorders. No serious complications resulted from the superior vena cava obstruction itself or the investigate procedures leading to the diagnosis. Prognosis and response to treatment were dependent on the underlying cause of SVCO. Chemotherapy was effective in induction of complete regression of SVCO in the majority of patients with underlying malignant disorders. We conclude that SVCO should be approached invasively for diagnosis and tissue diagnosis of the underlying disorder should dictate the appropriate therapy.

Cancer at king khalid university hospital, riyadh.

This study is based on data collected from a total of 1196 patients (725 males and 471 females) with histologically confirmed cancer seen in King Khalid University Hospital over a 5-year period between September 1985 to August 1990. Four hundred forty-five patients were non-Saudi (37.20%). The relative frequency and rank of order are determined for various cancers in Saudi patients and total group and compared with the results of the other published studies on cancer epidemiology in Saudi Arabia. The most common cancers among Saudi males were liver, non-Hodgkin's lymphomas, stomach, lung, central nervous system, prostate, lymphoid, leukemias, myeloid leukemias, urinary bladder and Hodgkin's lymphomas, central nervous cancers among Saudi females were breast, thyroid, non-Hodgkin's lymphomas, central nervous system, stomach, myeloid leukemias, esophagus, lymphoid leukemias, liver and ovary. Rank order and relative frequency for liver cancer in both sexes is the highest among any study previously published on the epidemiology of cancer in Saudi Arabia.

Pattern of primary gastrointestinal cancer: King Khalid University Hospital experience and review of published national data.

This study is based on data collected from a total of 629 patients (435 male and 194 female) with histoligically confirmed cancer of the primary gastrointestinal tract and its accessory glands, seen at King Khalid University Hospital (KKUH) between January 1985 and December 1993. During this period, a total of 2464 cancer cases were identified at KKUH. The relative frequency and rank of order are determined for various gastrointestinal cancers, as well as distribution according to age, sex and primary site affected. Gastrointestinal malignancy accounts for 25.5% of total cancer cases seen at KKUH. The mean age of patients was 59 +/- 17 years, with a male-to-female ratio 2.24:1. Primary liver cancer was the most common malignancy (34%), followed by gastric cancer (18%), colorectal (17%) and esophageal cancer (12%). We compared our finding with national published data from different provinces in Saudi Arabia. Results from this report stress the importance of prevention, screening and early detection for gastrointestinal malignancy.

Pernicious anemia in Saudi Arabs.

Over a five-year period extending from January 1986 to December 1990, seven cases of pernicious anemia in Saudi patients were diagnosed at King Khalid University Hospital in Riyadh. There were five males and two females. The age range was 45 to 73 with a mean age of 61 years. The presenting symptoms, laboratory features and the disease pattern were similar to those described in northern European patients with the possible exception of male predominance in our patients. One patient demonstrated an interesting phenomenon of masking the macrocytosis of pernicious anemia by concurrent beta thalassemia minor. No association with any other autoimmune diseases was detected in any of our patients.

Adult acute myeloblastic leukemia: Experience at King Khalid University Hospital.

BACKGROUND: The clinical features of acute myeloblastic leukemia (AML) and its response to therapy in adult patients in Saudi Arabia are not well defined, as only scanty data has been available. This situation will likely continue unless experience with AML is reported from different institutions in the Kingdom. PATIENTS AND METHODS: In this retrospective study, the records of 52 adult patients with previously untreated de novo acute myeloblastic leukemia (AML) who were treated at King Khalid University Hospital over a five-year period from January 1989 to December 1993 according to the conventional â3+7â regimen were reviewed. The clinical features of the disease, response to therapy and treatment-related complications were identified. RESULTS: There were 33 males and 19 females with a mean age of 30+/-13 years (mean+/-SD). M 4 and M 5 AML were the predominant French-American-British (FAB) subtypes encountered. Sixty-five percent of patients achieved complete remission (CR). The median duration of the first CR of all analyzable patients was 32 weeks. The median CR duration and survival of patients achieving complete remission who survived through their consolidation treatment was 36 and 49 weeks, respectively. CONCLUSION: Both median duration of the first complete remission and survival compare unfavorably with those reported in the literature despite a comparable remission rate. Infectious complications were frequent and accounted for a significant number of mortalities.

Extraskeletal Ewing's sarcoma family of tumours in adults: analysis of 57 patients from a single institution.

AIMS: Extraskeletal Ewing's sarcoma (EES) is a rare form of soft tissue sarcoma. The aim of the present study was to assess the outcome and the prognosis of adult patients presenting with EES treated with multi-modality therapy. MATERIALS AND METHODS: All EES patients older than 15 years referred to our institution between January 1995 and December 2004 were reviewed. In total, 57 patients were identified. Their median age at diagnosis was 20 years (range 15-57). RESULTS: The median size of the primary tumour was 11 cm (range 4-30 cm). Eighteen patients (31%) had metastatic disease at initial presentation. Wide surgical resection with negative margins was achieved in 23 cases (40%). Chemotherapy consisting of vincristine, adriamycin, ifosfamide, actinomycin D was given in 50 patients (88%). Radiotherapy was delivered in 37 patients (65%). Forty-one patients (72%) achieved complete remission and 16 (28%) progressed on therapy. Twenty-one patients (51%) relapsed. Local recurrence was encountered in 15 patients (36%). At a median follow-up of 46 months (range 6-143 months), the 5-year event-free survival and overall survival rates were 35 and 47%, respectively. Metastases at presentation, tumour size and surgical resection margin associated significantly with overall survival and event-free survival. CONCLUSION: EES is an aggressive type of tumour with a high incidence of local recurrence and distant metastasis. This series showed that the outcome of adult EES is not unlike that of skeletal Ewing's sarcoma in terms of response to multi-modality treatment and the prognostic factors influencing treatment outcome. Adequate surgical resection, aggressive chemotherapy and adjuvant local radiation therapy, when indicated, constitute the optimal treatment to achieve the best results in this rare type of disease.