A synthetic combinatorial approach to disabling deviant Hedgehog signaling.

Mutations in components of the Hedgehog (HH) signal transduction pathway are found in the majority of basal cell carcinoma (BCC) and medulloblastoma incidents. Cancerous cells with intrinsic or acquired resistance to antagonists targeting the seven transmembrane effector Smoothened (SMO) frequently invoke alternative mechanisms for maintaining deviant activity of the GLI DNA binding proteins. Here we introduce a chemical agent that simultaneously achieves inhibition of SMO and GLI activity by direct targeting of the SMO heptahelical domain and the GLI-modifying enzymes belonging to the histone deacetylase (HDAC) family. We demonstrate a small molecule SMO-HDAC antagonist (IHR-SAHA) retains inhibitory activity for GLI transcription induced by SMO-dependent and -independent mechanisms frequently associated with cancer biogenesis. Synthetic combinatorial therapeutic agents such as IHR-SAHA that a priori disable cancer drivers and anticipated mechanisms of drug resistance could extend the duration of disease remission, and provide an alternative clinical development path for realizing combinatorial therapy modalities.

Cancer-initiating cells derived from human rectal adenocarcinoma tissues carry mesenchymal phenotypes and resist drug therapies.

Accumulating evidence indicates that cancer-initiating cells (CICs) are responsible for cancer initiation, relapse, and metastasis. Colorectal carcinoma (CRC) is typically classified into proximal colon, distal colon, and rectal cancer. The gradual changes in CRC molecular features within the bowel may have considerable implications in colon and rectal CICs. Unfortunately, limited information is available on CICs derived from rectal cancer, although colon CICs have been described. Here we identified rectal CICs (R-CICs) that possess differentiation potential in tumors derived from patients with rectal adenocarcinoma. The R-CICs carried both CD44 and CD54 surface markers, while R-CICs and their immediate progenies carried potential epithelial-mesenchymal transition characteristics. These R-CICs generated tumors similar to their tumor of origin when injected into immunodeficient mice, differentiated into rectal epithelial cells in vitro, and were capable of self-renewal both in vitro and in vivo. More importantly, subpopulations of R-CICs resisted both 5-fluorouracil/calcium folinate/oxaliplatin (FolFox) and cetuximab treatment, which are the most common therapeutic regimens used for patients with advanced or metastatic rectal cancer. Thus, the identification, expansion, and properties of R-CICs provide an ideal cellular model to further investigate tumor progression and determine therapeutic resistance in these patients.

Expression patterns of cell cycle and apoptosis-related genes in a multidrug-resistant human colon carcinoma cell line.

BACKGROUND: An in vitro multidrug resistance (MDR) system from a human colonic cancer cell line (SW620-MDR) has been established. To further study the mechanisms at molecular level and prevention of multidrug resistance in clinical practice, it was demonstrated that the expressions of several apoptosis-related and cell cycle regulator genes were changed in the cells. METHODS: A multidrug-resistant colonic cell line (SW620-MDR) was established, and the Atlas human cDNA expression array was used for studying the pattern of gene expression in this cell line. Furthermore, Northern hybridization or real-time PCR analysis confirmed the pattern of gene expression. RESULTS: In the SW620-MDR cell line the pro-apoptosis genes, CASP4, BIK, PDCD2, and TACE were expressed with decreased levels, and the antiapoptosis genes CD27-L and IGFBP2 were over-expressed. Furthermore, the cell cycle regulator genes such as CDK6, CCND1, CDC27HS, CDC16HS, Wee1Hu, MAPKK1, and IGFBP6 were expressed with decreased levels in the drug-resistant cell line. CONCLUSIONS: It is worthwhile investigating whether the differentially expressed pattern of the aforementioned genes exists in the drug-resistant cancer specimens, and to further understand their functions in the cancer drug-resistance mechanism.

Primary colorectal lymphoma.

PURPOSE: The purpose of this study was to review the clinical presentation and characteristics of primary colorectal lymphoma, analyze the prognostic factors, and assess the results of treatment with adjuvant chemotherapy. METHODS: We identified 37 cases at our institution between 1980 and 1996. They comprised 0.48 percent of all cases of colon malignancies (37/7,658) during this period. The following clinical information was obtained: age, gender, signs and symptoms, tumor site, tumor size, histology grade, pathology, and adjuvant chemotherapy. RESULTS: The most common presenting signs and symptoms were abdominal pain (62 percent), abdominal mass (54 percent), and weight loss (43 percent). The most frequent site of involvement was the cecum (45 percent). Histologically, 29 (78 percent) were classified as high-grade, and 8 (22 percent) as intermediate-grade-to-low-grade lymphoma. Nine (24.3 percent) of the cases were Stage EI, 23 (62.2 percent) were Stage EII, and 5 (13.5 percent) were Stage EIV. Twenty-one (57 percent) cases received adjuvant chemotherapy. The five-year survival rate was 33 percent for all patients and 39 percent for patients treated with combination chemotherapy. Overall median survival time was 24 months and 36 months for those with adjuvant chemotherapy. Only histology grade, among the factors examined, was a significant prognostic factor for survival. The mean survival time of the patients with Stage II disease who received chemotherapy was 117.4 months, and it was 47.9 months for the patients with Stage II disease who did not received chemotherapy. CONCLUSIONS: In our retrospective study high-grade lymphoma was the only significant adverse prognostic factor for survival. Receiving adjuvant chemotherapy significantly improved survival in patients with Stage II disease. Patients with diffuse large-cell type had better survival than patients with small noncleaved-cell type in Stage II high-grade lymphoma.

Hospital-based stroke care in Ireland: results from one regional register.

BACKGROUND: Most patients with acute stroke are admitted to hospital. If stroke services in this country are to be improved, we need accurate and reliable information about the types of stroke patients being admitted, their present management and outcome. AIMS: To examine the demography, severity, level of investigation, length of stay, mortality and discharge location of prospectively identified consecutive stroke admissions to three general hospitals in South East Dublin. RESULTS: Three hundred and twenty nine consecutive stroke admissions to three general hospitals in South East Dublin were registered using the European Stroke Database over 50 weeks. The mean age was 73.3 years, whilst 20.1% patients were under 65 years. Prior to admission, 90% of patients were community dwelling with 14.9% of patients being dependent in activities of daily living. 22.4% of patients had some depression in level of consciousness on admission. The overall mortality rate was 26.1% whilst 136 (41.3%) were discharged home, 50 (15.2%) went to institutional care and 45 (13.7%) went to non general hospitals secondary rehabilitation units. The mean length of stay was 31.3 days. The combined poor outcome measure (mortality plus percentage of patients discharged to institutional care), was lower in one hospital compared to the other two hospitals (29.3% versus 44.65%, p > or = 0.05) probably reflecting case mix. Stroke accounted for 4.2% of all bed days in the major general hospital in this area. The overall CT scan rate was 84.5%, with 18.2% of CT scans showing a haemorrhagic component and two patients (0.8%) having brain tumours. Carotid doppler examinations were carried out in 37% of patients. CONCLUSION: The results demonstrate the high mortality and prolonged hospital stay for stroke patients in this area and emphasise the need for co-ordinated stroke care and regular audit to ensure most effective use of hospital resources.

Prevalence of risk factors for ischaemic stroke and their treatment among a cohort of stroke patients in Dublin.

BACKGROUND: The majority of strokes are due to ischaemia. Risk factors include atrial fibrillation, hypertension and smoking. The incidence can be reduced by addressing these risk factors. This study examines the prevalence of risk factors and their treatment in a cohort of patients with ischaemic stroke registered on a Dublin stroke database. METHODS: Patients admitted to any of three acute hospitals with a diagnosis of stroke during a one-year period in 1997/98 were registered on a database using the European Stroke Database format. Data relating to common risk factors were analysed. RESULTS: There were 238 ischaemic stroke cases registered. The most frequent medical risk factors were: hypertension (45%), atrial fibrillation (27.3%), and previous disabling or non-disabling stroke (33.2%). There was an increasing trend with advancing age for atrial fibrillation (p < 0.001). Some 23% (54/233) were current smokers. A significantly higher proportion of patients with no medical risk factors were smokers or consumed excessive alcohol compared with those who had medical risk factors. CONCLUSION: Medical risk factors for stroke were common among stroke patients and not optimally treated, particularly with regard to atrial fibrillation and previous stroke. Smoking was a major behavioural risk factor among younger patients and much health gain could be achieved in this group through primary prevention strategies.

Subtotal colectomy for colonic inertia.

The aim of this study was to assess the outcome of subtotal colectomy for colonic inertia (idiopathic slow transit constipation) that was resistant to laxative treatment. Twenty-four patients, 19 women and 5 men, with a mean age of 37 years, underwent subtotal colectomy with ileorectal or ascendo-rectal anastomosis. All patients were available for follow-up, with a mean follow-up of 23 months. Bowel frequency was significantly increased from 1.4+/-0.9 times per week to 22.8+/-9 times per week (average 3.2/day) after surgery (P <0.0001). The incidence of abdominal pain was decreased from 75% to 17%, as well as the severity (P <0.0001). Two patients who underwent ascendo-rectal anastomosis developed recurrent constipation. Two patients used antidiarrheal medication regularly. There was no major postoperative morbidity. Five patients were re-admitted due to small bowel obstruction; four received successful conservative management, and one required enterolysis. 'Excellent' or 'good' outcomes were reported by 21 patients (87.5%). Subtotal colectomy with ileorectal anastomosis produces satisfactory results in the majority of patients with proven colonic inertia.

Perforated rectal lymphoma in a renal transplant recipient: report of a case.

PURPOSE: We report the case of a renal transplant recipient with rectal lymphoma manifested by sudden onset of abdominal pain from a perforated rectum who was treated successfully with prompt surgical resection and reduction of immunosuppressants. METHODS: An emergent anterior resection with Hartmann's procedure was done. Immunosuppressants were drastically reduced by discontinuation of cyclosporine. RESULTS: Pathologic examination showed diffusely infiltrated large-cell malignant lymphoma with an immunoblastic feature. The patient has been followed-up for four years, with no tumor recurrence or graft rejection. CONCLUSION: Rectal lymphoma, although rare, should be kept in the list of differential diagnoses for transplant recipients who exhibit lower gastrointestinal bleeding, intestinal obstruction, or abdominal pain.