Medicinal plants in the treatment of urinary tract malignancies during the Araboislamic period (7th- 14th century AD).

Arabic medicine, or Arab-Islamic, mainly refers to all developments achieved in the Age of Khalifs, or the Golden Age of the Arab-Islamic civilization (ca 7th-14th centuries AD). Arab scholars adopted ancient Greek medicine and soon understood the essence of the fatal disease known as cancer. They introduced various new types of cancer, distinguishing other entities like infection and proposed new methods of treatment, both surgical and non-invasive. Herbal medicine after Dioscurides and Galen bloomed in the Arabic world. Malignancy of the urinary tract was identified and a plethora of herbs were used to slow down its expansion. Moreover, herbal drugs were introduced to alleviate cancerous symptomatology. Avicenna introduced Hindiba, while known scholars like Abulcasis and Rhazes noted the benefits of garlic, onion, black seeds, pomegranate, olive oil as well as leaf and bread wheat. Arabian herbal medicine may still be beneficial in anticancer fight and mainly in the palliative medicine. It should be emphasized that almost 50% of the drugs administered today have their point of origin in the plants used in antiquity.

CRHR2/Ucn2 signaling is a novel regulator of miR-7/YY1/Fas circuitry contributing to reversal of colorectal cancer cell resistance to Fas-mediated apoptosis.

Colorectal cancer (CRC) responds poorly to immuno-mediated cytotoxicity. Underexpression of corticotropin-releasing-hormone-receptor-2 (CRHR2) in CRC, promotes tumor survival, growth and Epithelial to Mesenchymal Transition (EMT), in vitro and in vivo. We explored the role of CRHR2 downregulation in CRC cell resistance to Fas/FasL-mediated apoptosis and the underlying molecular mechanism. CRC cell sensitivity to CH11-induced apoptosis was compared between Urocortin-2 (Ucn2)-stimulated parental and CRHR2-overexpressing CRC cell lines and targets of CRHR2/Ucn2 signaling were identified through in vitro and ex vivo analyses. Induced CRHR2/Ucn2 signaling in SW620 and DLD1 cells increased specifically their sensitivity to CH11-mediated apoptosis, via Fas mRNA and protein upregulation. CRC compared to control tissues had reduced Fas expression that was associated with lost CRHR2 mRNA, poor tumor differentiation and high risk for distant metastasis. YY1 silencing increased Fas promoter activity in SW620 and re-sensitized them to CH11-apoptosis, thus suggesting YY1 as a putative transcriptional repressor of Fas in CRC. An inverse correlation between Fas and YY1 expression was confirmed in CRC tissue arrays, while elevated YY1 mRNA was clinically relevant with advanced CRC grade and higher risk for distant metastasis. CRHR2/Ucn2 signaling downregulated specifically YY1 expression through miR-7 elevation, while miR-7 modulation in miR-7high SW620-CRHR2+ and miR-7low HCT116 cells, had opposite effects on YY1 and Fas expressions and cell sensitivity to CH11-killing. CRHR2/Ucn2 signaling is a negative regulator of CRC cell resistance to Fas/FasL-apoptosis via targeting the miR-7/YY1/Fas circuitry. CRHR2 restoration might prove effective in managing CRC response to immune-mediated apoptotic stimuli.

Inverse correlation between the metastasis suppressor RKIP and the metastasis inducer YY1: Contrasting roles in the regulation of chemo/immuno-resistance in cancer.

Several gene products have been postulated to mediate inherent and/or acquired anticancer drug resistance and tumor metastasis. Among these, the metastasis suppressor and chemo-immuno-sensitizing gene product, Raf Kinase Inhibitor Protein (RKIP), is poorly expressed in many cancers. In contrast, the metastasis inducer and chemo-immuno-resistant factor Yin Yang 1 (YY1) is overexpressed in many cancers. This inverse relationship between RKIP and YY1 expression suggests that these two gene products may be regulated via cross-talks of molecular signaling pathways, culminating in the expression of different phenotypes based on their targets. Analyses of the molecular regulation of the expression patterns of RKIP and YY1 as well as epigenetic, post-transcriptional, and post-translational regulation revealed the existence of several effector mechanisms and crosstalk pathways, of which five pathways of relevance have been identified and analyzed. The five examined cross-talk pathways include the following loops: RKIP/NF-κB/Snail/YY1, p38/MAPK/RKIP/GSK3ß/Snail/YY1, RKIP/Smurf2/YY1/Snail, RKIP/MAPK/Myc/Let-7/HMGA2/Snail/YY1, as well as RKIP/GPCR/STAT3/miR-34/YY1. Each loop is comprised of multiple interactions and cascades that provide evidence for YY1's negative regulation of RKIP expression and vice versa. These loops elucidate potential prognostic motifs and targets for therapeutic intervention. Chiefly, these findings suggest that targeted inhibition of YY1 by specific small molecule inhibitors and/or the specific induction of RKIP expression and activity are potential therapeutic strategies to block tumor growth and metastasis in many cancers, as well as to overcome anticancer drug resistance. These strategies present potential alternatives for their synergistic uses in combination with low doses of conventional chemo-immunotherapeutics and hence, increasing survival, reducing toxicity, and improving quality of life.

Hyperthermic isolated limb perfusion for recurrent melanomas and soft tissue sarcomas: feasibility and reproducibility in a multi-institutional Hellenic collaborative study.

Hyperthermic isolated limb perfusion with TNF-alpha and melphalan (TM-HILP) is a complicated surgical procedure. Herein, we present the experience of the Hellenic collaborating centers with TM-HILP for inoperable in-transit melanoma and soft tissue sarcoma (STS) of the extremities to examine safety and feasibility of collaborating as a multi-institutional group for future research studies. From 2001 to 2009, twenty patients (median age 63.5 years) underwent TM-HILP for locally advanced in-transit melanoma (n=14) or unresectable STS (n=6). All patients underwent a 90-min isolated limb perfusion with melphalan (10 mg/l limb volume) and TNF-alpha (1-2 mg) under mild hyperthermia (39-40 degrees C). No major intra-operative complications occurred and all patients completed the procedure successfully. One patient developed postoperative ischemic necrosis of the limb necessitating amputation. All melanoma patients showed a response to TM-HILP with 7 (62%) of them experiencing complete response. All STS patients attained complete response after excision of residual tumor. The median disease specific and limb-relapse-free survival was 15 and 12 months, respectively. TM-HILP can be safely applied even in low volume tertiary hospitals provided that technology to minimize intraoperative systemic leakage is available. Future prospective studies can be performed reproducibly by this multi-institutional collaborative group.

Rectoanal intussusception: presentation of the disorder and late results of resection rectopexy.

BACKGROUND: Rectoanal intussusception may cause symptoms of obstructed defecation, and functional results of prosthesis rectopexy are usually not satisfactory. The aim of this study was to assess several parameters of the disorder and to evaluate the outcome of resection rectopexy. METHODS: During a 10-year period, 27 female patients with symptomatic large rectoanal intussusception had resection rectopexy (23 laparoscopy; 4 laparotomy). Conservative treatment, including biofeedback treatment in 22 patients, had failed in all cases. Preoperative and postoperative evaluation included clinical assessment, anorectal manometry, evacuation defecography, and colon transit studies. Follow-up ranged between one and five years. RESULTS: Length of intussusception was 2 to 4.9 cm and was significantly related to pelvic floor descent (P = 0.003) and inversely related to resting anal pressures (P < 0.001). Eleven patients had undergone a previous hysterectomy, 9 had enterocele-sigmoidocele, 7 had incontinence of varying severity, and 8 had a solitary rectal ulcer. Colon transit was abnormal in all but five cases. Immediate functional results were bad in two-thirds of the cases; tenesmus, urge to defecate, and frequent stools were the main complaints. By the time these symptoms had subsided, and one year after surgery, all but two patients were satisfied with the outcome. Intussusception was reduced in all cases, anal sphincter tone recovered (P = 0.002), perineal descent decreased (P < 0.001), and colonic transit was accelerated (P < 0.001). Patients available at five-year follow-up had no or only minor defecatory problems. CONCLUSION: Resection rectopexy improves symptoms of obstructed defecation attributed to large rectoanal intussusception.