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PubMed2006

Neoadjuvant and adjuvant therapy for rectal cancer.

The currently available evidence from randomized clinical trials clearly supports the use of adjuvant therapy in general and preoperative combined modality therapy in particular as effective means of decreasing the rates of local recurrence, improving sphincter preservation rates, and probably im-proving overall survival when managing patients with locally advanced adenocarcinomas of the lower two thirds of the rectum. A radical surgical approach with adequately performed, sharp TME remains the standard of care for those patients. There is clearly a need to develop and validate surrogate biomarkers for the identification of patients who respond favorably to preoperative treatment. There is still a significant fraction of rectal cancer patients who ultimately die from their disease. The armamentarium of avail-able therapies is evolving rapidly, and hopefully local control rates and overall survival of rectal cancer patients will continue to improve in the near future.

Adenocarcinoma↗
PubMedDate not supplied

Management and imaging of low rectal carcinoma.

Large variations in recurrence rates have been reported with the best results following total mesorectal excision (TME) surgery for low and middle rectal cancers. However, the low rectal cancers still have higher rates of local recurrence (up to 30%) whether operated by low anterior resection or abdominoperineal excision (APE) due to high rates of circumferential margin involvement. The treatment of choice for low rectal cancers that encroach upon the potential circumferential resection margin is surgery combined with preoperative neoadjuvant treatment. Preoperative chemotherapy combined with long-term radiotherapy reduces recurrence rates and preoperative loco-regional staging can help to select the patients more likely to benefit from neo-adjuvant therapy. Surface coil MRI is the most promising modality for patient selection, which can provide good views of the circumferential resection margin especially the presence or absence of tumour encroaching the intersphincteric plane.

Adenocarcinoma↗
PubMed2026

Targeting of tripartite neuron-cancer-immune cell crosstalk augments response to chemotherapy and immunotherapy.

We report presence of cholinergic nerve fibers in the periphery and stroma of colon cancer tissues and their correlation with poor T cell and increased macrophage infiltration. We employed hydrogel-mediated localized delivery of an FDA-approved local anesthetic, bupivacaine (BUP), to target acetylcholine (ACh)-mediated crosstalk of cholinergic neurons with cancer and immune cells. Localized BUP-Gel therapy promotes T cell-mediated tumor inhibition and enhances the antitumor response of systemic chemotherapy and immunotherapy. Further, blockade of cancer- and immune cell-specific ACh receptors inhibits tumor growth, alters the TME, and augments the impact of chemotherapy and immunotherapy. Finally, we demonstrate that ACh receptor antagonists polarize macrophages toward an M1-like phenotype and activate T cell immunity in tumor explants of patients. Therefore, targeting cholinergic signals through localized delivery of anesthetics, as well as direct immune reprogramming via cholinergic receptor antagonists, may provide a means to modulate this tripartite crosstalk, with potential implications for therapeutic strategies.

Humans↗
PubMed2000

Detection of mutation of the p53 gene with high sensitivity by fluorescence-based PCR-SSCP analysis using low-pH buffer and an automated DNA sequencer in a large number of DNA samples.

Detection of mutations in genes responsible for hereditary diseases or tumors is important clinically. It is necessary to establish a simple technique for screening mutations in large numbers of samples. The polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method has proved to be a useful technique for analyzing mutations or DNA polymorphisms. Non-radioisotopic versions using fluorescent dye and an automated DNA sequencer have also been exploited to extend this technique into the clinical field. We have examined mutations of exons 5-9 of the p53 gene in 112 colorectal, 28 esophageal and 33 hepatocellular carcinomas by fluorescence-based PCR-SSCP (F-SSCP) under various conditions. We found 64 types of mutations in 63, 17 and 12 cases of colon, esophageal and hepatocellular carcinomas by F-SSCP. We determined the sequence of all samples, and confirmed that all mutations were successfully detected by F-SSCP. With the low-pH buffer system, 61 types of mutants were detected, while 51 types were detected by TBE and 57 types were detected by TBE with glycerol gel. The polyacrylamide gel in TME or TBE without glycerol was tough and could be used repeatedly, but the glycerol containing gel was fragile and could not stand repeated use. Thus, use of a low-pH buffer in the electrophoresis of F-SSCP is simpler and better at detecting mutations than the conventional TBE buffer system. We believe that low-pH F-SSCP analysis is an efficient and powerful technique for examination of a large number of samples, in particular clinical specimens obtained by biopsy or surgery.

DNA Mutational Analysis↗
PubMed2002

The role of total mesorectal excision in the management of rectal cancer.

During the past decade, it has been clearly demonstrated that adjuvant treatment has the potential of improving not only prognosis in terms of local recurrence, but also in terms of overall survival. However, one of the largest improvements in the outcome of rectal cancer has been the introduction of total mesorectal excision. TME, with its large decline in local recurrence rate, has become the new standard of operative management for rectal cancers, replacing conventional resection technique [68]. In addition, current clinical trials examining the role of adjuvant therapy in patients who are undergoing standardized operations are now setting the standard of surgical care in several countries.

Clinical Trials as Topic↗
PubMed2002

Autonomic nerve preserving total mesorectal excision.

The main objectives of surgery for rectal cancer are cure and the prevention of local or pelvic recurrence. Preservation of pelvic autonomic functions are important associated goals that have influenced the design of the operation. These changes began with modifications to the art of lateral pelvic lymphadenectomy, and with the introduction of sharp pelvic dissection along anatomical pelvic fascial planes for rectal cancer in the mid-1970s. These changes evolved to include deliberate autonomic nerve preservation as a part of the operation that was ultimately reported as TME with ANP [1]. While it is a small nuance. dissection was generally directed to the widest possible pelvic margin--medial to the autonomic nerves, as opposed to just peripheral to the mesorectum. Both sexual and urinary functions are complex. and patients undergoing surgery for rectal cancer may have differing baseline levels of function. Pre-existing benign prostatic hypertrophy or stress incontinence are common physical conditions. Patients bring personal or cultural attitudes to the subject of sexual function with advancing years. in a population with a median age in the mid-sixties. Other health issues such as coronary artery or peripheral vascular atherosclerotic disease, diabetes mellitus. smoking or alcohol intake, or the use of medications to treat these conditions, may influence sexual function. Radiation therapy, frequently used in conjunction with chemotherapy in the treatment of rectal cancer, may be associated with its own incidence of impotence caused via a different mechanism. While radiation may affect the vasa nervosa of the autonomic nerves, leading to fibrosis and dysfunction. radiation therapy may also be associated with smooth muscle fibrosis, causing vasculogenic impotence due to penile outflow dysfunction in the corpora cavernosa. The causes of impotence after surgery alone or after surgery. radiation, and chemotherapy for rectal cancer are complex, and not all answers to the problem reside in autonomic nerve-preservation. Attention to all of the potential causes of impotence and of urinary dysfunction will require continued longitudinal research by clinical investigators from multiple disciplines.

Autonomic Nervous System↗
PubMed2002

The transmissible spongiform encephalopathies: disease risks for North America.

Transmissible spongiform encephalopathies exotic to North America (BSE and associated diseases) are unlikely to be introduced or to persist should they be introduced into the United States [2]. Domestic TSEs (scrapie, CWD, and TME) seem to be relatively restricted in their host range, and none of these diseases is known to naturally cause disease in cattle. It is important that surveillance for TSEs continues, however, particularly in cattle because of the extreme consequences to the livestock industries, and potentially, public health, if BSE becomes established. Because the TSEs have implications beyond effects on their natural host species, adequate surveillance, control, and even eradication of these diseases should be goals for the livestock industries, wildlife managers, and animal health agencies in the United States.

Animal Diseases↗
PubMed2002

The role of pathologists in the quality control of diagnosis and treatment of rectal cancer-an overview.

Pathological examination of the rectal cancer resection specimen has an increasingly important role in influencing decisions about clinical management. Standardisation of the examination procedures and reporting are necessary. To evaluate the relevant pathological factors, data from randomised clinical trials with adequate follow-up are necessary. From a recently closed trial on the treatment of rectal cancer (preoperative radiotherapy or total mesorectal excision (TME) surgery alone?), the pathological data were used to evaluate the importance of pathological factors, like circumferential margin and tumour, lymph nodes, metastasis (TNM) stage. Furthermore, it was possible to evaluate the surgical procedures and correlate these findings to clinically relevant endpoints. In this review, we describe the standard evaluation of a rectal cancer specimen with special attention to preoperative irradiated specimens.

Humans↗
PubMed1990

1H NMR studies of tris(phenanthroline) metal complexes bound to oligonucleotides: characterization of binding modes.

The binding of Ru(phen)3(2+), Rh(phen)3(3+), and Co(phen)3(3+) to the oligonucleotides d(GTGCAC)2 and 5'-pd(CGCGCG)2 has been examined by 1H NMR spectroscopy as a function of temperature, concentration, and chirality of the metal complex. The duplex oligonucleotides act as chiral shift reagents for the metal complexes; phenanthroline protons associated with each enantiomer are resolved upon binding to the oligomer. The spectral titrations, consistent with photophysical studies, indicate that the complexes bind to the oligomer through two modes: one assigned as intercalation favoring the delta-isomer, and the other assigned as the surface-bound interaction favoring the lambda-isomer. The ligand protons are perturbed in a manner that implies sensitivity of particular protons to binding mode; specifically, the H4,7 protons appear to be altered most for the lambda-enantiomer while the H5,6 protons are perturbed more for the delta-enantiomer. The NMR chemical shift variations appear particularly sensitive to this surface-bound interaction, which, on the basis of a comparison of binding and photophysical parameters for Ru(phen)3(2+), appears more prominant in binding to oligonucleotides than that to polynucleotides. With respect to oligonucleotide proton shifts, the adenine H2 proton, positioned in the minor groove of the helix, shows the largest upfield shifts with metal binding, and more dramatically with lambda-isomers. The major groove thymine methyl protons (TMe) shift downfield to a lesser extent, and more so for delta-isomers. The different binding modes also differ with respect to their dynamics of association; the longitudinal relaxation rates of delta- and lambda-4,7 phenanthroline protons of Rh(phen)3(3+) are 0.88 and 1.14 s, respectively, in the presence of d(GTGCAC)2.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1998

IKP104-induced decay of tubulin: role of the A-ring binding site of colchicine.

Tubulin, the major subunit protein of microtubules, has a tendency to lose its ability to assemble or to interact with ligands in a time-dependent process known as decay. Decay involves the increase in exposure of sulfhydryl groups and hydrophobic areas. The antimitotic drug IKP104 [2-(4-fluorophenyl)-1-(2-chloro-3, 5-dimethoxyphenyl)-3-methyl-6-phenyl-4(1H)-pyridinone] accelerates the decay of tubulin [Ludueña et al. (1995) Biochemistry 34, 15751-15759]. In the presence of colchicine, however, IKP104 stabilizes tubulin against decay. We have shown that the stability and the acceleration of the decay of tubulin are mediated respectively by the high- and low-affinity binding site(s) of IKP104 [Chaudhuri et al. (1998) J. Protein Chem. 17, 303-309]. To better understand the mechanism by which colchicine protects tubulin from IKP104-induced decay, we examined the effect of colchicine and its analogues on this process. We found that IKP104 unfolds tubulin in a process involving a specific domain where colchicine interacts, although the binding sites of these two drugs are distinctly different. 2-Methoxy-5-(2',3',4'-trimethoxyphenyl) tropolone (MTPT), the bicyclic analogue of colchicine that lacks the B-ring, can also protect tubulin from IKP104-induced decay. An A-ring analogue of colchicine, 3,4,5-trimethoxybenzaldehyde (TMB), can also stop IKP104-induced unfolding of tubulin significantly. Interestingly, the C-ring analogue of colchicine, tropolone methyl ether (TME), does not prevent this process. Our results thus suggest that neither the B-ring nor the C-ring binding regions of colchicine are involved in the IKP104-induced decay and that the A-ring binding site of colchicine on tubulin plays a crucial role in IKP104-induced decay.

Alkylation↗
PubMed2002

Synthesis, characterization, and structure of [[PtMe(3)(9-MeA)](3)] (9-MeAH = 9-Methyladenine): a cyclic trimeric platinum(IV) complex with a nucleobase.

Reaction of [[PtMe(3)I](4)] with AgOAc in acetone results in formation of trimethylplatinum(IV) acetate (1) that reacts with 9-methyladenine (9-MeAH) in ratio 1:1 with its deprotonation yielding a trimethyl(9-methyladeninato)platinum(IV) complex (2) that was obtained from acetone/diethyl ether as [[PtMe(3)(9-MeA)](3)] x Me(2)CO (2a) and from chloroform/diethyl ether as [[PtMe(3)(9-MeA)](3)] x 1.5Et(2)O x 2H(2)O (2b). Single-crystal X-ray investigations revealed that 2a and 2b in the solid state form cyclic trimeric molecules in which three PtMe(3) moieties are bridged by deprotonated 9-methyladenine ligands in mu-kappa N(1):kappa(2)N(6),N(7) coordination mode. The methyladeninato ligands include angles with the plane defined by the Pt(3) unit between 55.9(3) degrees and 66.6(3) degrees. Thus, the structures of the cyclic trimers resemble hollow truncated cones. Crystals of the acetone solvate 2a consist of stacks of unidirectional trimeric molecules; the solvate acetone molecules lie between the trimers. In the crystals of complex 2b, the trimeric molecules are arranged head-to-head, and the cavity between is filled with four water molecules. Complex 2 was also fully characterized by (1)H, (13)C, and (195)Pt NMR spectroscopies. The existence of the cyclic trimeric structure of complex 2 in acetone solution was confirmed by ESI mass spectrometry exhibiting the protonated trimeric complex [[tMe(3)(9-MeA)]3)H](+) [2 + H](+) (m/z 1165) as base peak. CID experiments of that parent ion showed as main fragmentation processes loss of two methyl ligands (probably as ethane) and cleavage of a methyladenine ligand.

Journal Article↗
PubMed2001

Survival and proliferation of alginate encapsulated Trichoderma spp. in Egyptian soil in comparison with allyl alcohol soil fumigation.

Conidia of Trichoderma harzianum and T. pseudokoningii (Rifai) were formulated to make alginate pellets with or without 10% cellulose as a food-base material. The formulations were compared for their ability for survival and proliferation of Trichoderma spp. in clay-loamy soil (50% moisture content) with allyl alcohol fumigation (0.05, 0.1 and 0.2 ml/1,000 ml space). Trichoderma medium E (TME) containing 100 microg/ml pentachloronitrobenzene (PCNB) was valuable for isolation and counting of Trichoderma spp. from the tested soil than the Glucose-Czapek's agar medium containing 1:15,000 Rose-bengal. The promotive effect of Trichoderma by different doses of allyl alcohol fumigation still enhanced after two-month incubation period. Conidia entrapped in alginate with or without cellulose and introduced into the soil survived better than conidia added directly to the same soil after three months incubation period. Sterile soil provided a more favorable environment for the proliferation and survival of immobilized conidia than the non-sterile soil, and the addition of 10% cellulose increased the survival of the entrapped conidia more than those prepared without cellulose. Soil fumigation inhibited the occurrence of other fungal species; however, inoculation of the soil with alginate immobilized conidia or conidial suspension had such inhibitory effect but in a less extent.

Alginates↗
PubMed2004

[Radiotherapy of rectal cancer].

The hallmark of successful management of rectal cancer is complete resection. In early stage disease, removal of all of the perirectal soft tissue structures, the mesorectum can be achieved with a total mesorectal excision (TME), resulting in high rates of local control. In cases of cancer extending through the muscularis propria or in case of lymphonodal involvement, additional radiation therapy can further substantially reduce the risk of pelvic recurrences. The combined treatment with radiotherapy followed by surgery is more effective than postoperative radiotherapy. Preoperative radiotherapy increases the survival rate of rectal cancer patients using limited doses of ionizing radiation and customized treatment volumes. The introduction of functional imaging with positron-emission tomography integrated in a conventional computer-associated tomography system (PET/CT) can be used for radiation treatment planning enhancing treatment precision and standards. The PET/imaging can be reliably used therapy for the purpose of combined staging and treatment volume assessment.

Combined Modality Therapy↗
PubMed2001

Surgery, radio- and chemotherapy for multimodal treatment of rectal cancer.

The possibilities and results of multimodal treatment in rectal cancer were reviewed with respect to the results of surgical treatment only. Based on the results of 4 studies, reducing local relapse rates and increasing long term survival rates significantly, postoperative radiochemotherapy (RCT) + chemotherapy (CT) should remain the recommended standard for R0 resected UICC II and III rectal cancers. The addition of RT to adjuvant CT reduces local relapses without significant impact on survival (NSABP R-02). Vice versa, the addition of CT to RT or an improved CT in the RCT-concept prolongs survival. Preoperative neoadjuvant radiotherapy (RT) reduced local relapse rates in 9 studies, and extended survival in one study that evaluated all eligible patients. Preoperative RT reduced local relapse rates in addition to total mesorectal excision (TME) but did not extend survival. The preoperative RCT + CT downstages resectable and nonresectable tumors and induces a higher sphincter preservation rate. Phase III data justifying its routine use in all UICC II + III stages are not yet available. This treatment may be routinely applied in nonresectable primary tumors or local relapses. Preoperative RCT (or RT) may evolve as standard, if the patient selection is improved and postoperative morbidity and long term toxicity reduced. Intraoperative RT could be added to this concept or be used together with preoperative/postoperative RT at the same indications. Postoperative adjuvant RT reduced local relapses significantly in a single trial, and no impact on survival time is reported. Since postoperative RT is inferior to preoperative RT, this treatment cannot be recommended, if RT is chosen as a single treatment modality in adjunction to surgery. The results of local tumor excisions may be improved with pre- or postoperative RCT + CT. In the future, multimodal treatment of rectal cancer might be more effective, if individualized according to prognostic factors.

Chemotherapy, Adjuvant↗
PubMed1994

Regulation of embryonic growth and lysosomal targeting by the imprinted Igf2/Mpr gene.

The receptor for insulin-like growth factor type 2, also known as the cation-independent mannose-6-phosphate receptor (Igf2/Mpr), is a multifunctional receptor thought to play a role in lysosomal targeting, cell growth and signal transduction. Igf2/Mpr has been mapped to the mouse Tme locus and shown to be an imprinted gene, which further suggests a role in embryonic growth regulation. To define the functions of Igf2/Mpr, we have generated mice lacking this gene. We report here that maternal inheritance of an Igf2/Mpr null allele (-/+) as well as homozygosity for the inactive allele (-/-) is generally lethal at birth and mutants are about 30% larger, indicating that maternal expression of Igf2/Mpr is essential for late embryonic development and growth regulation. The phenotype is probably caused by an excess of Igf2 because the introduction of an Igf2 null allele rescued the Igf2/Mpr mutant mice. Mutant mice also have organ and skeletal abnormalities and missort mannose-6-phosphate-tagged proteins. A few (-/+) mice reactivated their paternal Igf2/Mpr allele in some tissues and survived to adults. But no (-/-) mice survived, indicating a role for the reactivated paternal allele in postnatal survival.

Alleles↗
PubMed2006

CPT-11 and concomitant hyperfractionated accelerated radiotherapy induce efficient local control in rectal cancer patients: results from a phase II.

Patients with rectal cancer are at high risk of disease recurrence despite neoadjuvant radiochemotherapy with 5-Fluorouracil (5FU), a regimen that is now widely applied. In order to develop a regimen with increased antitumour activity, we previously established the recommended dose of neoadjuvant CPT-11 (three times weekly 90 mg m(-2)) concomitant to hyperfractionated accelerated radiotherapy (HART) followed by surgery within 1 week. Thirty-three patients (20 men) with a locally advanced adenocarcinoma of the rectum were enrolled in this prospective phase II trial (1 cT2, 29 cT3, 3 cT4 and 21 cN+). Median age was 60 years (range 43-75 years). All patients received all three injections of CPT-11 and all but two patients completed radiotherapy as planned. Surgery with total mesorectal excision (TME) was performed within 1 week (range 2-15 days). The preoperative chemoradiotherapy was overall well tolerated, 24% of the patients experienced grade 3 diarrhoea that was easily manageable. At a median follow-up of 2 years no local recurrence occurred, however, nine patients developed distant metastases. The 2-year disease-free survival was 66% (95% confidence interval 0.48-0.83). Neoadjuvant CPT-11 and HART allow for excellent local control; however, distant relapse remains a concern in this patient population.

Adenocarcinoma↗
PubMed1998

Improved survival in patients with rectal cancer: a population-based register study.

BACKGROUND: Between 1985 and 1989, only one centre in Sweden combined preoperative radiotherapy with total mesorectal excision (TME) in the primary treatment of rectal cancer. The aim of this study was to investigate whether this change in primary treatment had an impact on the outcome. METHOD: The survival rate of 94,262 patients with colorectal cancer from the total Swedish population between 1960 and 1989 was analysed. RESULTS: A continuous improvement in relative survival rate occurred during the first year of follow-up for both colonic and rectal cancer. Some improvement was also seen during follow-up years 2-5, but this was much more pronounced during the last period (1985-1989) for rectal cancer in the county of Uppsala. The improvement was particularly marked during follow-up years 3-5. CONCLUSION: There are strong indications from this study that altered primary treatment for rectal cancer results in improved long-term survival.

Combined Modality Therapy↗
PubMed2001

A prospective study of genito-urinary dysfunction after surgery for colorectal cancer.

OBJECTIVE: To establish the incidence of impotence and urinary dysfunction after different forms of pelvic and colorectal surgery. PATIENTS AND METHODS: Over a period of one year, 78 consecutive patients, mean age 66.8 years (range 43-91 years), underwent surgery for colorectal cancer. Genito-urinary function was studied by clinical assessment and a postoperative questionnaire. RESULTS: Pre-operatively all males except one claimed to be potent. Of the 56 patients who had operations on the sigmoid colon and rectum, 12 (21.4%) developed urinary dysfunction; 6 (5 males, 1 female) had increased frequency while 6 (4 females, 2 males) had stress incontinence. Four (12.9%) of the 31 male patients became impotent. Of the control 22 patients who had had operations on the ascending colon, one female developed stress incontinence and none of the male patients developed impotence. CONCLUSION: Although the introduction of autonomic nerve sparing techniques and total mesorectal excision (TME) may have lowered the incidence of genito-urinary dysfunction after rectal surgery, there remains a degree of morbidity compared to procedures where the rectum is not mobilized.

Journal Article↗