Interventions for Managing Late Gastrointestinal Symptoms Following Pelvic Radiotherapy: a Systematic Review and Meta-analysis.

AIMS: Pelvic radiotherapy can induce gastrointestinal injury and symptoms, which can affect quality of life. We assessed interventions for managing these symptoms. MATERIALS AND METHODS: A review of randomised controlled trials published between January 1990 and June 2023 from databases including MEDLINE, EMBASE, CENTRAL, CINAHL, clinicaltrials.gov, ISRCTN and grey literature sources was conducted. Meta-analyses were carried out using the DerSimonian and Laird random effects model to produce overall treatment differences with 95% confidence intervals. RESULTS: Twenty-eight studies (2392 participants) of varying methodological quality were included. 4% formalin was superior to sucralfate for improving gastrointestinal symptom score (standardised mean difference [SMD] -1.07, 95% confidence interval -1.48 to -0.65). Argon plasma coagulation (APC) was inferior to sucralfate (SMD 1.22, 95% confidence interval 0.84 to 1.59). Counselling positively influenced symptom score (SMD -0.53, 95% confidence interval -0.76 to -0.29), whereas hyperbaric oxygen therapy showed conflicting results. Sucralfate combined with APC increased endoscopic markers of moderate-severe bleeding versus APC alone (risk ratio 2.26, 95% confidence interval 1.12 to 4.55). No definite conclusions on pain, incontinence, diarrhoea, tenesmus or quality of life interventions were confirmed. CONCLUSIONS: Small study sizes, methodological quality and heterogeneity limit support of any individual intervention. APC and 4% formalin seem to be promising interventions, with further larger randomised controlled trials now warranted.

Simultaneous analysis of 1176 gene products in normal human aorta and abdominal aortic aneurysms using a membrane-based complementary DNA expression array.

BACKGROUND: A number of changes in gene expression have been described in abdominal aortic aneurysms (AAAs), but the spectrum of molecular alterations in this disease is unknown. The purpose of this study was to characterize the expression of approximately 1000 gene products in human AAA tissue and to compare the profile of genes expressed in AAAs with that observed in normal aorta. MATERIALS AND METHODS: Total RNA was isolated from abdominal aortic wall tissues (4 AAAs and 4 normal aortas), and array-specific [(32)P]-labeled complementary DNA (cDNA) probes were created with reverse transcription. The cDNA probes were hybridized with nylon membranes containing an array of 1176 cDNA clones (AtlasArray Human 1.2 I; Clontech, Palo Alto, Calif), and autoradiographs were scanned to identify the patterns of gene expression characteristic of each tissue type. Densitometric analysis was used to standardize the expression of individual genes to a panel of housekeeping controls, and differential gene expression was defined by a signal ratio of at least 2:1. RESULTS: One hundred forty-five (12.3%) of the 1176 genes were consistently expressed in aortic tissue. Thymosin beta-4 was the most abundant of 101 transcripts detected in both AAAs and normal aorta, whereas 44 genes exhibited differential patterns of expression (39 predominant in AAAs and 5 in normal aorta). Densitometric analysis confirmed differences in expression for 20 of these gene products between AAAs and normal aorta, with the greatest increases seen for myeloid cell nuclear differentiation antigen (31-fold), cathepsin H (30-fold), platelet-derived growth factor-A (23-fold), apolipoprotein E (13-fold), gelatinase B/matrix metalloproteinase-9 (12-fold), and interleukin-8 (11-fold). The only gene products substantially decreased in AAAs were myosin light chain kinase (39-fold) and beta-1 integrin (twofold). AAA tissues thereby exhibited a distinct pattern of gene expression reflecting chronic inflammation, extracellular matrix degradation, atherosclerosis, and smooth muscle cell depletion. CONCLUSIONS: cDNA expression arrays provide a powerful new approach to help identify the molecular mechanisms responsible for aneurysmal degeneration. Further studies will be needed to elucidate the functional and pathophysiologic significance of the individual genes that exhibit altered levels of expression in AAA tissue.

Allelotype of follicular thyroid carcinomas reveals genetic instability consistent with frequent nondisjunctional chromosomal loss.

Numerous studies aimed at the identification of chromosomal regions that are frequently deleted in specific tumor types have pointed to the location and involvement of specific tumor suppressor genes. Previous studies of loss of heterozygosity (LOH) among thyroid tumors have revealed frequent allelic deletions at a few chromosomal regions. A systematic genome-wide examination of LOH in a substantial number of follicular carcinomas, however, has not been performed previously. We assessed LOH at polymorphic markers from each nonacrocentric autosomal arm in a panel of 28 follicular thyroid carcinoma tumor and normal pairs. In contrast to the results of previous allelotype studies, we found high rates of LOH at multiple chromosomal regions. The highest rate of loss in our study was at 2p (50.0%), and 2q (50.0%), and the mean rate of LOH was 20.4%. Marked genetic instability in a subset of tumors was demonstrated by high fractional allelic loss, which accounted for more than 80% of observed LOH in this study. High fractional allelic loss was significantly associated with oxyphilic features and poor differentiation of these tumors. Our data provide evidence of a prevalent phenotype of nondisjunctional whole chromosomal loss in follicular thyroid carcinomas.

Infrequent CDKN2 mutation in human differentiated thyroid cancers.

We examined the frequency of cyclin-dependent kinase (CDK) N2 alterations in differentiated and anaplastic thyroid cancers to assess the involvement of CDKN2 in the development of these cancers. The CDKN2 gene, which encodes the cell-cycle regulator p16, was recently shown to be mutated or deleted in many tumor cell lines. Its role in the genesis of primary tumors is uncertain, however. Tumor and corresponding normal DNAs were prepared by microdissection of paraffin-embedded tissue blocks or from frozen surgical specimens of 15 papillary, 15 follicular, and five anaplastic thyroid carcinomas. The entire CDKN2 coding region was screened by single-strand conformational variant analysis and direct sequencing of variants. The presence of homozygous deletions was evaluated by multiplex polymerase chain reaction (PCR) analysis. Loss of heterozygosity (LOH) in the CDKN2 region was assessed by using flanking polymorphic markers. Two somatic missense mutations were found among the 35 thyroid cancers, one in a follicular tumor and one in an anaplastic tumor. Multiplex PCR suggested the presence of homozygous deletion in one anaplastic tumor and hemizygous deletions in four tumors. LOH studies revealed loss of 9p sequences in four follicular (27%) and two anaplastic (50%) cancers. Our data suggest that alterations in CDKN2 played a role in a minority of thyroid cancers (three of 35). LOH in the region of CDKN2 is seen in a significant proportion of follicular and anaplastic but not papillary cancers. Loss of 9p sequences suggests a role for a tumor suppressor gene in the development of follicular and anaplastic thyroid cancers.

Laparoscopic detection of hepatic metastases in patients with residual or recurrent medullary thyroid cancer.

BACKGROUND: After initial operations for medullary thyroid cancer (MTC), reoperation with removal of metastatic disease confined to the neck may benefit some patients. The identification of distant metastases precludes the possibility of curative reoperation. METHODS: Forty-one patients with hypercalcitoninemia after initial surgical treatment for MTC underwent laparoscopic (n = 36) or open (n = 5) examination and biopsy of the liver. Thirty-seven of these patients underwent imaging by computed tomography (CT), magnetic resonance imaging (MRI) of the liver, or both, and 17 underwent selective venous catheterization (SVC) with measurement of hepatic and peripheral vein stimulated calcitonin levels. RESULTS: Liver metastases were found in eight patients, seven by laparoscopy and one by open examination. Seven of these patients had normal CT or MRI scans of the liver. Laparoscopy or open liver examination revealed metastases in 2 of 11 patients with elevated hepatic vein-peripheral vein stimulated calcitonin ratios (greater than 1.3). Metastases appeared as small (less than 5 mm), bright white nodules on the surface of the liver. CONCLUSIONS: Direct examination and biopsy of the liver by laparoscopy may show small deposits of metastatic MTC in patients with normal CT and MRI scanning.

Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas.

The gene encoding the cell-cycle regulatory protein p16, CDKN2, is localized on chromosome band 9p21. CDKN2 is frequently deleted or mutated in a variety of tumor cell lines, including pancreatic cancer cell lines and xenografts, as well as in some primary tumors. We examined 32 primary pancreatic adenocarcinomas for CDKN2 mutations and for loss of heterozygosity of 9p21 sequences to assess the role of CDKN2 in pancreatic carcinogenesis. Single-strand conformation variant analysis (SSCV) and direct sequencing of the variants revealed somatic CDKN2 mutations in 11 of 32 tumors (five frame-shift mutations, five nonsense mutations, and one missense mutation). One tumor appeared to be characterized by homozygous deletion of CDKN2. These results suggest that CDKN2 plays an important role during tumorigenesis or tumor progression in a significant proportion of pancreatic adenocarcinomas.

Histamine-2-receptor blockade does not affect hyperemia after cerebral ischemia in young swine.

OBJECTIVE: To determine whether histamine-2 (H2) receptor antagonists can blunt the increase in cerebral blood flow after cerebral ischemia. DESIGN: Prospective, randomized trial. SETTING: Animal laboratory. SUBJECTS: Piglets aged 1 to 2 wks. INTERVENTIONS: Three groups of piglets were anesthetized with pentobarbital, mechanically ventilated, and hemodynamically monitored. Each animal was randomized to receive one of three treatments 20 mins before ischemia: famotidine (0.6 mg/kg i.v.), cimetidine (5 mg/kg i.v.), or an equivalent volume of saline (3 mL). Ischemia was maintained for 15 mins by tightening ligatures around the brachiocephalic trunk and left subclavian arteries plus the induction of hemorrhagic hypotension (50 mm Hg). Reperfusion was initiated by the reinfusion of shed blood and removal of the ligatures. MEASUREMENTS AND MAIN RESULTS: The three groups were not different with regard to baseline arterial blood gases, cerebral perfusion pressure, microsphere-determined cerebral blood flow, or oxygen consumption (VO2). Ischemia (cerebral blood flow < 5 mL/min/100 g of tissue) was demonstrated in all brain regions for all groups during arterial ligation with hemorrhage-induced hypotension. Blood flow rates were increased compared with preischemic values in all regions at 7 mins of reperfusion. For example, mean forebrain blood flow rates increased from 36 +/- 3 to 95 +/- 14 (SEM) mL/min/100 g of tissue in the group receiving saline, from 36 +/- 3 to 102 +/- 9 mL/min/100 g of tissue in the group receiving famotidine, and from 31 +/- 4 to 119 +/- 26 mL/min/100 g in the group receiving cimetidine. Overall, the three groups did not differ in regard to blood flow rates and cerebral VO2 values during ischemia and at 30 mins of reperfusion. CONCLUSIONS: We demonstrated that famotidine or cimetidine as compared with saline did not affect the pattern or extent of hyperemia after ischemia. This finding does not support the hypothesis that a H2-receptor mechanism is necessary for postischemic hyperemia.