Prediction of AVM obliteration after stereotactic radiotherapy using radiobiological modelling

This study was carried out in order to derive the radiobiological parameters of the dose-response relation for the obliteration of arteriovenous malformation (AVM) following single fraction stereotactic radiotherapy. Furthermore, the accuracy by which the linear Poisson model predicts the probability of obliteration and how the haemorrhage history, location and volume of the AVM influence its radiosensitivity are investigated. The study patient material consists of 85 patients who received radiation for AVM therapy. Radiation-induced AVM obliterations were assessed on the basis of post-irradiation angiographies and other radiological findings. For each patient the dose delivered to the clinical target volume and the clinical treatment outcome were available. These data were used in a maximum likelihood analysis to calculate the best estimates of the parameters of the linear Poisson model. The uncertainties of these parameters were also calculated and their individual influence on the dose-response curve was studied. AVM radiosensitivity was assumed to be the same for all the patients. The radiobiological model used was proved suitable for predicting the treatment outcome pattern of the studied patient material. The radiobiological parameters of the model were calculated for different AVM locations, bleeding histories and AVM sizes. The range of parameter variability had considerable effect on the dose-response curve of AVM. The correlation between the dosimetric data and their corresponding clinical effect could be accurately modelled using the linear Poisson model. The derived response parameters can be introduced into the clinical routine with the calculated accuracy assuming the same methodology in target definition and delineation. The known volume dependence of AVM radiosensitivity was confirmed. Moreover, a trend relating AVM location with its radiosensitivity was observed.     

Multifocal squamous cell carcinoma of the oesophagus following radiotherapy for bilateral breast carcinoma

A 60 year old woman who presented with dysphagia and weight loss was found to have multiple foci of dysplasia and in situ and invasive squamous cell carcinoma scattered along the whole length of the oesophagus, with intervening areas of normal mucosa. The patient had a history of two breast carcinomas 19 and one year previously for which she had repeated radiotherapy. Several members of the patient's close family had histories of malignant disease. All oesophageal lesions and the more recent breast cancer showed positive immunostaining for p53 protein. p53 mutations, some involving different exons, were also detected in these lesions. No p53 immunostaining or mutations were detected in the normal oesophageal mucosa. The findings suggest an independent origin of the multiple dysplastic and neoplastic foci, which might have developed in a background of a field change, possibly related to the previous radiotherapy. The strong family history of malignant diseases raises the possibility that, in addition, genetic factors might have played a role in the development of the oesophageal disease.     

Falloposcopy in conjunction with laparoscopy: possibilities and limitations

Falloposcopy is a transvaginal microendoscopic technique to explore the human Fallopian tube from the uterotubal ostium to the fimbrial end. Falloposcopy provides a unique possibility to visualize endotubal disease and may be used therapeutically for removal of debris and for cutting down filmy intraluminal adhesions. To assess the clinical performance of falloposcopy as part of an infertility investigation, a total of 43 women scheduled for laparoscopy as part of an investigation of infertility had a falloposcopy performed in conjunction with the laparoscopy. All women were investigated at Danderyd Hospital, Stockholm and Akademiska Hospital, Uppsala, during 1995 and 1996. Images from the endosalpinx were obtained in 26 of 43 women (60.5%). In 10 women (23.3%), it was possible to obtain images from both tubes. No images were of sufficient quality to describe the entire tubal mucosa in detail. Falloposcopy represents a unique tool for visualization of endotubal disease and may provide a valuable instrument for in-vivo exploration of tubal physiology. However, certain technical problems limit the usefulness of this method in routine clinical practice. These technical problems have to be solved before falloposcopy can achieve a central position in investigation and treatment of tubal disease.      

Causal pathways of the effects of age and the CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on AIDS development

OBJECTIVE: To investigate the causal pathways by which age and the CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles influence progression to AIDS. DESIGN: Analysis of follow-up data from 2 cohort studies among homosexual men (n=400), having >10 years of follow-up. METHODS: The effects of the 4 cofactors on the CD4 and HIV-1 RNA trajectories after seroconversion were modeled in a random-effects model. A proportional hazards model was used to investigate their effect on the risk of AIDS after correction for CD4 cell count and RNA level. This approach allows investigation as to whether they influence AIDS progression by affecting CD4 count and RNA level or by other pathways. RESULTS: Persons of younger age or having the CCR2-64I or SDF-1 3'A mutation have significantly higher CD4 levels. Persons with the CCR5-Delta32 deletion or CCR2-64I mutation have significantly lower RNA levels. After correction for both CD4 count and RNA level, only the SDF-1 3'A mutation significantly increases the AIDS risk. CONCLUSIONS: Age and the CCR5-Delta32 deletion and CCR2-64I mutation influence AIDS progression by affecting CD4 and HIV-1 RNA. The SDF-1 3'A allele increases the AIDS risk, but this effect is countered by its effect on CD4 and HIV-1 RNA level.     

High level of unequal meiotic crossovers at the origin of the 22q11. 2 and 7q11.23 deletions

Interstitial chromosomal deletions at 22q11.2 and 7q11.23 are detected in the vast majority of patients affected by CATCH 22 syndromes and the Williams-Beuren syndrome, respectively. In a group of 15 Williams- Beuren patients, we have shown previously that a large number of 7q11.23 deletions occur in association with an interchromosomal rearrangement, indicative of an unequal crossing-over event between the two homologous chromosomes 7. In this study, we show that a similar mechanism also underlies the formation of the 22q11.2 deletions associated with CATCH 22. In eight out of 10 families with a proband affected by CATCH 22, we were able to show that a meiotic recombination had occurred at the critical deleted region based on segregation analysis of grandparental haplotypes. The incidences of crossovers observed between the closest informative markers, proximal and distal to the deletion, were compared with the expected recombination frequencies between the markers. A significant number of recombination events occur at the breakpoint of deletions in CATCH 22 patients (P = 2.99x10(-7)). The segregation analysis of haplotypes in three- generation families was also performed on an extended number of Williams-Beuren cases (22 cases in all). The statistically significant occurrence of meiotic crossovers (P = 4.45x10(-9)) further supports the previous findings. Thus, unequal meiotic crossover events appear to play a relevant role in the formation of the two interstitial deletions. The recurrence risk for healthy parents in cases where such meiotic recombinations can be demonstrated is probably negligible. Such a finding is in agreement with the predominantly sporadic occurrence of the 22q11.2 and 7q11. 23 deletions. No parent-of-origin bias was observed in the two groups of patients with regard to the origin of the deletion and to the occurrence of inter- versus intrachromosomal rearrangements.      

Recombination pattern of the TCR γ locus in human peripheral T-cell lymphomas

The recombination events of the γ and β T-cell receptor (TCR) loci were analysed in a series of 39 peripheral T-cell lymphomas (PTCLs) in association with the expression of TCR chains. In TCR αβ PTCLs, 22/23 cases showed a γ-gene rearrangement while only 18/23 showed a concomitant β-gene rearrangement. The germline configuration of the β locus was found in angioimmunoblastic lymphadenopathy and lymphoepithelioid lymphomas. Three γδ PTCLs rearranged both γ and β genes. TCR silent PTCLs showed three different patterns of γ- and β-gene rearrangements. Three cases were in germline configuration for both loci; five cases had a rearranged γ and a germline β locus; and five cases had the two loci rearranged. Regarding the variable genes in the γ-rearranged alleles, members of the VγI subgroup were the most frequently presented (39/50), followed by VγII, VγIII, and VγIV (9/50, 1/50, and 1/50, respectively). Joining segment usage was as follows: J1 or J2 (32/50), JP1 or JP2 (17/50), and JP (1/50). Taken together, these data demonstrate that the γ locus is more frequently rearranged whatever the TCR expression. The γ-locus analysis provides a better diagnostic yield than the β locus in the study of PTCL clonality.     

Incidence and histological findings of unsuspected prostatic adenocarcinoma in radical cystoprostatectomy for transitional cell carcinoma of the bladder

OBJECTIVE: The present study is designed to evaluate the incidence, histological features and significance of prostatic adenocarcinoma in patients undergoing cystoprostatectomy for Transitional Cell Carcinoma (TCC) of the bladder. PATIENTS, MATERIAL AND METHODS: From January 1990 to December 1996, 59 male patients (mean age 66.5 years), with no evidence of prostatic malignancy on preoperative clinical and biochemical assessment, underwent cystoprostatectomy for TCC of the bladder. The bladder was adequately sampled and the entire prostate sectioned at 5-mm intervals and examined histologically, in order to identify unsuspected prostatic cancer (PCa). RESULTS: Sixteen out of 59 patients (27%) were found to have PCa, which was multifocal in 5 cases (31.25%). The mean tumor size was 0.24 cm. The tumors were equally distributed in the anterior and posterior parts of the prostate and in the peripheral and transition zones, with uniform distribution in both prostatic lobes. In 5 patients (31.25%), the single focus of the tumor was in the apex. All were grade I tumors except one, and all were organ-confined with no capsular penetration. The follow-up ranged from 12-74 months (mean 39 months). Within this period, 7 patients died from metastatic bladder cancer. One patient with PCa localized in the prostatic apex had recurrent prostatic disease in the urethro-ileal anastomosis of an orthotopic bladder substitute; he is alive and on androgen deprivation. The remaining patients are relapse-free. CONCLUSIONS: Incidental PCa is quite a common finding in cystoprostatectomy specimens of bladder cancer patients. Its tendency to appear in the apex of the prostate demands careful and complete excision of the organ.     

Reduction of the nociceptive response to gastric distension by nitrate ingestion in rats

BACKGROUND: Dietary nitrates are known to produce nitric oxide in the stomach, which may influence gastric function. AIM: To investigate whether nitrate ingestion modifies gastric sensitivity to distension through a mechanism involving nitric oxide production. METHODS: Nociception, associated with gastric distension ranging from 10 to 40 mmHg, was assessed in anaesthetized rats by the amplitude of cardiovascular depressor responses. Gastric volume corresponding to each distension was recorded. The following intragastric administrations (1 mL) were performed before distension: water (control), KNO3, NaNO3, KCl, NaCl (all at 0.1 mmol/kg), standard food (0.5 g), sodium nitroprusside, a nitric oxide donor (5 mg/kg), and haemoglobin, a nitric oxide scavenger (150 mg/kg) given either with water or KNO3. RESULTS: In controls, the fall in blood pressure increased from 7.8 +/- 2.0 to 31.6 +/- 2. 7 mmHg at distending pressures from 10 to 40 mmHg, respectively. KNO3 significantly reduced the amplitude of blood pressure response for the highest distending pressures (35 and 40 mmHg), while KCl induced a reduction in blood pressure response at all gastric pressures. NaNO3 and NaCl did not induce significant changes in distension-induced depressor responses. Administration of 0.5 g of standard food or sodium nitroprusside reproduced the effect of KNO3, which was reversed by haemoglobin. None of the compounds modified the gastric pressure-volume relationship, except KNO3, which increased gastric volume for the lowest distending pressures, and haemoglobin, which reduced the volume for the highest pressure. CONCLUSIONS: Ingestion of potassium nitrate reduces the sensitivity to gastric distension, through a mechanism involving nitric oxide.     

Unusually aggressive rectal carcinoid metastasizing to larynx, pancreas, adrenal glands, and brain

Rectal carcinoids are slow-growing tumors. They metastasize when their size is more than 2 cm. Common sites of metastasis are the liver, lungs, and bones. Metastases to thyroid, pancreas, kidneys, adrenal glands, pituitary glands, posterior fossa, and spleen are very rare. We present the case of a 79-year-old white man with dysphagia and left vocal cord paralysis from a rapidly growing mass in his neck. Needle biopsy suggested thyroid anaplastic carcinoma, and the patient underwent total laryngectomy, total thyroidectomy, and left radical neck dissection. Pathology showed undifferentiated carcinoid of the larynx. Biopsy of a rectal mass suggested poorly differentiated carcinoma. Postoperatively the patient developed cardiac arrhythmias and died after 5 weeks. Autopsy showed a 5-cm carcinoid of the rectum with extensive vascular invasion extending into the perirectal fat. There was metastatic disease to both lungs, liver, pancreas, both adrenal glands, peritoneum, subcutaneous tissues of thorax and abdomen, ribs, vertebrae, skull, and the leptomeninges of the cerebrum. Rectal carcinoids may present a variable histologic picture. Poorly differentiated tumors can present with widespread metastases and have poor prognosis. Extensive surgery may not improve the survival of patients with this pattern of unusually aggressive carcinoid.