Preoperative hyperfractionated radiotherapy for locally advanced rectal cancers: a phase I-II trial

PURPOSE: To assess the toxicity, pathologic response rates, type of surgery, and oncologic results in a prospective Phase I-II trial using pure hyperfractionated radiotherapy (RT) preoperatively in locally advanced rectal cancer. METHODS AND MATERIALS: Between September 1997 and April 2000, 50 patients with T3-T4 or N1 rectal cancers were treated preoperatively with 50 Gy (45 Gy to the pelvis and a 5-Gy tumor boost) in 40 fractions of 1.25 Gy during 4 weeks. The pretreatment tumor stage as determined by CT and endorectal ultrasonography (80% of patients) included 1 Stage T2 (2%), 45 T3 (90%), and 4 T4 (8%). Nodal involvement (N1) was documented in 26 patients (52%). Surgery was performed at a median interval of 45 days (range 26-114 days) after RT completion. Seventeen patients who presented with pT4 or pN1 and/or pM1 received 5-fluorouracil-based chemotherapy postoperatively. RESULTS: All patients completed the RT schedule as planned. Severe acute toxicities included two Grade 3 skin reactions (4%) that did not require a break. The other acute toxicities were Grade 2 or less (skin, diarrhea, urinary, rectal tenesmus, and fatigue). A complete pathologic response was observed in 7 patients (14%), and microscopic residual cancer was found in 10 (20%). Of the 20 patients presenting with tumor located < or = 6 cm from the anal verge, sphincter-saving surgery was performed in 14 (70%). At 3 years, the actuarial locoregional control rate was 90.5%, and the disease-free survival rate was 74.6%. At a median follow-up of 32 months, 4 patients (8%) presented with severe late complications (Grade 3-4) that might have been RT related (one rectovaginal fistula, two chronic perineal fistulas, and one bilateral ureteral stenosis). CONCLUSION: In locally advanced rectal cancer, preoperative hyperfractionated RT to a total dose of 50 Gy is feasible, with acceptable acute and late toxicity and an objective downstaging effect. In view of these results, this schedule might be used as a basis for additional investigation regarding RT dose escalation or the addition of concomitant chemotherapy.     

Cognitive aging and inhibitory efficiency in the Daneman and Carpenter's working memory task

This study tests the hypothesis that the ability to inhibit already processed and actually irrelevant information influences performance in the reading span task (RST). French versions of the Stroop color-word task and of the Daneman and Carpenter's RST were administered to 151 participants from 30 to 80 years. In addition to the traditional span score, a score of vulnerability to intrusions was also computed as the number of intruding responses (words from preceding trials of the RST or nonfinal words). An analysis of variance showed a significant age effect on the reading span and on the resistance to interference, but no significant age effect on the vulnerability to intruding responses. A multiple-regression analysis was also made with the reading span score as the dependent variable, and with age, vulnerability to intrusions, and resistance to Stroop interference as independent variables. This analysis revealed that there was a relation between participants' vulnerability to intruding responses and their working memory span scores; the contribution of age and resistance to interference were very weak. In conclusion the present findings first support the idea that the working memory capacity undoubtedly involves some inhibitory control; however, because the participants' vulnerability to intruding responses is not clearly affected by age, the present findings also suggest that some part of age effects upon the working memory span has to be explained by another factor than a growing inefficiency in inhibitory control.     

Glutathione S-transferase P1 polymorphism (Ile105Val) predicts cumulative neuropathy in patients receiving oxaliplatin-based chemotherapy.

PURPOSE: Glutathione S-transferases (GST) are xenobiotic metabolizing enzymes involved in the detoxification of a variety of chemotherapeutic drugs, including platinum derivatives. Genetic polymorphisms of GSTs have been associated with enzyme activity variations. Thus, a study was done to investigate the relationship between GST polymorphisms and oxaliplatin-related cumulative neuropathy in gastrointestinal cancer patients treated with oxaliplatin-based chemotherapy. EXPERIMENTAL DESIGN: Ninety patients were included. Clinical neurologic evaluation was done at baseline and before each cycle of treatment. We determined genetic variants for GSTP1 exon 5 (Ile105Val), GSTP1 exon 6 (Ala114Val), GSTM1 (homozygous deletion), and GSTT1 (homozygous deletion). We conducted analyses in a subgroup of 64 patients receiving a minimal cumulative dose of 500 mg/m2 of oxaliplatin to examine whether the GST polymorphisms are associated with oxaliplatin-related cumulative neuropathy. RESULTS: Among patients receiving a minimal cumulative dose of 500 mg/m2 of oxaliplatin, 15 patients showed clinically evident oxaliplatin-related cumulative neuropathy scored grade 3 according to an oxaliplatin-specific scale. The oxaliplatin-related cumulative neuropathy scored grade 3 was significantly more frequent in patients homozygous for the GSTP1 105Ile allele than in patients homozygous or heterozygous for the GSTP1 105Val allele (odds ratio, 5.75; 95% confidence interval, 1.08-30.74; P = 0.02). No association was found with respect to any of the GSTM1, GSTT1, or GSTP1 exon 6 genotypes. Conclusions: The results of the current study suggest that the 105Val allele variant of the GSTP1 gene at exon 5 confers a significantly decreased risk of developing severe oxaliplatin-related cumulative neuropathy.     

Dialysate partitioning in the Genius batch hemodialysis system: effect of temperature and solute concentration

BACKGROUND: The Genius batch system contains a 75-L closed reservoir from which fresh dialysate is extracted at the top, and to which spent dialysate is returned at the bottom. In vivo studies have demonstrated that almost the entire amount of dialysate can be used before contamination of fresh with spent dialysate occurs. The question is raised whether density differences cause this separation, and what the relative contributions of temperature and solute content are. METHODS: As patient substitute, a container filled with dialysate was loaded with various amounts of urea. Temperature differences between spent and fresh dialysate were imposed by not heating the dialysate at the outlet line from the dialyzer (A), heating the outlet to obtain continuously equal temperatures at inlet and outlet (B), or to temperatures as in vivo (C). With a dialysate flow set at 300 mL/min, urea is not expected at the inlet before 250 minutes. RESULTS: With a urea concentration of 33 mg/dL, urea contamination at the dialysate inlet line occurred after 185 +/- 20 (A), 122 +/- 11 (B), and 175 +/- 12 minutes (C) of dialysis, whereas with 67 mg/dL, this happened at 219 +/- 5 (A), 162 +/- 11 (B), and 202 +/- 8 minutes (C). With 100 and 150 mg/dL, urea contamination appeared at 224 +/- 2 (A) and 204 +/- 14 minutes (B), and 227 +/- 5 (A) and 232 +/- 3 minutes (B), respectively. CONCLUSION: Both temperature differences between spent and fresh dialysate and solute content of spent dialysate contribute to dialysate partitioning in the Genius dialysis system.     

Therapeutic schedules influence the pattern of intellectual decline after irradiation of posterior fossa tumors

BACKGROUND: To evaluate intellectual decline in children with posterior fossa (PF) tumors treated with different therapeutic protocols. PROCEDURE: Forty children had a complete neuropsychological evaluation prospectively twice, at least 6 months year (y) after the end of their treatment. Patients were classified into four groups according to treatment schedules: Group 1 (n = 7) PF radiotherapy (PFRT) alone at 50 Gy; Group 2 (n = 13) reduced-dose cranio-spinal irradiation (CSI) at 25 Gy with a PF boost; Group 3 (n = 9) standard CSI at 35 Gy and a PF boost; and Group 4 (n = 11) high-dose chemotherapy with stem cell support followed by PFRT at 50 Gy. RESULTS: At the first evaluation (mean interval since diagnosis 3.7 y), the mean Full-Scale Intellectual Quotient (FSIQ) was 80 (SD = 19). Only patients in Group 1 had a normal mean IQ score of 92 (SD = 14). At the second evaluation (mean interval since diagnosis 6.3 y), the mean FSIQ scores were significantly lower with a mean difference of 2.4 points, i.e., a yearly decline of one point. The magnitude of the FSIQ decline was positively correlated with the first IQ score (P = 0.0001) and inversely correlated with age at diagnosis (P = 0.0005). A FSIQ decline was observed in all treatment groups except Group 1 (P = 0.005). The differences in FSIQ observed initially between the four treatment groups persisted at the second evaluation. CONCLUSIONS: This study shows that FSIQ continues to decline more than 4 years after the diagnosis but this yearly decline seems to decrease with time from diagnosis. Therapeutic schedules influence the magnitude of this decline. Long-term follow-up into adulthood is necessary to effectively adapt patient rehabilitation.     

Cuff electrode implantation around the sciatic nerve is associated with an upregulation of TNF-alpha and TGF-beta 1

Epineurial fibrosis, fiber loss, limited reproducibility of recordings and variability of stimulation conditions have been documented after extraneural cuff electrode implantation. These morphological and electrophysiological modifications could be due to the local release of cytokines. We report the expression of two cytokines, tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta1 (TGF-beta1) in the rat sciatic nerve after 'cuff' implantation for 18 h, 7 days and 1 month. Immunohistochemical and Western blot analyses showed a transient upregulation of TNF-alpha, during the first week, and a prolonged increase of TGF-beta1, over the 1-month period duration of this study. Considering the known pro-inflammatory roles of TNF-alpha and the pro-fibrotic action of TGF-beta, our results strongly suggest that these cytokines may contribute to nerve alterations occurring within the acute and sub-acute phases after cuff electrode implantation.     

Alcohol increases tumor necrosis factor alpha and decreases nuclear factor-kappab to activate hepatic apoptosis in genetically obese mice

Both obesity and alcohol can cause oxidative stress, cytokine induction, and steatohepatitis. To determine the consequences of their combination, we compared the hepatic effects of moderate ethanol binges in lean and obese ob/ob mice. Mice received water or ethanol (2.5 g/kg) by gastric intubation daily for 4 days, and were killed 2 hours after the last administration. Some obese mice also received pentoxifylline, an inhibitor of tumor necrosis factor-alpha (TNF-alpha) production, before each ethanol administration. In lean mice, these moderate ethanol doses did not increase plasma TNF-alpha and hepatic caspase-3 activity, but triggered some apoptotic hepatocytes. Naive ob/ob mice had a few necrotic and apoptotic hepatocytes, but exhibited little oxidative stress, possibly because of adaptive increases in manganese superoxide dismutase, heat shock protein 70 (Hsp70), mitochondrial cytochrome c, and mitochondrial DNA. Alcohol administration to ob/ob mice did not increase oxidative stress despite increased CYP2E1, but increased plasma TNF-alpha, further increased Hsp70, and profoundly decreased p65 nuclear factor kappaB (NF-kappaB) protein and DNA-binding activity in nuclear extracts. Caspase-3 was activated, and more apoptotic hepatocytes were found in intoxicated obese mice than naive obese mice. In intoxicated obese mice, pentoxifylline fully prevented the increase in plasma TNF-alpha the decrease in nuclear NF-kappaB activity, and the increase in hepatic caspase-3, and it also decreased hepatic triglycerides. In conclusion, obese mice develop adaptations that may limit oxidative stress. Moderate ethanol intoxication does not increase oxidative stress in obese mice, but increases TNF-alpha and also decreases nuclear NF-kappaB activity, thus unleashing the apoptotic effects of TNF-alpha.     

Subarachnoid hemorrhage as the initial presentation of dural sinus thrombosis

Cerebral venous thrombosis (CVT) can be difficult to diagnose because of its wide spectrum of clinical manifestations. Its diagnosis may be further complicated when patients initially present with acute subarachnoid hemorrhage (SAH). We report on four patients with SAH revealing a CVT and discuss the role of imaging for diagnostic and pretherapeutic workup. In three women and one man presenting with severe headaches, images initially suggested SAH with no associated parenchymal bleeding. In all patients, SAH involved the sulci of the convexity and spared the basal cisterns. Digital subtracted angiography showed occlusion of intracranial venous sinuses but did not reveal any other cause of SAH. All patients improved with anticoagulant therapy. Risk factors for CVT and SAH, namely, head trauma and oral contraception, were identified in two patients. These cases highlight the fact SAH may reveal a CVT, which should be considered in the diagnostic workup of SAH, especially when the basal cisterns are not involved.     

Endocrine involvement in pediatric-onset Langerhans' cell histiocytosis: a population-based study

OBJECTIVE: To document the frequency and outcome of endocrine involvement in pediatric-onset Langerhans' cell histiocytosis (LCH), and the association with other types of organ involvement. STUDY DESIGN: This retrospective nationwide multicenter study involved 589 patients with pediatric-onset LCH, 148 of whom had endocrine dysfunction. Median follow-up was 11.6 years. RESULTS: Pituitary dysfunction was present in 145 patients, and 141 had diabetes insipidus (DI). The estimated 10-year risks of pituitary involvement were 24.2% +/- 1.8%. GH deficiency occurred in 61 patients. Median age at onset was 2.8 years for LCH, 3.9 years for DI, and 7.7 years for GH deficiency. The risk of cranial involvement; ear, nose, and throat involvement; pneumothorax; and cholangitis was significantly higher in patients with endocrinopathy. The chronology of episodes did not support a causal link between pituitary involvement and involvement of other organs. Systemic treatment of LCH did not prevent pituitary involvement. The most severe complication was a neurodegenerative syndrome, which affected 4.3% and 10.8% of patients, respectively, 5 and 15 years after initial diagnosis, and appeared to be linked to pituitary involvement. CONCLUSION: Patients who develop endocrine LCH disorders are at a high risk of neurodegenerative LCH and require long-term follow-up.