Somatic responses of ventrobasal thalamic neurones in polyarthritic rats

Rats rendered polyarthritic by injection ofMycobacterium butyricum into the tail were used as a model for the study of ‘chronic pain’.In such rats unitary responses of ventrobasal thalamic neurons to somatic stimulations were dramatically modified by comparison to those described in normal rats investigated in the same anaesthetic conditions.

(1) Only the neurons with receptive fields located on inflamed areas (168/194 in 33 rats) have been considered in this study. 27/168 activated only by brushing displayed the classical properties of lemniscal responses; only 20/168 were activated exclusively by intense cutaneous stimuli and 13/168 already activated by light cutaneous stimuli had enhanced discharges when the stimulus intensity was increased. By contrast numerous units (108/168) were excited by mild stimulations applied to the joints or to adjacent cutaneous areas (82 were driven by joint movement and/or mild lateral pressure on the articulation, 26 by brushing the overlapping skin); these responses presented atypical characteristics and displayed unusual patterns with very long afterdischarges of duration several times that of the stimulus.

(2) In 20 additional arthritic rats, responses to transcutaneous electrical stimulation (TES) and/or to noxious heat, were obtained for 34 neurones responding to joint stimuli.

(a) 16 of 18 neurones tested with transcutaneous electrical stimulation had latencies of 25–100 ms, and thresholds of 1–4 mA (width of shock 2 ms). (b) Neurones activated by joint stimuli frequently responded to noxious heat (radiant or waterbath). Initially, their response thresholds tested in 16 neurones were higher by about 4°C than those of ‘noxious’ VB neurones in normal rats; however, following sensitization to heat, thresholds were decreased by 4°C. For 8 neurones there was a linear relation between stimulus intensity and responses.

(3) Several different factors which could explain the important modifications of neuronal responses in VB complex of arthritic rats by comparison with normal are proposed in the discussion.

Early splenectomy and polychemotherapy versus polychemotherapy alone in chronic myeloid leukemia

The effect of early splenectomy and of polychemotherapy with hydroxyurea, busulfan, and alternate bimonthly courses of arabinosyl cytosine and vincristine plus prednisone, was evaluated in 139 previously untreated patients with chronic myeloid leukemia (CML), consecutively admitted to 18 hospitals from March 1973 to October 1974. Fifty-six patients were splenectomized and 83 patients were not splenectomized. Splenectomy did not influence the duration of chronic and blastic phase, and did not prolong survival. The prognosis of high risk patients was not improved. During the chronic phase, high platelet counts were more frequent in splenectomy group, and five patients developed thrombotic or thromboembolic complications, 5 to 19 months after the operation. The median survival of the whole group was 50 months, with 32 of 139 patients (actuarial proportion 30%) remaining alive 72 months after diagnosis, but the slope of the survival curve was similar to that of historical controls. The results of this trial suggests that new strategies should be developed for the therapy of CML.     

Evidence for a receptor supersensitivity following impairment of central serotoninergic activity in the rabbit

Summary In order to investigate whether a chronic impairment of neuronal serotoninergic transmission in the CNS could result in a receptor supersensitivity, rabbits were pretreated either with 5,6-dihydroxytryptamine (5,6-DHT) or p-chlorophenylalanine (PCPA) and then tested for their hyperthermic response to serotoninergic agonists.A previous (10 days before) intracerebroventricular injection of 5,6-DHT (75 g into each cerebral ventricle) significantly potentiated the increase in body temperature induced either by quipazine (1 mg/kg i.v.) or by 5-hydroxytryptophan (5-HTP 2 mg/kg i.v.) in combination with a MAO inhibitor (phenylethylhydrazine 10 mg/kg i.v. 16 h before). Pretreatment with PCPA (100 mg/kg s.c. four times on alternate days, the last dose 48 h before the experiment) also enhanced the hyperthermic effect of quipazine, whereas it inhibited the hyperthermic response to 5-HTP plus MAO inhibitor.These results suggest the exstence of a receptor supersensitivity following prolonged blockade of serotoninergic neuronal transmission in the CNS.Supported by C.N.R. grant n. 75.00620.04.115.2380     

Influence of sleep deprivation on neuroactive steroids in major depression.

There is evidence from preclinical and clinical studies that concentrations of neuroactive steroids are altered in depression and normalize after antidepressant pharmacotherapy. However, no data are available concerning the impact of sleep deprivation on the concentrations of neuroactive steroids. A total of 29 drug-free patients (12 men, 17 women) suffering from major depression according to DSM-IV criteria were treated with partial sleep deprivation (PSD). Response to PSD was defined as a reduction of at least 30% according to the six-item version of the Hamilton depression scale (6-HAMD). Plasma samples were taken the day before and after PSD (days 0 and 1) and after one night of recovery sleep (day 2) at 8:00 am. The samples were quantified for neuroactive steroids by means of a highly sensitive and specific combined gas chromatography/mass spectrometry analysis. There was no influence of PSD on the concentrations of neuroactive steroids either in PSD responders (n=20) or in nonresponders (n=9). However, nonresponders showed significantly higher concentrations of 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP), 3alpha,5beta-tetrahydroprogesterone (3alpha,5beta-THP), and dehydroepiandrosterone (DHEA) before or after PSD compared to responders. In contrast to antidepressant drugs, which correct the dysequilibrium of neuroactive steroids in major depression within several weeks, PSD does not affect the concentrations of neuroactive steroids either in responders or in nonresponders.     

Trastuzumab down-regulates Bcl-2 expression and potentiates apoptosis induction by Bcl-2/Bcl-XL bispecific antisense oligonucleotides in HER-2 gene--amplified breast cancer cells.

PURPOSE: To investigate the possible existence of an antiapoptotic cross-talk between HER-2 and antiapoptotic Bcl-2 family members. EXPERIMENTAL DESIGN: Bcl-2 and Bcl-XL expression and apoptosis induction were analyzed in HER-2 gene-amplified (BT474) and nonamplified (ZR 75-1) breast cancer cell lines exposed to trastuzumab, alone or in combination with either Bcl-2/Bcl-XL bispecific antisense oligonucleotides (AS-4625) or the small-molecule Bcl-2 antagonist HA14-1. RESULTS: In addition to HER-2 and epidermal growth factor receptor, trastuzumab down-regulated Bcl-2, but not Bcl-XL, protein, and mRNA expression in BT474 cells. Interestingly, trastuzumab-induced down-regulation of HER-2 and Bcl-2 was also observed in three of five and two of three breast cancer patients undergoing trastuzumab treatment, respectively. Despite Bcl-2 down-regulation, however, trastuzumab only marginally increased the rate of apoptosis (7.3 +/- 3.5%). We therefore investigated whether a combination of AS-4625 and trastuzumab might increase proapoptotic efficiency. AS-4625 treatment of BT474 cells decreased both Bcl-2 and Bcl-XL expression, resulting in a 21 +/- 7% net apoptosis induction; the combination of AS-4625 followed by trastuzumab resulted in a significantly stronger induction of apoptosis (37 +/- 6%, P <0.01) that was not observed with the reverse treatment sequence (trastuzumab followed by AS-4625). Similar results were obtained with the Bcl-2 antagonist HA14-1; indeed, exposure of BT474 cells to HA14-1 followed by trastuzumab resulted in a striking proapoptotic synergism (combination index=0.58 +/- 0.18), as assessed by isobologram analysis. CONCLUSIONS: Altogether our findings suggest that combined targeting of HER-2 and Bcl-2 may represent a novel, rational approach to more effective breast cancer therapy.     

Alcohol exposure and breast cancer: results of the women's contraceptive and reproductive experiences study.

OBJECTIVES: To explore associated biological outcomes and clarify the role of timing of exposure in the alcohol-breast cancer relationship.METHODS: In a population-based study of 4,575 women ages 35 to 64 years diagnosed with invasive breast cancer between 1994 and 1998 and 4,682 controls, we collected details of lifetime alcohol use and factors that could confound or modify the alcohol-breast cancer relationship. We used conditional logistic regression to compute the odds of breast cancer among drinkers relative to nondrinkers at all ages and at ages 35 to 49 and 50 to 64 years separately.RESULTS: Recent consumption (at reference age minus two) of >/=7 drinks per week was associated with increased risk [odds ratio (OR), 1.2; 95% CI, 1.01-1.3] and evidence of dose response was observed. Most of the excess was observed among women ages 50-64 years (OR 1.3; 95% CI, 1.1-1.6), although the test for age interaction was not statistically significant. Exposure later in life seemed more important than early exposure. Excess breast cancer associated with recent consumption was restricted to localized disease. When outcome was examined according to tumor hormone receptor status, highest risks were observed for estrogen receptor-positive/progesterone receptor-negative tumors (OR 1.6; 95% CI, 1.2-2.3).CONCLUSIONS: The effect of timing of alcohol exposure on breast cancer risk is complicated and will require additional study focused on this one issue. Further work is needed to explain how alcohol exposure, sex hormones, and tumor receptor status interact.     

Molecular marker profiles predict locoregional control of head and neck squamous cell carcinoma in a randomized trial of continuous hyperfractionated accelerated radiotherapy.

PURPOSE: Identification of factors that assist prediction of tumor response to radiotherapy may aid in refining treatment strategies and improving outcome. Possible association of molecular marker expression profiles with locoregional control of head and neck squamous cell carcinoma was investigated in a randomized trial of conventional versus continuous hyperfractionated accelerated radiotherapy (CHART). EXPERIMENTAL DESIGN: Tumor material was obtained from 402 patients. Immunohistochemistry was used to assess Ki-67, CD31, p53, Bcl-2, and cyclin D1 expression. A hierarchical clustering algorithm with a Bayesian information criterion was used to group tumors with similar marker expression; resulting expression profiles were then compared in terms of their difference in outcome after CHART and conventionally fractionated radiotherapy. RESULTS: Molecular marker profile was an independent prognostic factor for locoregional control. This was confirmed in multivariate analysis, including clinical variables such as tumor and nodal status, primary site, histological grade, age, and gender (P < 0.001 and P = 0.006 for local and nodal relapse, respectively). In particular, Bcl-2-positive tumors responded significantly better than average in both arms of the trial. Tumors negative for p53- and Bcl-2, with high and randomly patterned Ki-67 expression, responded worse than average with no benefit from CHART. Tumors with similarly negative p53 and Bcl-2, but low Ki-67 staining, with an organized pattern, benefit significantly from CHART schedule. CONCLUSIONS: This study demonstrates the potential of molecular profiles to predict radiotherapy response of head and neck squamous cell carcinoma and for treatment stratification. Distinct expression profiles correlate with three distinct clinical phenotypes, including good locoregional control, poor locoregional control, and an outcome strongly dependent upon fractionation schedule.     

The immunohistochemical assessment of hypoxia, vascularity and proliferation in bladder carcinoma.

BACKGROUND AND PURPOSE: Hypoxia and proliferation are important determinants of radiation responsiveness; prospective measures of these before radiotherapy may enable individualisation of treatment schedules. Immunohistochemical techniques offer a potential means of achieving this in routine biopsy material. MATERIAL AND METHODS: Cellular hypoxia as measured by pimonidazole fixation and immunohistochemistry has been evaluated in a series of human bladder cancers with dual staining of sections for pimonidazole and either the vascular markers, CD31/34, or proliferation markers, Ki-67 or cyclin A. Twenty one tumour specimens were examined suitable for the double staining technique. RESULTS: The median hypoxic fraction was 9% (range 0-38). Seven tumours did not stain for pimonidazole and 11 exhibited necrosis. The mean vascular density ranged from 16.7 to 160.6 vessels per mm2. The median hot spot count was 30 (range 16-43). There was a statistically significant increase in vessel density in hypoxic compared to oxic regions measured by both vessel density (P = 0.02) and hot spot count (P = 0.004). Proliferation indices decreased from oxic to hypoxic areas close to blood vessels. CONCLUSIONS: We have demonstrated that bladder cancer exhibits a range of hypoxia, proliferation and vascular density which may be used to form the basis for patient selection for hypoxia modification, accelerated radiotherapy and vascular targeting agents.     

Prevention of ovarian cancer: intraepithelial neoplasia.

To reduce the incidence and mortality associated with invasive cancers, the Intraepithelial Neoplasia (IEN) Task Force recommends that carcinogenesis be viewed as a disease that requires treatment. This publication outlines the current knowledge of IEN of the ovary and reviews chemoprevention possibilities for ovarian cancer. Ovarian cancer has the highest mortality of all of the gynecological cancers and is the fourth leading cause of death from cancer in women. The IEN Task Force has defined precancer as a noninvasive lesion that has genetic abnormalities, loss of cellular control functions, and some phenotypic characteristics of invasive cancer with a substantial likelihood of developing invasive cancer. The IEN Task Force recommends targeting moderate to severe dysplasia for new IEN treatment agents in clinical trials. Ovarian cancer does not have a clear preinvasive lesion yet merits considerable study for new prevention strategies because of the high mortality associated with ovarian cancer. There is a great unmet clinical need for treatments that can prevent ovarian cancer by providing nonsurgical options that treat the entire epithelial layer. New prevention strategies hold significant promise to reduce the mortality from ovarian cancer.     

HER2 status in non-small cell lung cancer: results from patient screening for enrollment to a phase II study of herceptin.

PURPOSE: For the first time a large number (563) of non-small cell lung cancer (NSCLC) samples was used to compare three different technologies for the assessment of HER2 status. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) were used for tumor tissue samples, and ELISA for serum samples. The results were compared with other tumor entities, mainly breast. EXPERIMENTAL DESIGN: Samples (563) from patients suffering from primary advanced or metastatic NSCLC were evaluated. RESULTS: HER2 overexpression was demonstrated using IHC in 20% (83 of 410) of the specimens, whereas 2% (7 of 378) were positive by FISH and 6% (31 of 511) showed elevated serum HER2 levels (>15 ng/ml) by ELISA. Sixty-six specimens were positive by IHC only and 13 by ELISA only, whereas none of the specimens was positive only by FISH. Concordance between all of the techniques was seen for only 3 specimens. Of 7 IHC 3+ specimens, 4 showed gene amplification by FISH, and 3 were positive by ELISA (>15 ng/ml), whereas of 76 IHC 2+ cases only 2 were amplified by FISH, and 4 were positive by ELISA. HER2 positivity by at least one of the three techniques was most common in adenocarcinomas, at 29% (42 of 143). CONCLUSION: Gene amplification and HER2 protein overexpression at the 3+ level appear to be uncommon in NSCLC. The concordance between FISH and IHC 3+ disease was good in this study, in addition, ELISA would have detected several patients without IHC/FISH-positive disease.