Low CHD5 expression activates the DNA damage response and predicts poor outcome in patients undergoing adjuvant therapy for resected pancreatic cancer.

The DNA damage response (DDR) promotes genome integrity and serves as a cancer barrier in precancerous lesions but paradoxically may promote cancer survival. Genes that activate the DDR when dysregulated could function as useful biomarkers for outcome in cancer patients. Using a siRNA screen in human pancreatic cancer cells, we identified the CHD5 tumor suppressor as a gene, which, when silenced, activates the DDR. We evaluated the relationship of CHD5 expression with DDR activation in human pancreatic cancer cells and the association of CHD5 expression in 80 patients with resected pancreatic adenocarcinoma (PAC) by immunohistochemical analysis with clinical outcome. CHD5 depletion and low CHD5 expression in human pancreatic cancer cells lead to increased H2AX-Ser139 and CHK2-Thr68 phosphorylation and accumulation into nuclear foci. On Kaplan-Meier log-rank survival analysis, patients with low CHD5 expression had a median recurrence-free survival (RFS) of 5.3 vs 15.4 months for patients with high CHD5 expression (P=0.03). In 59 patients receiving adjuvant chemotherapy, low CHD5 expression was associated with decreased RFS (4.5 vs 16.3 months; P=0.001) and overall survival (OS) (7.2 vs 21.6 months; P=0.003). On multivariate Cox regression analysis, low CHD5 expression remained associated with worse OS (HR: 3.187 (95% CI: 1.49-6.81); P=0.003) in patients undergoing adjuvant chemotherapy. Thus, low CHD5 expression activates the DDR and predicts for worse OS in patients with resected PAC receiving adjuvant chemotherapy. Our findings support a model in which dysregulated expression of tumor suppressor genes that induce DDR activation can be utilized as biomarkers for poor outcome.

Sertraline and desmethylsertraline in human breast milk and nursing infants.

OBJECTIVE: The purpose of this study was to determine the concentrations of sertraline and desmethylsertraline in both human breast milk and infant serum. METHOD: Breast milk samples from 12 women were collected at specific time intervals after oral doses of sertraline (25-200 mg once daily). For 11 mother-infant pairs, maternal serum levels 24 hours after a dose and their infants' serum levels 2-4 hours after nursing were ascertained by high-performance liquid chromatography. RESULTS: Sertraline and desmethylsertraline were present in all breast milk samples, with a gradient from "fore" milk to "hind" milk. The highest concentrations of sertraline were observed in hind milk 7-10 hours after maternal dose. Increasing the maternal dose of sertraline resulted in increased breast milk concentrations of both sertraline and desmethylsertraline. Detectable concentrations of sertraline were found in three nursing infants and desmethylsertraline in six. No adverse effects of exposure were observed in any infant. CONCLUSIONS: Sertraline and desmethylsertraline were present in the breast milk of nursing women treated with sertraline. Concentrations were affected by aliquot of milk sampled, time after maternal dose, and maternal daily dose. The infants' serum concentrations detected were below the detection limit of most commercial laboratories. The presence of desmethylsertraline in six infants' samples underscores the importance of metabolite monitoring in determining infant exposure. Estimates of daily infant exposure can be determined after analysis of sertraline and desmethylsertraline concentrations from one full breast at maternal serum steady state. Future studies of breast milk and infant serum samples should address these issues.

Cellulitis of the breast as a complication of breast-conserving surgery and irradiation.

Breast-conserving therapy (BCT) has become a standard treatment option for patients with early-stage breast cancer. We have observed cellulitis of the treated breast as a complication occurring before, during, and after breast irradiation. The cases of five women (median follow-up, 28 months; range, 24-65 months) who developed cellulitis before (n = 1), during (n = 2), or after (n = 2) breast irradiation were reviewed. A consecutive series of BCT patients at Emory University was reviewed to determine the incidence of this complication. Four of five women had an axillary dissection, yielding a median of 14 negative lymph nodes (range, 6-22 nodes). Two of four patients developed axillary seromas requiring aspiration. In these four patients, only the breast was irradiated. A fifth patient had no axillary dissection and had breast and supraclavicular/axillary irradiation. The median whole breast dose was 50 Gy (range, 46-50.4 Gy). The clinical features of cellulitis included erythema, edema, tenderness, and warmth in all patients. Cellulitis was a relapsing problem for four of the five patients. The incidence of this complication in our series of BCT patients was approximately 1%. Cellulitis in the ipsilateral breast can be a relapsing complication of BCT and can be seen before, during, or after breast irradiation. Axillary seromas and aspiration seem to indicate a subset of patients at risk of early cellulitis. Late cellulitis may be caused by a variety of factors related to modifications of vascular and skin integrity by surgery and radiotherapy. Prompt diagnosis and appropriate antibiotic therapy is recommended. This problem need not interrupt a course of breast irradiation, and does not necessarily lead to a poor cosmetic result.

Anatomic variation of extrahepatic biliary tree structures: importance in treatment planning for radiation therapy.

PURPOSE: To demonstrate the variable location of biliary tree components and to assess two treatment planning rules of thumb used for locating porta hepatic nodes for radiation therapy. MATERIALS AND METHODS: The distance of the common hepatic duct bifurcation and duodenal papilla from adjacent vertebral bodies was measured on 34 cholangiograms, and their relationships to particular vertebral body levels were recorded. Adequacy of treatment volume to encompass porta hepatic lymph nodes was evaluated in 30 of these cholangiograms by constructing radiation portals according to the two rules of thumb. RESULTS: Location of the common hepatic duct bifurcation and duodenal papilla varied widely. The treatment portal encompassed 13% (four of 30) of cases when the first rule of thumb was used and 80% (24 of 30) of cases when the second rule of thumb was used. CONCLUSION: The wide variability of location of extrahepatic biliary tree structures suggests the need for individualized treatment planning so that sensitive and dose-limiting healthy tissues can be optimally excluded from radiation treatment portals. Computed tomography and other imaging modalities enable precise location of biliary tree components for radiation treatment planning.

Conservative treatment of early-stage breast cancer in a medically indigent population.

The compliance with a program of breast-conservation treatment for early-stage breast cancer and the results of that treatment among women treated between January 1983 and January 1992 was investigated in a large inner-city public hospital serving a primarily black population. Medical records and charts were reviewed for 25 consecutive patients with stage I and II breast cancer seen in consultation in the radiation oncology department. Of those 25 patients, 20 underwent lumpectomy and radiation therapy. Survival, disease-free survival, and local recurrence-free survival were computed using the Kaplan-Meier method. Compliance was evaluated based on time to complete the prescribed course of radiotherapy after a lumpectomy. Five-year local recurrence-free survival for stage I and II patients was 95% (confidence interval [CI]: 71% to 99%). Five-year overall survival for stage II patients was 71% (CI: 31% to 92%), and disease-free survival was 74% (CI: 36% to 91%). This study demonstrates that a program of breast-conservation treatment for early-stage breast cancer can be implemented with good results, excellent treatment compliance, and 100% follow-up in a population of medically indigent women.

Definitive radiation therapy for extrahepatic bile duct carcinoma.

PURPOSE: To evaluate retrospectively the role of radiation therapy for extrahepatic bile duct (EHBD) carcinoma. MATERIALS AND METHODS: Twenty-seven patients with local-regional EHBD carcinomas were treated with definitive radiation therapy. Radiation therapy was delivered by means of external beam radiation therapy (EBRT) alone or combined with transcatheter iridium-192 brachytherapy. The median total dose was 54 Gy (range, 30-144 Gy). Survival rates were calculated and compared by using the log-rank test. Possible prognostic factors affecting survival were evaluated by means of univariate analysis. RESULTS: The median survival of all patients was 13 months, with 1- and 2-year actuarial survival rates of 52% and 10%, respectively. Univariate analysis revealed that men, patients with tumors limited to the bile duct, and patients receiving EBRT doses of at least 45 Gy had significantly better outcomes. Local-regional recurrence was the main cause of treatment failure (82%). Two patients developed gastric outlet obstruction. CONCLUSION: Patients with locally advanced EHBD carcinomas have a low survival rate. Certain factors, however, appear to have prognostic significance.

Conservative treatment of early-stage breast cancer. The Emory experience.

Between January 1983 and December 1991, 80 women with AJCC clinical stage I or II breast cancer were treated with conservative surgery and radiation therapy. Reexcision of the primary was performed in 40 breasts, and residual tumor was identified in 40% of these. Margins of resection were assessed in 80% and, of these, 46 patients had final margins of resection that were negative, 86% had axillary node dissection, 45 patients had histologically negative axillary nodes, and 24 had histologically positive axillary nodes. Of patients with histologically positive lymph nodes, 92% received systemic adjuvant treatment consisting of chemotherapy in 19/24 and tamoxifen in 14/24. Median follow-up was 34 months (range: 6-90 months). The adjusted 5-year actuarial Overall Survival for the group was 92%, and Disease-Free Survival was 80%. The 5-year Local Recurrence-Free Survival was 96%. The present study confirms the excellent results that can be obtained with conservative surgery plus radiation therapy.

Preoperative irradiation and fluorouracil chemotherapy for locally advanced rectosigmoid carcinoma: phase I-II study.

From June 1988 to July 1991, 20 patients with locally advanced rectal or rectosigmoid cancer were treated prospectively with a strategy of combining preoperative irradiation and fluorouracil chemotherapy before surgical resection. The preoperative radiation dose was 5,000 cGy, and fluorouracil chemotherapy was administered on the first and last 3 days of irradiation in an intravenous bolus dose of 500 mg/m2. In a median follow-up of 25 months, the local regional failure rate was 10%. The 3-year actuarial overall survival and disease-free survival were 92% and 82%, respectively. Twenty percent of the surgical specimens showed no residual tumor, and only 10% showed positive lymph nodes. Significant leukopenia occurred in 10% of patients. Preoperative irradiation and fluorouracil chemotherapy increased surgical downstaging and improved local regional control. The overall toxicity was acceptable. The results of this particular multimodality approach was encouraging and warrant further investigation in phase III trials.

A patient rotator for stereotactic radiosurgery.

A new technique for stereotactic radiosurgery by use of a patient rotator is described. Using the rotator with a small collimated beam of 6 MV x-rays, a small well-defined region of the brain can be irradiated to a high dose with rapid fall off of the dose outside the target volume. Since the linear accelerator gantry does not move during therapy the possibility of a collision between the gantry and the patient or stereotactic equipment is eliminated. The system is also independent of the rotational stability of the linear accelerator gantry axis and turntable axis. Dose distributions measured in a Lucite head phantom with film exhibited properties well suited for radiotherapy. Tests carried out to evaluate the ability to irradiate a selected target point within the brain with the rotator system showed a maximum positional error of 1.0 and 2.0 mm for angiography and CT localisation respectively.

Accidental bromine exposure in an urban population: an acute epidemiological assessment.

In November 1984, because of an accident at a chemical plant, the population of a large area in the town of Geneva, Switzerland, was exposed to toxic bromine gas during several hours at concentrations above the short-term exposure limit. We describe the development of the disaster, the reactions of the fire brigade, the police and the first aid services as well as the breakdown of communications that occurred. On-the-spot epidemiological assessment of the exposed area and of the characteristics of the exposure syndrome was combined with the emergency care of 91 self-referred patients that were seen at the University Hospital. Follow-up was obtained one month later. The clinical course was moderate (eyes and upper airways irritation) and self-limiting in all cases. Immediate definition of the exposed population permitted effective follow-up. Such early evaluation could prove to be of crucial importance for managing more serious accidents of a similar nature.

[Bromine cloud in Geneva. Epidemiologic study of the short-term effects on a population sample]. / Nuage de brome à Genève. Etude épidémiologique des effets à court terme sur un échantillon de la population.

In November 1984, due to an accident at a chemical plant, toxic bromine gas spread into the town of Geneva, Switzerland, at concentrations over five times the maximal admissible concentration (MAC). Monitoring of atmospheric brome concentrations allowed the determination both of the duration of exposure and the geographical area concerned. Description of the immediate measures taken at the time of the accident illustrates how mass panic reactions can be generated or controlled, and clearly shows the vital importance of an effective communication network: it was lacking in this case and caused further insecurity for the population and isolation of the hospital. Immediate and systematic data collection enabled us to carry out an "acute" epidemiological survey of the accident. It is the first report of mass bromine intoxication in the medical literature. 91 patients with symptoms of bromine exposure were seen in the outpatient and casualty departments of the cantonal Hospital, but the clinical course was mild and self-limited in nearly all cases. One patient was admitted for 24 hours. The most common symptoms were upper respiratory tract symptoms, cough and headache. In 20-30% of cases these pesisted for more than three days, and sometimes up to one month. Recording the location of patients at the time when their first symptoms occurred made it possible to define the exposed area with precision. When the initial data collected in this "acute" fashion is reliable, it should be possible to undertake more elaborate epidemiological studies at a later stage if necessary.

[Manganese in the water supply of the town of Beaucaire: origins and solutions]. / Manganese dans l'eau d'alimentation de la ville de beaucaire: origines et solutions.

Changes in domestic water supply appearance and quality linked with increasing manganese amount and iron at a lesser degree, having been found by the inhabitants of Beaucaire (Rhône Valley), a study was made by chemists, hydrogeologists and biologists to detect the origin. The problem is not specific to this town and can frequently be found in the Saône and Rhône valleys. The results show that we have to deal with an aquifer with semi-captive groundwater whose supply is double: the Rhône and calcareous mountain masses. The low-oxygen waters are enriched, by dissolution from gravel, with manganese and iron which are preferentially fixed on porous and cracked surface elements. The conditions for manganese liberation are connected with the presence of organic matters, bacteria (capable to reduce the manganic compounds) and anaerobiosis. The supply does not seem to be the only cause in the low-oxygen contents; the action of heterotrophic microorganism using organic matter and consuming oxygen, at the groundwater periphery, must be taken into account. Thus the central part of the groundwater system is a reducing environment which allows the modification of the bacterial metabolism towards a ferric and manganic compounds reduction process. The result is the transformation of insoluble manganic and ferric compounds into manganous and ferrous compounds which are liberated into the groundwater.

[Design and methodology in environmental acoustics]. / Conception et méthodologies en acoustique environnementale.

On the basis of many experiments of urban acoustics carried out in the canton of Geneva, the authors come to the conclusion that the normative values cannot be applied when the estimate of discomfort level is concerned. They must be applied to prevent the risk of auditive acuteness loss. In order to establish discomfort, it is necessary to use methods to measure and analyse the results which are suitable for each condition, and to take into account the acoustic charge, the noise dynamics, the acoustic spectrum and the socio-economic environment of the people concerned. The conception has been accepted by Court of Justice in Geneva, which is now legally accepted: one may consider a uncomfortable any increase of 4-6 dB(A) of the acoustic level, as compared to the previous situation or to the background noise. The ability to differentiate between two stimuli is based on the physiological mechanisms of hearing.

The monitoring of ozone immissions in rural and urban areas.

It has been shown, by a statistical study of the concentrations of ozone in air as measured by two monitoring stations--one being situated in an urban and the other a rural area--that photochemical smog episodes to occur. The ratio O3 urban/O3 rural is normally less than 1. This ratio, however, has been shown to be greater than 1, when certain conditions prevail, notably on days of high solar radiation and low velocity winds. At nigh-time, in the absence of photochemical reactions, the higher concentrations of ozone observed in town as opposed to the country side has been attributed to air transport phenomena.

[CO-pollution, a health risk in Geneva?]. / Pollution due au CO, un risque pour la santé à Genève?

The results from CO measurements at different locations in Geneva show that the highest levels are found in streets in the center of the city. An evaluation of the medical risks is performed against the most sensitive criteria--effects on the central nervous system, the cardiac muscle and the fetus. It is concluded that symptoms of anoxia may develop among persons with existing cardiovascular diseases.

Potassium hexacyanoruthenate(II) as an analytical reagent for iron.

Fe(III) undergoes a reaction with colourless Ru(CN)(4-)(6) to produce an intensely violet-blue complex that absorbs at 550 nm and obeys Beer's law over the iron concentration range 0.04-2 mug/ml in acidic medium. Some common cations and anions are tolerable at low concentrations. The procedure is applicable for determination of total iron in potable water. Destruction of organic matter is required for contaminated surface waters or soil samples.