Residence times of groundwater along a flow path in the Great Artesian Basin determined by 81Kr, 36Cl and 4He: Implications for palaeo hydrogeology.

Understanding the age distribution of groundwater can provide information on both the recharge history as well as the geochemical evolution of groundwater flow systems. Of the few candidates available that can be used to date old groundwater, 81Kr shows the most promise because its input function is constant through time and there are less sources and sinks to complicate the dating procedure in comparison to traditional tracers such as 36Cl and 4He. In this paper we use 81Kr in a large groundwater basin to obtain a better understanding of the residence time distribution of an unconfined-confined aquifer system. A suite of environmental tracers along a groundwater flow path in the south-west Great Artesian Basin of Australia have been sampled. All age tracers (85Kr, 39Ar 14C, 81Kr, 36Cl and 4He) display a consistent increase in groundwater age with distance from the recharge area indicating the presence of a connected flow path. Assuming that 81Kr is the most accurate dating technique the 36Cl/Cl systematics was unravelled to reveal information on recharge mechanism and chloride concentration at the time of recharge. Current-day recharge occurs via ephemeral river recharge beneath the Finke River, while diffuse recharge is minor in the young groundwaters. Towards the end of the transect the influence of ephemeral recharge is less while diffuse recharge and the initial chloride concentration at recharge were higher.

Influence of chemotherapeutic agents on chorionic gonadotropin-alpha subunit secretion in a human lung cancer cell line (ChaGo): discordance of cytotoxic and secretory effects.

Cells from cultures of ChaGo, a cell line of a human lung cancer that ectopically produces chorionic gonadotropin (hCG) and its alpha subunit (hCG-alpha) were exposed to five different cancer chemotherapeutic agents in vitro in separate experiments (one drug/expt). The control doubling time averaged 4 days, with molar biphasic secretory rates of hCG-alpha ranging from a high of 58.1 to a low of 10.5 pmoles/10(6) cells/24 hours. Drug concentrations were chosen to induce a 30-60% inhibition of cell replication over a period of 8-10 days. Neither methotrexate nor vincristine demonstrated major effects on extracellular hCG-alpha production, but each agent moderately depressed cell number and each produced major inhibition of intracellular protein synthesis. Procarbazine inhibited marker production only in slight excess of inhibition of cell growth and cell protein. Actinomycin D and mechlorethamine, however, had profound effects on inhibition of hCG-alpha production in excess of cell growth. Our results indicated that cancer chemotherapeutic agents have specific and differing effects on cell growth and cell protein on the one hand and marker production on the other. These data suggested a mechanism for certain cases of discordance between hormone production and clinical status.

Apoptosis mediates cell death following traumatic injury in rat hippocampal neurons.

A model of in vitro traumatic injury with dissociated rat hippocampal neurons was studied to explore the mechanism of cell death. The neurotoxicity induced by traumatic injury to the cell culture can be transferred to a naive uninjured culture by media exchange. This toxicity is attenuated by dimethylsulfoxide or superoxide dismutase, suggesting that this toxicity is mediated by a free radical generation. Ionotropic glutamate receptor antagonists had no effect. This toxicity was effectively blocked by the pretreatment of the naive uninjured recipient cultures with cycloheximide or with actinomycin D. The DNA fragmentation could be illustrated with in situ nick translation in the cells which seem to have lost their cytoplasm. The nuclear morphology of neurons labeled by a neurofilament-specific antibody, SMI-31, demonstrated chromatin condensation and nucleosome formation. Traumatic injury induces release of an unknown toxin into the extracellular space. These observations suggest that a traumatized neuronal culture can propagate cell death of naive uninjured cells by releasing a neurotoxin that causes apoptosis.

Vitamin A serum and dietary vitamin A intake in lung cancer patients.

Clinical and experimental evidence indicates a possible role for vitamin A deficiency in the pathogenesis of bronchogenic carcinoma. We, therefore, measured serum vitamin A levels in 67 newly diagnosed non-resectable lung cancer patients. In 43 of these patients daily vitamin A intake was also determined. Serum vitamin A levels were within the normal range of the general population of 66 of the 67 patients. Eighteen of 43 patients had daily vitamin A intakes less than 5000 IU/day while 25 patients had daily intake above this level. The serum vitamin A level did not correlate with histologic subtype, extent of disease or presence or absence of hepatic metastases. While these data suggest that vitamin A deficiency was not implicated in pulmonary carcinogenesis, more definitive conclusions await prospective evaluation of high risk individuals followed serially for many years.

A controlled clinical trial testing two potentially non-cross-resistant chemotherapeutic regimens in small-cell carcinoma of the lung.

With the objectives of improving response rate, duration of response, and survival in small-cell carcinoma of the lung, 39 patients were randomized to remission-induction with either one of two potentially non-cross-resistant drug combinations: APE (consisting of adriamycin, 35 mg/m2 IV, D1 Q 3 weeks; procarbazine, 60 mg/m2 PO, D1-10 Q 3 weeks; and the epipodophyllotoxin (VP16-213), 130 mg/m2 IV, D8, 15 Q 3 weeks) or MOCC (composed of methotrexate, 15 mg/m2 IV (with [vincristine] Oncovin) or PO twice weekly D8-21 Q 3 weeks; Oncovin, 1.5 mg/m2 IV, D8, 15 Q 3 weeks; cyclophosphamide, 600 mg/m2 IV, D1 Q 3 weeks, and CCNU, 60 mg/m2 PO Q 6 weeks). A fixed crossover to the alternate regimen occurred at three months. Radiotherapy was delivered to the primary tumor (locoregional disease only) by a split course technique (1,750 rads for five days with a three-week split, followed by 3,400 rads over 17 days). The median survival including both arms was 11 months for regional and nine months for extensive disease. The chemotherapeutic activity of both regimens was comparable, with 15/17 (88 percent) of the patients responding to APE (including six complete) and 14/17 (82 percent) responding to MOCC (including five complete). The median survival for the complete responders was 11.7 months, while the partial responders survived for a median of 9.7 months. There were 2/9 (22 percent) responders to the alternate regimen at progressive disease. The overall incidence of CNS progression was 17 percent. The toxicity of the regimens was moderate, except for one instance of granulocytopenic death. This study establishes two equipotent drug combinations for the treatment of small-cell carcinoma of the lung.

Differential changes in central monoaminergic metabolism during first and multiple sodium depletions in rats.

To investigate the role of central monoamines in the behavior of sodium appetite, serotonergic and dopaminergic metabolism in regions of the forebrain and dorsal hindbrain were measured in sodium-depleted rats. Male Sprague-Dawley rats were sodium depleted by injection of the diuretic-natriuretic drug, Lasix (furosemide, 10 mg), and maintained on a sodium-deficient diet overnight. Rats were tested at a first sodium depletion or after multiple sodium depletions. There were three test conditions: 1) mock depletion consisted of vehicle injection and overnight sodium-deficient diet; 2) sodium depletion alone consisted of Lasix injection and overnight sodium-deficient diet; and 3) intake of NaCl following sodium depletion consisted of 9-min access to 0.3 M NaCl after Lasix injection and overnight sodium-deficient diet. Dopamine (DA), DOPAC, HVA, 5-HT, and 5-HIAA were measured by HPLC in the olfactory tubercle, amygdala-pyriform lobe, n. accumbens, hypothalamus, caudate nucleus, and the dorsal hindbrain. Ingestion of 0.3 M NaCl for 9 min after the first sodium depletion increased 5-HIAA/5-HT ratio significantly in the n. accumbens and amygdala, and increased DOPAC/DA ratio in the n. accumbens and olfactory tubercle compared to the mock treatment. In contrast to the results after the first sodium depletion, rats that ingested 0.3 M NaCl after four or more sodium depletions had no changes in 5-HT and DA metabolism in the forebrain, but they did have a significantly larger 5-HIAA/5-HT ratio in the dorsal hindbrain than mock-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

A phase II clinical trial evaluating the use of two sequential, four-drug combination chemotherapy regimens in ambulatory bronchogenic adenocarcinoma patients.

Forty-three ambulatory patients with locally advanced or metastatic bronchogenic adenocarcinoma were sequentially treated with two potentially mutually non-cross-resistant chemotherapy regimens. A new regimen, MVPF (mitomycin-c, vinblastine, procarbazine, and 5-fluorouracil), was given until progressive disease occurred. Then, a second regimen--MOCC (methotrexate, vincristine [Oncovin], cyclophosphamide, and CCNU)--was initiated. At further progression, regional disease patients received radiotherapy, whereas extensive disease patients received Phase II agents. Of the 43 patients entered on the study, 40 were evaluable. Three patients withdrew early due to poor tolerance of the regimen. The response rate for MVPF was 33% (12 of 40 PR, 1 of 40 CR) compared to a 4% (1 of 23 PR) response for MOCC (difference: p < or = .03), for a total response rate of 35%. Although there was an initial improvement in survival for responders (31.7 weeks) versus nonresponders (15.7 weeks) at the 75th percentile (p < or = .05), there was no significant difference in median survival. The hematologic toxicity was equivalent for both groups, whereas nonhematologic toxicity revealed a high incidence of nausea and vomiting in the MVPF group. It is concluded that this approach lent itself well to ambulatory care, and MVPF could be considered an alternative to cyclophosphamide-based regimens. However, the absence of a meaningful CR rate and lack of influence of response on median survival were factors limiting its effectiveness.

A randomized clinical trial in bronchogenic small-cell carcinoma evaluating alternating maintenance therapy of vincristine, adriamycin, procarbazine, and etoposide (VAPE) with cyclophosphamide, CCNU, and methotrexate (CCM) versus CCM maintenance alone in complete responders following VAPE induction and late intensification.

Initially, 109 evaluable patients with locally advanced or metastatic small cell lung cancer (SCLC) were treated with vincristine, Adriamycin, procarbazine, and etoposide (VAPE). Partial (PR) or nonresponders (NR) were crossed to CCM (cyclophosphamide, CCNU, and methotrexate) and then to HMiVe (hexamethylmelamine, mitomycin C, vinblastine) sequentially at maximum response. Complete responders (CR) were intensified by 50% with VAPE primarily and randomized to VAPE, alternating with CCM or CCM alone during maintenance. CR patients with limited disease received local thoracic irradiation and prophylactic cranial irradiation (PCI), whereas those with extensive disease received PCI alone. There were 45 patients (41%) who achieved a CR to chemotherapy, and 27 patients were eligible for randomization. Of 12 CR patients randomized to alternating therapy (VAPE/CCM), the median survival was 25.9 months compared to 12.9 months for 15 CR patients randomized to continuous CCM (P = .049). In addition, 35 patients achieved a PR (32%) and 29 were NR (27%). Overall median survivals were significantly different for the CR patients (13.0 months) as compared to PR (7.6 months) and NR patients (6.4 months). Late intensification did not appear to add substantially to survival while contributing to toxicity. In summary, VAPE is a new outpatient regimen for SCLC, which is highly effective as an induction regimen with moderate hematologic toxicity and predominantly gastrointestinal nonhematologic toxicity.

[Our current results with acoustic neurinoma surgery]. / Nos résultats actuels de la chirurgie du neurinome de l'acoustique.

Out of 130 CPA tumors operated on between 1993 and 1997, 91 were vestibular schwannomas less than 25 mm with preoperative hearing and normal facial function. The pre and postoperative facial and hearing functions were analyzed prospectively. The surgical technique applied was the complete tumor removal via retrosigmoid approach under facial nerve monitoring and CPA endoscopy. Clinical features were analyzed to determine postoperative facial grading (House-Brackmannn) and tonal and vocal audiometrical datas (PTA-SDS) at 8 days, 90 days and 1 year. We achieved 96 % of good facial results (Grade I and II/HB) and 46,5 % of postoperative conserved hearing. For tumors less than 25 mm in the CPA, good preoperative hearing level, preoperative AOE and BER seem to be predictive factors for hearing preservation. Early diagnosis associated with the advances in minimal invasive otoneurological techniques leads to perform complete removal of this type of tumors with respect of facial and hearing functions.

[Are we sectioning the cochlear efferent system during vestibular neurotomy?]. / Sectionne-t-on le système efférent cochléaire au cours de la neurotomie vestibulaire?

INTRODUCTION: In addition to sensory neurons which transmit information from the inner ear to the brain, there is a system of efferent feedback fibers, called the olivocochlear system, carrying signals from the brain to the ear. Over the past half-century, the efferent system has been extensively studied in animals and results provided theories as to the functional significance of these efferents: to improve signal-to-noise ratio in the auditory periphery, to mediate selective attention, and to protect the inner ear from acoustic overexposure. The results of several studies conducted in man rely on the study of patients who have undergone a vestibular neurectomy. Indeed, anatomical data show that olivocochlear efferents could travel along or inside the vestibular part of the auditory nerve before reaching the organ of Corti. Therefore, these patients may be considered as an experimental model of unilaterally de-efferented subjects. However, to date, none has reported the existence of olivocohlear efferents in the vestibular section following neurectomy. MATERIALS AND RESULTS: In this study, we present the histological results from 18 vestibular sections and show the absence of olivocochlear efferents. CONCLUSION: These results provide a reason to reconsider the results of previous experiments conducted in similar patients and ask for further studies on the olivocochlear efferents pathways.

Cisplatin-induced autonomic neuropathy.

A 57-year-old man with bronchogenic squamous cell carcinoma developed an autonomic neuropathy following treatment with a chemotherapy combination which included cisplatin. The autonomic neuropathy resolved following discontinuation of the cisplatin and treatment with dextroamphetamine. The following case represents a patient with bronchogenic carcinoma treated with cyclophosphamide, doxorubicin, and cisplatin, who developed a severe autonomic neuropathy following chemotherapy administration. This is the first report of cisplatin-associated autonomic neuropathy to appear in the literature.

Pharmacokinetic considerations in the design of optimal chemotherapeutic regimens for the treatment of breast carcinoma: a comceptual approach.

Pharmacological data are currently available for a number of antineoplastic agents which have shown clinical activity in advanced breast carcincoma. Preclinical data reveal a relationship between therapeutic response and certain pharmacokinetic parameters such as time of effective cytotoxic exposure (Teff) and the product of concentration with time (Cxt). We have attempted to apply human pharmacologic data to get estimates of these parameters for 6 active agents in breast cancer, to relate them to response rates, and to suggest a method for estimating the role of individual drugs in a multidrug combination. The response rates for 6 single agents were obtained from literature review and related to estimates of Teff and Cxt. The Cxt-response relations for single drugs were linear for cyclophosphamide, 5-fluorouracil, and thiotepa; exponential for vincristine; and relatively flat for methotrexate and cytoxine arabinoside. Most Teff values for the active single agents clustered about 15 hr/dose. From the graphs of response rate vs Cxt, the individual contribution of each agent in a combination study was estimated to arrive at a predicted response rate. The predicted response rates for the combination studies correlated with the actual response rates determined in the clinical study, for 6 of 6 nonrandomized studies and for 12 of 14 randomized studies analyzed. In 2 studies, deviations from the predicted response rate were attributed to differences in study design or analysis. There was no correlation between Teff and predicted response rate. Analyses of pharmacokinetic data may be useful to simulate combination chemotherapy studies to predict the effectiveness of clinical trials in breast cancer. Since the pharmacologic data were not obtained for any of the agents in the actual clinical trials done, we can only speculate on the usefulness of this method. We would encourage the prospective collection of this data in future clinical trails.

Lobular carcinoma of the breast metastatic to bone with unusual clinical, radiologic, and pathologic features mimicking osteopoikilosis.

A 55-year-old woman who underwent a right radical mastectomy for infiltrating lobular carcinoma was found to have multiple diffuse osteoblastic bone lesions. Since she was asymptomatic, had no elevation of alkaline phosphatase, and the lesions did not take up technetium pyrophosphate on bone scan, she was thought to have osteopoikilosis. An iliac bone biopsy was performed that showed greatly thickened bony trabeculae with diffuse delicate marrow fibrosis entrapping easily overlooked short strands of small malignant cells. The histologic picture also closely resembled osteopoikilosis. Although infiltrating lobular carcinoma has been recognized as separate from ductal carcinoma in the primary site, its recognition in metastatic foci is still vague. Attention is drawn to its histologic appearance in skeletal metastases so that such lesions will be more recognizable in the future.

Phase I study of thalicarpine (NAC-68075), a plant alkaloid of noval structure.

An initial clinical trial of daily and weekly X 6 ihtravenous infusions of thalicarpine, a plant alkaloid of novel structure, was carried out in 36 patients. Twenty-eight patients received 33 courses of single-dose administration at doses of 200-1900 mg/m2. At the maximum tolerable dose of 1400 mg/m2, toxic effects included arm pain (nine or ten), central nervous system depression (seven of ten), nausea and vomiting (two of ten), hypotension (two of ten), hypertension (two of ten), arrhythmia (premature ventricular contractions) (one of ten), and electrocardiographic changes (mainly T-wave flattening) (five of ten). At the maximum tolerable dose for weekly administration, 1100 mg/m2/week X 6, arm pain was seen in seven of eight, central nervous system depression in three of eight, hypotension in one of eight, and electrocardiographic changes in three of eight. The recommended dose for phase II trials is 1100 mg/m2/week by a 2-hour intravenous infusion.

Placental proteins and their subunits as tumor markers in prostatic carcinoma.

Sixteen patients with Stage D adenocarcinoma of the prostate were prospectively evaluated for the presence of human placental lactogen (hPL), placental alkaline phosphatase (PAP), and human chorionic gonadotropin (hCG). Ectopic production of hCG was found in one of the 16 cases and is described in detail. Serial serum hCG levels in that patient mirrored his course more reliably than concomitant acid phosphatase levels. Serum estradiol, testosterone, the hCG-alpha subunit, hPL and PAP were not elevated. There was a minimal elevation of serum FSH. There were no elevations of the other placental proteins in ten evaluable cases. A retrospective evaluation of serum bank specimens from 47 patients with prostatic carcinoma revealed no elevation of the placental proteins hPL, hCG-beta, and hCG-alpha. To our knowledge this report documents the first case of a chorionic gonadotropin-producing prostatic carcinoma appearing the literature.

Trauma-induced neurotoxicity in rat hippocampal neurons.

BACKGROUND AND PURPOSE: We have previously shown that traumatic injury of hippocampal cells triggers release of a soluble neurotoxin that can be transferred to an uninjured culture. The mechanism of this trauma-induced neurotoxicity is independent of glutamate receptor activation. We extended this observation to study the mechanism of this neurotoxicity. METHODS: Dissociated rat hippocampal neurons were traumatized by disrupting the culture by scratching the plate. The toxicity expressed by the injured culture was studied by transferring the medium to an uninjured culture and assessing the death rate by trypan blue exclusion. RESULTS: This neurotoxin is stable in the medium at room temperature for several hours and withstands boiling. The molecular weight is between 100 and 500. The release and the effect of this toxin seem to be independent of glutamate receptor activation. The toxicity is unaffected by removal of extracellular calcium. However, dantrolene dose-dependently blocked the toxicity in the recipient culture, suggesting that the release of intracellular stores of calcium is involved in the toxic effect. This release of calcium is likely to be followed by an activation of nitric oxide synthase because competitive nitric oxide synthase inhibitors attenuated this toxicity. Consistent with this result, cholecystokinin octapeptide significantly reduced cell death when combined with this toxic medium. CONCLUSIONS: Traumatic injury of dissociated cells can propagate neurotoxicity in uninjured cells by a soluble toxin released into the extracellular space. This toxin causes a rise in cytosolic calcium that activates nitric oxide synthase that can be blocked by cholecystokinin.

Intensive chemotherapy of small cell bronchogenic carcinoma.

Thirty-two patients (27, extensive disease; five, regional disease) with histologically documented small cell carcinoma entered a randomized study to determine the efficacy of intensive induction chemotherapy. The necessity of a protected environment (laminar air flow room) during this treatment was also evaluated. Patients received high-dose or standard-dose cyclophosphamide, methotrexate, and CCNU (CMC) during the first 6 weeks of treatment. Subsequent maintenance therapy consisted of standard-dose CMC until disease progression. In 23 patients treated with high-dose chemotherapy there were responses in 96% (30% complete). Standard-dose chemotherapy gave responses in 45%, none of which were complete. Median survival correlated with completeness of response and was 16+ months for the seven complete responders. Patients receiving high-dose CMC spent an average of 10 days with neutrophil counts less than 1000/mm3. There was only one documented, non-fatal infection. High-dose chemotherapy gives better responses and longer survival than previously utilized standard doses of the same drugs. Patients could safely be treated in the hospital ward.