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PubMed2005

Nonauditory events of a behavioral procedure activate auditory cortex of highly trained monkeys.

A central tenet in brain research is that early sensory cortex is modality specific, and, only in exceptional cases, such as deaf and blind subjects or professional musicians, is influenced by other modalities. Here we describe extensive cross-modal activation in the auditory cortex of two monkeys while they performed a demanding auditory categorization task: after a cue light was turned on, monkeys could initiate a tone sequence by touching a bar and then earn a reward by releasing the bar on occurrence of a falling frequency contour in the sequence. In their primary auditory cortex and posterior belt areas, we found many acoustically responsive neurons whose firing was synchronized to the cue light or to the touch or release of the bar. Of 315 multiunits, 45 exhibited cue light-related firing, 194 exhibited firing that was related to bar touch, and 268 exhibited firing that was related to bar release. Among 60 single units, we found one neuron with cue light-related firing, 21 with bar touch-related firing, and 36 with release-related firing. This firing disappeared at individual sites when the monkeys performed a visual detection task. Our findings corroborate and extend recent findings on cross-modal activation in the auditory cortex and suggests that the auditory cortex can be activated by visual and somatosensory stimulation and by movements. We speculate that the multimodal corepresentation in the auditory cortex has arisen from the intensive practice of the subjects with the behavioral procedure and that it facilitates the performance of audiomotor tasks in proficient subjects.

Acoustic Stimulation↗
PubMed2002

Stereotactic guided laser-induced interstitial thermotherapy (SLITT) in gliomas with intraoperative morphologic monitoring in an open MR: clinical expierence.

Stereotactic guided laser-induced interstitial thermotherapy (SLITT) is a minimal invasive method to produce thermonecrosis in cerebral tumour tissue. Clinical data are sparse due to its limited application until now and the value of this approach for tumour control and survival time remain to be defined. Twenty-four patients (7 low-grade gliomas, 11 anaplastic gliomas, 6 glioblastomas) with brain tumours, most recurrences, were treated with SLITT, in total 30 laser procedures were performed. Under local anaesthesia a 600 micro m laser-fiber was inserted by the stereotactic-guided technique. In open low-field MR the denaturation of the tumour by a Nd-YAG-laser (1064 nm) was monitored using T 1 -weighted 3-D turbo FLASH sequences. The ablation procedure had to be stopped twice because of neurological deficit, one major infection occurred. In two cases neurological improvement was observed. Mean survival times for low grade astrocytomas, anaplastic gliomas and glioblastomas were 144 months, 39 months, 17 months, respectively. Mean survival times after SLITT were 34 months, 30 months and 9 months, respectively. Mean times to progression after SLITT for the 3 histological subgroups were 16 months, 10 months and 4 months, respectively. Five patients with low grade astrocytoma and a KI greater or equal 70 maintained a high quality functional status for 11, 20, 21, 33 and 43 months. In anaplastic tumours patients maintained a KI of 70 for a median time of 15 months and for those with glioblastoma the respective high quality duration was 7.5 months after SLITT. SLITT for selected patients with glioma could have a clinical value in a multimodality treatment schedule maintaining quality of live. Due to the minimal invasive technique, the method is a therapy of choice and may be favoured to reoperation. Major indications of this treatment are small tumours, in eloquent regions and deep seated, as well as in older patients or patients in poor functional status.

Adult↗
PubMed1996

Radiological diagnosis of skeletal metastases.

The clinical management of patients with skeletal metastases puts new demands on imaging. The radiological imaging in screening for skeletal metastases entails detection, metastatic site description and radiologically guided biopsy for morphological typing and diagnosis. Regarding sensitivity and the ease in performing surveys of the whole skeleton, radionuclide bone scintigraphy still is the first choice in routine follow-up of asymptomatic patients with metastatic disease of the skeleton. A negative scan has to be re-evaluated with other findings, with emphasis on the possibility of a false-negative result. Screening for metastases in patients with local symptoms or pain is best accomplished by a combination of radiography and MRI. Water-weighted sequences are superior in sensitivity and in detection of metastases. Standard spin-echo sequences on the other hand are superior in metastatic site description and in detection of intraspinal metastases. MRI is helpful in differentiating between malignant disease, infection, benign vertebral collapse, insufficiency fracture after radiation therapy, degenerative vertebral disease and benign skeletal lesions. About 30% of patients with known cancer have benign causes of radiographic abnormalities. Most of these are related to degenerative diseases and are often easily diagnosed. However, due to overlap in MRI characteristics, bone biopsy sometimes is essential for differentiating between malignant and nonmalignant lesions. Performing bone biopsy and aspiration cytology by radiologist and cytologist in co-operation has proven highly accurate in diagnosing bone lesions. The procedure involves low risk to the patient and provides a morphological diagnosis. Once a suspected metastatic lesion is detected, irrespective of modality, the morphological diagnosis determines the appropriate work-up imaging with respect to the therapy alternatives. The integration of multimodality imaging in the assessment of skeletal metastases is complex and requires multidiciplinary co-operation in order to optimize screening and medical clinical care with respect to the prognosis and life quality of patients with bone metastatic disease.

Biopsy↗
PubMed1994

Similarity of fluorescence lifetime distributions for single tryptophan proteins in the random coil state.

The picosecond time-resolved fluorescence decay data of nine single-tryptophan (trp) proteins and two multi-trp proteins in their native and denatured states were analyzed by the maximum entropy method (MEM). In the denatured state (6 M guanidine hydrochloride) a majority of the single-trp proteins show bimodal (at 25 degrees C) and trimodal (at 85 degrees C) distributions with similar patterns and similar values for average lifetimes. In the native state of the proteins the lifetime distributions were bimodal or trimodal. These results (multimodal distributions) are contradictory to the unimodal Lorentzian distribution of lifetimes reported for some proteins in the native and denatured states. MEM analysis gives a unimodal distribution of lifetimes only when the signal-to-noise ratio is poor in the time-resolved fluorescence decay data. The unimodal distribution model is therefore not realistic for proteins in the native and denatured states. The fluorescence decay components of the bi- or trimodal distribution are associated with the rotamer structures of the indole moiety when the protein is in the random coil state.

Amino Acid Sequence↗
PubMed2006

Vision and touch are automatically integrated for the perception of sequences of events.

The purpose of the present experiment was to investigate the integration of sequences of visual and tactile events. Subjects were presented with sequences of visual flashes and tactile taps simultaneously and instructed to count either the flashes (Session 1) or the taps (Session 2). The number of flashes could differ from the number of taps by +/-1. For both sessions, the perceived number of events was significantly influenced by the number of events presented in the task-irrelevant modality. Touch had a stronger influence on vision than vision on touch. Interestingly, touch was the more reliable of the two modalities-less variable estimates when presented alone. For both sessions, the perceptual estimates were less variable when stimuli were presented in both modalities than when the task-relevant modality was presented alone. These results indicate that even when one signal is explicitly task irrelevant, sensory information tends to be automatically integrated across modalities. They also suggest that the relative weight of each sensory channel in the integration process depends on its relative reliability. The results are described using a Bayesian probabilistic model for multimodal integration that accounts for the coupling between the sensory estimates.

Adult↗
PubMed2006

Performance test of an LSO-APD detector in a 7-T MRI scanner for simultaneous PET/MRI.

UNLABELLED: PET combined with CT has proven to be a valuable multimodality imaging device revealing both functional and anatomic information. Although PET/CT has become completely integrated into routine clinical application and also has been used in small-animal imaging, CT provides only limited soft-tissue contrast and, in preclinical studies, exposes the animal to a relatively high radiation dose. Unlike CT, MRI provides good soft-tissue contrast even without application of contrast agents and, furthermore, does not require ionizing radiation. METHODS: This project focused on combining a high-resolution PET scanner with a 7-T MRI system for animal research. Because classic PET detectors based on photomultiplier tubes cannot be used in high magnetic fields, we used a detector technology based on 10 x 10 lutetium oxyorthosilicate crystal arrays and 3 x 3 avalanche photodiode arrays. A ring of such PET detectors will ultimately be used as an insert for the 119-mm-diameter MRI bore. RESULTS: Initial measurements with 1 PET detector module in the 7-T field during application of MRI sequences were encouraging. Position profiles from the PET detectors and a first MR image of a mouse could be acquired simultaneously. CONCLUSION: Further work will concentrate on the construction of a full PET detector ring with compact, integrated electronics.

Animals↗
PubMed2005

Multimodality therapy for stage III non-small-cell lung cancer.

The treatment of stage III non-small-cell lung cancer has evolved over the last two decades, with combined-modality therapy the current standard of care. As a result, intermediate and long-term survival has improved for patients in this common stage category, compared to the poor outcomes achieved with the historical standard of once-daily radiation therapy alone. This review summarizes two decades of clinical research regarding bimodality and trimodality approaches for the heterogenous stage subsets within the stage III designation, discusses the rationale and status of prophylactic brain irradiation, and concludes with perspectives on progress and future directions. Chemotherapy plus radiotherapy given concurrently is the optimal treatment for the group of patients with advanced stage III disease. The potential role of a surgical resection following chemotherapy (with or without radiation) in this setting is still controversial. The only subsets for which trimodality treatments are clearly preferred include T4N0-1 disease and superior sulcus tumors. The other major stage III subgroup has a minimal disease burden with low tumor volume and/or microscopic N2 disease, thus technically could undergo a surgical resection upfront. Induction chemotherapy before surgery may yield a survival advantage, although the phase III trials in this area are not conclusive. Given the marked survival benefit from adjuvant chemotherapy after surgery in even earlier stages of non-small-cell lung cancer, the proper sequence of surgery and chemotherapy (before v after surgery) remains an important unresolved question in this subgroup. Furthermore, how to incorporate radiation therapy, as well as whether it should be given at all in this subset of patients, are other important issues actively under study in ongoing trials.

Carcinoma, Non-Small-Cell Lung↗
PubMedDate not supplied

In vitro studies on interaction of 4-hydroperoxy-ifosfamide and radiotherapy in malignant gliomas.

Drug-radiation multimodal chemotherapy for malignant brain tumor cells was stimulated in vitro by a recently developed computer program, based on evaluation of 3D-response surfaces and interaction isoboles. Three malignant glioma tumor cell cultures (HTZ17, 146 and 209 B) were sequentially treated in vitro by increasing doses of 4-hydroperoxy-ifosfamide, according to in vivo/in vitro pharmacokinetic correlation (0.01 to 10 microM), and increasing single doses of Gamma-radiation (clinical60Co-radiotherapy unit, 0.26 to 4 Gy or 1 to 3.38 Gy, respectively). After approximately five population doubling times with standard tissue culture conditions, 3H-Tdr-incorporation was determined by a liquid scintillation counting protocol. Data points were evaluated for mono- and combined treatment dose-effects. A model-free 3D-response surface was created and compared to the theoretical additive response surface. Local additivity was analysed for any desired ratio of combined treatment as well as for isoboles. No significant sub- or supraadditive effects were observed, indicating additive effects in all 3 tumors. No sequence dependence of effects could be demonstrated. In case radiotherapy and ifosfamide-chemotherapy are active treatment modalities and additive effects are found, we conclude that the combination of ifosfamide and radiotherapy might be attractive for the treatment of malignant brain tumors and should be further studied.

Astrocytoma↗
PubMed1996

Reading with magnifiers.

The design of low vision aids for partially sighted people, such as magnifiers, is evaluated theoretically in order to identify meaningful directions of research for improving these aids. Both reading with and without a magnifier involves alternating sequences of locating and recognizing textual information. Little is known, however, about these processes in magnifier reading. On the basis of an extensive review of the literature, two topics are identified that stand out as being in need of experimental investigation: (1) the relationship between the (typo)graphical characteristics of printed text and the location and recognition of textual information, and (2) the interplay of location and recognition processes in magnifier reading, including the role of non-visual factors, such as movements of the hand, trunk, head and eyes in this interplay. With regard to the first topic, it is expected that the visibility and, hence, the recognition of textual information by partially sighted people can be improved by matching the fundamental spatial frequencies of graphical structures with the spatial contrast sensitivity of partially sighted people. With regard to the second topic, it is argued that persistent problems in the design of the magnifiers, such as the optimal window size, can only be resolved by studying reading with a magnifier as a (multimodal) perceptual-motor activity.

Data Display↗
PubMed2005

Concurrent chemoradiotherapy for unresectable stage III non-small cell lung cancer.

Over the last two decades, several approaches to multimodality therapy have been investigated in patients with advanced unresectable non-small cell lung cancer. These include induction chemotherapy and concurrent chemoradiotherapy. Both approaches have been shown to be superior to radiation therapy alone. However, in several randomized trials, concomitant chemoradiotherapy was shown to be superior to the induction chemotherapy approach. It has been hypothesized that the addition of systemic dose sequential chemotherapy to concurrent chemoradiotherapy, either as induction or as consolidation chemotherapy, might further improve survival rates. Recently, the Cancer and Leukemia Group B reported on a randomized phase III trial directly evaluating the addition of two cycles of carboplatin and paclitaxel to concurrent chemoradiotherapy. In this study, induction chemotherapy failed to further improve survival rates of concurrent chemoradiotherapy. A previously conducted randomized phase II study also suggested no benefit from the addition of induction chemotherapy to concomitant chemoradiotherapy. Favorable phase II data have been published supporting the use of consolidation chemotherapy. However, to date, no large randomized study evaluating a possible benefit from consolidation chemotherapy has been completed. In addition to evaluating optimal sequencing strategies of combined modality therapy, current investigations are also focusing on the integration of novel agents, including chemotherapeutic and targeted therapies. Currently ongoing trials involving novel approaches are reviewed here.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

The research logic of radiation oncology in combined modality therapy.

The integration of radiation, chemotherapy, and surgery depends on the delineation of failure patterns for each specific cancer. By identifying the failure pathways it is possible to design therapeutic strategies for each pattern. The main issues focus upon selecting the best therapeutic sequence and combination that can be employed first to reduce the tumor to subclinical stages, but ultimately to achieve a total cure. Although radiation therapy and chemotherapy can be given simultaneously or sequentially the variety of drugs now available and the many dose schedules for radiation therapy and chemotherapy make the possible permutations almost infinite. It is for this reason that the drug-radiation therapy interactions should be better understood, and that is why new terminology is being developed to describe the different types of interactions that may occur. With the innovations in radiation therapy (systemic half-body irradiation, radiosensitizers, and hyperthermia), there are now more potential combinations of standard modalities and new investigative techniques than can be explored clinically. For this reason, experimental models may be able to offer a better scientific basis for combining modes, but even in the laboratory too many probabilities exist. The need for a cooperative effort (both in laboratory and clinical investigations) for combined modality treatment approaches to cancer has become a mandate for oncology protocol design in this multimodal era.

Clinical Trials as Topic↗
PubMed1998

Combined-modality treatment of locally advanced non-small cell lung cancer: incorporation of novel chemotherapeutic agents.

The role of multimodality management in locally advanced non-small cell lung cancer (NSCLC) continues to evolve and is a subject of ongoing clinical research. Induction chemotherapy followed by surgical resection with or without thoracic radiotherapy has proved superior to surgical resection alone in patients with ipsilateral mediastinal (N2) disease. Whether surgery alone still plays a role in these patients is the subject of an ongoing intergroup study. As no definitive, optimal effective chemotherapy regimen currently exists for NSCLC, future studies will attempt to incorporate novel and active agents like the taxanes, irinotecan, vinorelbine, and gemcitabine into combined-modality therapy for locally advanced NSCLC. Thoracic radiation therapy by itself provides local control and effective palliation of tumor-related symptoms but has minimal impact on the survival of patients with locally advanced disease. Novel schemes such as hyperfractionated radiotherapy and continuous hyperfractionated accelerated radiotherapy are currently being investigated and appear promising but need to be tested in combination with chemotherapeutic agents. Randomized studies have demonstrated the benefit of concurrent or sequential chemoradiation in selected patients with a good performance status and minimal weight loss. The exact sequence of combined-modality therapy has yet to be determined. The combination of paclitaxel and platinum compounds has shown impressive activity in advanced NSCLC in both phase II and III randomized studies. We have incorporated weekly low-dose paclitaxel and carboplatin with concurrent thoracic radiation in treating patients with locally advanced, inoperable NSCLC, and long-term follow-up has shown remarkable survival rates. Confirmation of these phase II combined-modality studies is needed. Combination sequential chemotherapy followed by concurrent chemoradiation in patients with advanced NSCLC has the potential to improve overall survival by increasing both local and distant control.

Antineoplastic Agents↗
PubMed1998

The endovascular treatment of brain arteriovenous malformations.

Advances in superselective microcatheterization techniques, which took place in the past decade, established superselective endovascular exploration as an integral and indispensable tool in the pretherapeutic evaluation of brain AVMs. The strict and routine application of superselective angiography furthered our knowledge on the angioarchitecture of brain AVMs, including vascular composition of the nidus, types of feeding arteries and types and patterns of venous drainage. In addition, various types of weak angioarchitectural elements, such as flow-related aneurysms, intranidal vascular cavities and varix formation proximal to high-grade stenosis of draining veins, could be identified as factors predisposing for AVM rupture. A wide spectrum of secondary angiomorphological changes induced by the arteriovenous shunt of the nidus and occurring up- and downstream of the nidus have been identified as manifestations of high-flow angiopathy. These data help to better predict the natural history, understand the widely variable clinical presentation and to define therapeutic targets of brain AVMs. Correlation of the topography of the AVM as demonstrated by MR with the angioarchitecture as demonstrated by superselective angiography provided a system for topographic-vascular classification of brain AVMs, which proved very useful for patient selection and definition of therapeutic goals. This study showed, that 40% of patients with brain AVMs can be cured by embolization alone with a severe morbidity of 1.3% and a mortality of 1.3%. Part of theses patients can, however, be cured equally effective by microsurgery or radiosurgery. Which modality will be chosen for a particular patient will mainly depend on the locally available expertise and experience, but also on the preference of the patient following its comprehensive information about the chances for cure and the risks associated with each of these therapeutic modalities. Embolization has a significant role in the multimodality treatment of brain AVMs, by either enabling or facilitating subsequent microsurgical or radiosurgical treatment. Appropriately targeted embolization in otherwise untreatable AVMs represents a reasonable form of palliative treatment of either ameliorating the clinical condition of the patient or reducing the potential risk of hemorrhage. Regarding the practical aspects of the endovascular treatment the following conclusions could be drawn from the experience obtained with this series of 387 patients with a brain AVM: (1) The goal of endovascular treatment should be defined prior to the procedure. This does not preclude a change in the goal, if additional information obtained during the procedure make this necessary. (2) The result of endovascular treatment of a brain AVM in terms of the degree of obliteration achieved and complication rate depends mainly on the endovascular strategy developed and the technique applied. These depend on the specific angioarchitecture and topography of the individual AVM, on the past history and clinical presentation of the patient and on the predefined goal of embolization. The strategy should include the definition of embolization targets, the selection of the most appropriate approach for endovascular navigation, the determination of the sequence of catheterization of individual feeding arteries, the selection of the type of catheters and microcatheters, the selection of the appropriate embolic materials as well as the site and mode of their delivery. Thereafter, every endovascular move should be, as in a chess game, the result of a logical plan. (3) Atraumatic superselective microcatheterization is a key point in the endovascular treatment of brain AVMs. It requires manual skills, knowledge of anatomy and respect for the vascular wall. (4) All locations of brain AVMs should be regarded as eloquent, and no distinction should be made between eloquent and non-eloquent areas of the brain when deciding on the execution of embolizatio

Adolescent↗
PubMed1998

Expression domains of the medaka (Oryzias latipes) Ol-Gsh 1 gene are reminiscent of those of clustered and orphan homeobox genes.

Screening of a medaka (Oryzias latipes) adult brain cDNA library, with a degenerated probe corresponding to the most conserved region of helix III of the homeodomain, led to the isolation of a gene homologous to a murine orphan Hox gene, named Gsh-1. We have called this gene Ol-Gsh 1 (Oryzias latipes-Gsh 1). Molecular analysis of the Ol-Gsh 1 putative protein points to potential functional domains which are highly conserved between fish and mouse genes. Whole-mount in situ hybridization shows that Ol-Gsh 1 is expressed in several waves during embryonic development. Transcripts are found in many regions of the central nervous system: the spinal cord, dorsal rhombencephalon, optic tectum, dorsal diencephalon, hypothalamus anlagen and rostral telencephalon. This multimodal expression pattern, strikingly conserved between fish and mammals, is reminiscent of both clustered and orphan homeobox genes. In addition, each expression wave is initiated in the fish embryo earlier than in the mammalian embryo, relative to the time scale defined by somitogenesis. We propose that Ol-Gsh 1 may be involved in conserved developmental pathways and in particular may be linked to proliferation events. Mouse Gsh-1 was shown to participate in neuro-endocrine functions of the hypothalamus. From late developmental stages onwards, Ol-Gsh 1 expression is also restricted to the hypothalamus. The expression pattern in this structure raises interesting questions concerning a fully or partially conserved function for these genes.

Amino Acid Sequence↗
PubMed2000

High-throughput comprehensive peptide mapping of proteins by multiplexed capillary electrophoresis.

A novel multimodal method for peptide mapping of proteins by multiplexed capillary electrophoresis (CE) is presented. By combining charge to size separations in four different channels and micellar electrokinetic chromatography for hydrophobicity-based separations in two different channels in a 96-capillary array, peptide fragments of digested proteins were readily resolved and showed unique fingerprints. Each capillary spanned several diodes in a photodiode array (PDA) for absorption measurement. The 96 capillaries were monitored simultaneously at 214 nm by a single PDA element with 1,024 diodes, and analysis was completed within 45 min. This demonstrates that it is possible to rapidly screen biotechnological products as well as to efficiently optimize separation conditions in CE by a combinatorial approach.

Amino Acid Sequence↗
PubMed2000

Paclitaxel-based chemotherapy for patients with refractory or relapsed nonseminomatous germ cell tumors.

Germ cell tumors have been the paradigm for successful solid tumor therapy. With multimodality treatment including surgery and/or chemotherapy and/or radiation therapy 75% of all patients with germ cell tumors will be cured of their malignancy. However, in patients who have primary refractory or relapsed disease, the cure rate is less than 20%. Treatment strategies in this patient population have included: (1) dose intense therapies such as alternating sequential chemotherapy with multiple active regimens given in short intervals, (2) dose dense therapy with high-dose chemotherapy and stem cell support, (3) new agents, and (4) salvage surgery. Prognostic stratification of patients in a salvage setting can help to determine which therapeutic modalities may provide the greatest opportunity for success. The evaluation of new agents has historically occurred in the salvage setting followed by the development of combinations and then advancement to nonsalvage therapy. The introduction of paclitaxel, with its novel mechanism of action and preclinical activity, resulted in its evaluation as a single agent in patients with refractory or relapsed nonseminomatous germ cell tumors. As a single agent, paclitaxel has an overall response rate of 13.3% in a heavily pretreated salvage population. The preclinical evaluation of the combination of paclitaxel and cisplatin allowed for the most appropriate sequencing and dosing of the two agents. In addition, preclinical evaluation suggests that these agents are synergistic as well as active in cisplatin-refractory disease. The combination of paclitaxel and cisplatin was evaluated clinically and demonstrated an overall response rate of 30%. Doxorubicin is an active agent in germ cell tumors and has nonoverlapping toxicity with pactitaxel and cisplatin. The majority of patients treated in a community setting have not had prior exposure to this agent. Therefore, the regime of doxorubicin, paclitaxel, and cisplatin (ATP) was developed and in a small number of patients was utilized in the salvage setting with a 25% response rate. A pilot study with ATP therapy for patients with nonseminomatous germ cell tumors who have disease progression during induction therapy or first and second salvage regimens and who have received a total of more than six courses of prior chemotherapy is ongoing.

Journal Article↗
PubMed1999

Phase I-II study of 5-fluorouracil, recombinant interferon alpha2a, and cisplatin in combination with external beam radiation therapy followed by surgery in patients with locally advanced carcinoma of the esophagus.

Multimodality therapy has been demonstrated to be superior to external beam radiation therapy and possibly surgery alone for the treatment of carcinoma of the esophagus. The combination of 5-fluorouracil (5-FU), cisplatin, and recombinant interferon alpha2a (IFN) has yielded 65% response rates in metastatic and regionally advanced carcinoma of the esophagus. A phase I-II study was performed to assess the feasibility of combining 5-FU, IFN, and cisplatin with external beam radiation therapy followed by surgery in potentially resectable patients. Eligibility included biopsy-proven stage II-III squamous cell or adenocarcinoma of the esophagus with no prior therapy. External beam radiation therapy was administered concurrently with chemotherapy beginning on day 1, 5 days per week, twice a day with 1.5 Gy/fraction to a total dose of 45 Gy. 5-FU was administered at 750 mg/m2 on days 1, 8, 15, 22, and 29 after the administration of IFN and cisplatin. IFN was given at a dose of 6 million units subcutaneously three times per week beginning on day 1. Dose levels I, II, and III of cisplatin were 25, 30, and 35 mg/m2 administered on days 1, 8, 15, 22, and 29. The sequence of administration was IFN followed by cisplatin followed immediately by 5-FU. Dose escalation between patient cohorts occurred if 0/3 or < or = 1/6 patients had dose-limiting toxicity, i.e., grade II-III toxicity attributable to cisplatin. A phase II trial was planned using the maximum tolerated dose of cisplatin determined from the phase I trial. Patients who successfully completed therapy underwent thoracic exploration to resect residual disease. Twelve patients were enrolled; all were eligible. The demographics of the population were median age, 60 years (range, 44-77); nine male and three female patients; nine squamous cell carcinoma, one adenocarcinoma, and two adenosquamous histology; stage II:III, 2:10. Grade 3-4 toxicities included granulocytopenia (12 patients), thrombocytopenia (six), anemia (three), infection (six), diarrhea (two), mucositis (two), and renal and hepatic toxicities (one). Five patients had a clinical complete response, among whom four underwent surgery. At surgery, one patient had no evidence of residual disease and three patients had microscopic disease only. Two patients had progressive disease and five could not complete the therapy because of toxicities. Two patients are alive and disease free at 25 and 23 months, respectively. This regimen, though active, demonstrated an unfavorable toxicity profile and cannot be recommended for further study.

Adenocarcinoma↗
PubMed1993

Responses of rat medullary dorsal horn neurons following intranasal noxious chemical stimulation: effects of stimulus intensity, duration, and interstimulus interval.

1. Most quantitative examinations of nociception are performed with thermal or mechanical stimuli. Because nociceptive processing mechanisms may depend on the modality of the stimuli, comparable studies on chemonociception are necessary. 2. We examined the activity of chemonociceptive medullary dorsal horn neurons in halothane-anesthetized rats. For controlled noxious chemical stimulation, defined CO2 pulses were applied to the nasal mucosa. The effects of stimulus intensity, duration, and interstimulus interval (ISI) were tested by performing three different CO2 stimulation protocols (see below). 3. The recorded neurons were characterized by intranasal and facial stimuli of different modalities. The cells received input from intranasal A delta- and/or C-fibers. All tested neurons also responded to other intranasally applied irritants, e.g., mustard oil. Furthermore, the units were sensitive to intranasal high-threshold mechanical stimulation and to facial mechanical stimulation. According to the properties of their facial mechanoreceptive fields, the units were classified as wide dynamic range (WDR) or nociceptive specific (NS) neurons. The majority of the cells also responded to facially applied noxious heat stimuli, so that most of the recorded neurons were found to be multimodal. Some of the neurons, in addition, had convergent input from primary afferents innervating the maxillary tooth pulps or the cornea and periorbital structures. 4. In the first stimulation protocol we presented four different CO2 concentrations (25, 50, 75, and 100%; stimulus duration 2 s). In total, each concentration was applied 10 times (2 trains of 5 stimuli). Stimulus response functions (SRFs) were computed with average responses to identical stimuli. All but 2 of the 23 tested neurons displayed enhanced responses after stimulation with increasing intensities. In general, WDR cells (n = 15) discharged more vigorously to the same CO2 concentration than NS cells (n = 8). WDR neurons discriminated more reliably between stimulus intensities in the low to moderate range (25-50% CO2) than NS cells. Both categories of neurons, however, discriminated equally well in the moderate- to high-intensity range (50-75% CO2). The discriminatory capacity of WDR and NS neurons was reduced in the highest concentration range (75-100% CO2). The proportion of NS neurons significantly discriminating between these intensities tended to be higher compared with WDR neurons when stimuli were applied with long ISIs (120 s). 5. To examine the effects of the duration of the ISI, identical test sequences were performed with ISIs of 30 and 120 s. (ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗