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Local hyperthermia, radiation therapy, and chemotherapy in patients with local-regional recurrence of breast carcinoma.

We retrospectively reviewed the response rate and the acute and long-term toxicity of combined treatment using radiation therapy, hyperthermia, and chemotherapy in 29 patients with locally or regionally recurrent or advanced adenocarcinoma of the breast who completed at least 4 of the 6 prescribed hyperthermia treatments as part of a Phase I-II trial. Thirty-nine separate hyperthermia treatment fields were evaluated. Cisplatin alone or cisplatin with etanidazole or bleomycin was delivered just prior to hyperthermia once weekly. Hyperthermia was delivered to a target minimum tumor temperature of 43 degrees C +/- 0.5 for 60 min. Following hyperthermia, a 400 cGy fraction of radiation was given. The radiation fraction size on other days was 200 cGy. Twenty-two fields had previously been irradiated and 17 fields had not. Prior chemotherapy had been given in 24 of 29 patients (83%) and hormonal therapy given in 21 (72%). The median follow-up time is 10 months; 16/29 patients (55%) have died of disease. The overall complete response rate for all fields was 53%. Response rate was not related to any clinical factor, radiation dose, microwave or ultrasound technique, type of chemotherapy, or tumor temperatures, but the number of patients in the study population was small. A statistically significant association between the likelihood of complications and the total radiation therapy dose (previous radiation and present radiation) was found. Persistent ulceration lasting greater than 1 month after completing treatment was seen in 67% of previously irradiated fields compared to 21% of fields that had not been previously treated (p = 0.015). Surgical wound repair was needed for 38% of fields with a history of prior irradiation versus 6% of those without prior treatment (p = 0.050). A statistically significant radiation therapy dose response was found for the likelihood of these complications. None of the hyperthermia temperature parameters studied correlated with an increased risk of complication. We conclude that the combination of radiation therapy, hyperthermia, and chemotherapy results in a high rate of complete response. However, in patients who have been treated with prior radiation therapy, this combination may be more locally toxic than treatment with hyperthermia and radiation therapy alone. The precise impact of chemotherapy on the therapeutic index of hyperthermia and radiation therapy remains to be determined in randomized clinical trials.

Adenocarcinoma↗

Down-regulation of norepinephrine transporter function induced by chronic administration of desipramine linking to the alteration of sensitivity of local-anesthetics-induced convulsions and the counteraction by co-administration with local anesthetics.

Alterations of norepinephrine transporter (NET) function by chronic inhibition of NET in relation to sensitization to seizures induce by cocaine and local anesthetics were studied in mice. Daily administration of desipramine, an inhibitor of the NET, for 5 days decreased [(3)H]norepinephrine uptake in the P2 fractions of hippocampus but not cortex, striatum or amygdalae. Co-administration of lidocaine, bupivacaine or tricaine with desipramine reversed this effect. Daily treatment of cocaine increased [(3)H]norepinephrine uptake into the hippocampus. Daily administration of desipramine increased the incidence of appearance of lidocaine-induced convulsions and decreased that of cocaine-induced convulsions. Co-administration of lidocaine with desipramine reversed the changes of convulsive activity of lidocaine and cocaine induced by repeated administration of desipramine. These results suggest that down-regulation of hippocampal NET induced by chronic administration of desipramine may be relevant to desipramine-induced sensitization of lidocaine convulsions. Inhibition of Na(+) channels by local anesthetics may regulate desipramine-induced down-regulation of NET function. Repeated administration of cocaine induces up-regulation of hippocampal NET function. Desipramine-induced sensitization of lidocaine seizures may have a mechanism distinct from kindling resulting from repeated administration of cocaine.

Adrenergic Uptake Inhibitors↗

Disruption of two putative nuclear localization sequences is required for cytosolic localization of mitogen-activated protein kinase phosphatase-2.

MAP kinase phosphatase-2 (MKP-2) is a member of a family of dual specificity phosphatases (DSPs) that function in both the cytosol and nucleus to inactivate the MAP kinases. The mechanism that controls the subcellular distribution of these proteins is currently unclear. In this study, we have used site-directed mutagenesis to remove two novel nuclear localization sequences, NLS-1 and -2, either alone or in combination (DNLS). Loss of NLS-1 or NLS-2 alone did not alter the nuclear targeting of MKP-2 but mutation of both resulted in MKP-2 being retained within the cytosol. Furthermore, whilst expression of WT-MKP-2, NLS-1 or NLS-2 reduced both sorbitol- or UV-stimulated nuclear c-Jun N-terminal kinase (JNK) activity in HEK293 cells, this effect was absent in cells expressing DNLS-MKP-2. Similarly, transient transfection of WT-MKP-2, NLS-1 or NLS-2, but not DNLS-MKP-2 was able to substantially reduce agonist-stimulated ANF reporter activity in rat cardiac myocytes. Taken together, these results indicate that whilst both novel NLS participate in the nuclear localization of MKP-2, the expression of either sequence is sufficient to retain nuclear targeting.

Amino Acid Sequence↗

Localization of human T-cell lymphotropic virus type II Tax protein is dependent upon a nuclear localization determinant in the N-terminal region.

Human T-cell lymphotropic viruses (HTLV) types I and II are closely related oncogenic retroviruses that have been associated with lymphoproliferative and neurological disorders. The proviral genome encodes a trans-regulatory Tax protein that activates viral genes and upregulates various cellular genes involved in both cell growth and transformation. Tax proteins of HTLV-I (Tax-I) and HTLV-II (Tax-II) exhibit more than 77% aa homology and expression of either Tax-I or Tax-II is sufficient for immortalization of cultured T lymphocytes. Tax-I shuttles from the nucleus to the cytoplasm and accumulates within the nucleus, whereas Tax-II is found mainly in the cytoplasm. In the present study we have used recombinant vectors to analyze the size and structure of the nuclear localization domain within the Tax-II protein sequence. The Tax-II protein was expressed in HeLa cells either as the complete protein, or regions thereof, that were individually fused to the green fluorescent protein (GFP). Immunoblot analysis of the fused Tax-II products confirmed their expression and size. Fluorescence microscopy studies indicated that the complete Tax-II as well as N-truncated forms presented a punctuate cytoplasmic distribution and that a nuclear localization determinant is confined to within the first 60 aa of Tax-II. Accordingly, site directed mutagenesis and deletion of specific sequences within the first 60 aa showed that the nuclear determinant lies within the first 41 residues of Tax-II. These results point to a direct involvement of the amino-terminal residues of Tax-II protein in determining its nuclear functionality.

Amino Acid Sequence↗

Variation in the definition of biochemical recurrence in patients treated for localized prostate cancer: the American Urological Association Prostate Guidelines for Localized Prostate Cancer Update Panel report and recommendations for a standard in the reporting of surgical outcomes.

PURPOSE: The American Urological Association Prostate Guideline Update Panel was charged with updating the Guidelines for Clinically Localized Prostate Cancer. In assessing outcomes with treatment, it became apparent that a highly variable number of definitions exist with respect to biochemical recurrence. Herein, we review the variability in published definitions of biochemical recurrence and make recommendations directed toward improving this terminology by recommending a standard definition in patients treated with radical prostatectomy. MATERIALS AND METHODS: Four PubMed literature searches were performed between May 2001 and April, 2004 and covered articles published from 1991 through early 2004. The search terms included the MeSH major headings of prostate cancer and prostatic neoplasm. All potentially relevant articles were retrieved and a more detailed screen for relevance was performed. An article was considered relevant if it reported treatment outcomes of patients with clinical T1 or T2N0M0 prostate cancer. Data extractors recorded the definition of biochemical recurrence and definitions were then collapsed into categories representing the same criteria. The results of biochemical failure were subcategorized by initial treatment. RESULTS: Of 13,800 citations, a total of 436 articles were selected. Among these, a total of 145 articles contained 53 different definitions of biochemical recurrence for those treated with radical prostatectomy. Of these, the most common definition (35) was a prostate specific antigen of >0.2 ng/mL or a slight variation thereof. In addition, a total of 208 articles reported 99 different definitions of biochemical failure among those treated with radiation therapy. Of these, the American Society for Therapeutic Radiology and Oncology definition (70) and/or a variation thereof was the most commonly reported. In total, 166 different definitions of biochemical failure were identified. Following radical prostatectomy, the Panel recommends defining biochemical recurrence as an initial serum prostate specific antigen of > or =0.2 ng/mL, with a second confirmatory level of prostate specific antigen of >0.2 ng/mL. The Panel recommends the use of the American Society for Therapeutic Radiology and Oncology criteria for patients treated with radiation therapy and acknowledges that these criteria will soon be updated although not yet published. CONCLUSIONS: A high degree of variability in the definition of biochemical recurrence exists following treatment for localized prostate cancer. Strict definitions for biochemical recurrence are necessary to identify men at risk for disease progression and to allow meaningful comparisons among patients treated similarly. The Panel acknowledges the American Society for Therapeutic Radiology and Oncology criteria and future modifications thereof for those receiving radiation therapy and recommends the newly developed American Urological Association criteria for those treated with radical prostatectomy. The purpose for the establishment of this standard is for data reporting purposes and for comparison of similarly treated patients. It is not intended to represent a threshold value for which to initiate treatment. The Panel acknowledges that the clinical decision to initiate treatment will be dependent on multiple factors including patient and physician interaction rather than a specific prostate specific antigen threshold value.

Humans↗

The truncated 23-230 form of the prion protein localizes to the nuclei of inducible cell lines independently of its nuclear localization signals and is not cytotoxic.

The mechanisms of prion-induced neurological dysfunction observed in prion diseases are poorly understood. Transgenic mice expressing a truncated form of the prion protein (23-230 PrP) acquire cerebellar degeneration (Ma and Lindquist, Science, 2002). To decipher the mechanisms of neurodegeneration induced by 23-230 PrP, we established inducible cell lines expressing this truncated form of PrP. We found that 23-230 PrP, expected to be cytosolic, accumulated mostly in the nucleus of the cells and was not cytotoxic. Nuclear localization of this mutant form of PrP is independent of its predicted nuclear localization signals. In contrast to what we previously described for PrPSc, nuclear accumulation of 23-230 PrP does not require a functional microtubule network. We observed that 23-230 PrP interacts with chromatin in vivo, as already described for recombinant PrP and for PrPSc. Our data demonstrate that the 23-230 PrP model does not reflect the situation of a cytosolic PrP but could represent a very useful tool to understand the consequences of the accumulation of the prion protein in the nucleus.

Active Transport, Cell Nucleus↗

Repetitive low-energy shock wave application without local anesthesia is more efficient than repetitive low-energy shock wave application with local anesthesia in the treatment of chronic plantar fasciitis.

BACKGROUND: It remains unclear whether application of local anesthesia (LA) interferes with clinical efficacy of extracorporeal shock wave therapy (ESWT) for chronic plantar fasciitis. AIMS: To evaluate the effect of local anesthesia on the clinical outcome after repetitive low-energy ESWT for chronic plantar fasciitis. METHODS: Eighty-six patients with chronic plantar fasciitis were randomly assigned to receive either low-energy ESWT without LA, given weekly for three weeks (Group I, n=45; 3 x 2000 pulses, total energy flux density per shock 0.09 mJ/mm2) or identical ESWT with LA (Group II, n=41). Primary outcome measure was: Reduction of pain from baseline to month 3 post-treatment in a pain numeric rating scale [0-10 points] during first steps in the morning, evaluated by an independent blinded observer. Calculations were based on intention-to-treat. RESULTS: No difference was found between the groups at baseline. At 3 months, the average pain score was 2.2+/-2.0 points for patients of Group I, and 4.1+/-1.5 points for patients of Group II. The mean between-group difference was 1.9 points (95% CI: [1.1-2.7 points]; P<.001). Significantly more patients of Group I achieved 50% reduction of pain compared to Group II (67% vs 29%, P<.001). CONCLUSION: ESWT as applied should be done without LA in patients suffering from chronic heel pain. LA applied prior treatment reduced the efficiency of low-energy ESWT.

Adult↗

Alkalinization of local anesthesia with sodium bicarbonate--preferred method of local anesthesia.

Effective anesthetic techniques include local anesthetic infiltration with or without sedation and general anesthesia. Local anesthesia is a safe and effective anesthetic technique, that when performed properly is applicable to many outpatient urologic procedures. We have found that the pain usually associated with intradermal injection of lidocaine is attenuated by the addition of sodium bicarbonate.

Anesthesia, Local↗

Family history of breast cancer and local recurrence after breast-conserving therapy. The Dutch Study Group on Local Recurrence after Breast Conservation (BORST).

The impact of a family history of breast cancer on the local recurrence (LR) risk after breast-conserving therapy (BCT) was performed within the framework of a large, multicentre matched case-control study of risk factors for LR after BCT (BORST study). Family history was assessed for 218 breast cancer patients with LR (cases) and 480 patients without LR (controls). Detailed histological tumour features were determined by review of the primary tumour. The risk of LR for patients with a positive family history was similar to or less than that of non-familial patients (unadjusted odds ratio (ORunadj) 0.66 (95% confidence interval (CI) 0.40-1.08)). Familial patients were older than non-familial patients (P = 0.07) and their tumours had a lower histological grade (P = 0.07). A second primary tumour occurred significantly more often in familial patients (P = 0.02). Adjustment for these factors did not essentially alter the results (ORadj 0.71 (0.38-1.32)). Separate analyses according to age at onset (younger and older than 50 years) and time to LR/site of LR produced similar results. The sole presence of a positive family history of breast cancer does not appear to be a risk factor for local recurrence after BCT. Whilst this might be different for genetically predisposed patients, a positive family history does not appear to be a contra-indication for BCT.

Breast Neoplasms↗

Bone marrow harvesting using EMLA (eutectic mixture of local anaesthetics) cream, local anaesthesia and patient-controlled analgesia with alfentanil.

Bone marrow harvesting (BMH) was performed on 40 consecutive allogeneic or autologous donors using EMLA (eutectic mixture of local anaesthetics), local anaesthesia (LA) and patient-controlled analgesia with alfentanil (PCA-A). The effect of alkalinizing the LA solution on reducing pain during LA infiltration in the presence of EMLA was also investigated. EMLA 10 g with occlusive dressing was applied to the harvest sites at least 60 min before BMH. The PCA device was programmed to deliver an intravenous loading dose of 15 microg/kg alfentanil, followed by a background alfentanil infusion of 0.05 microg/kg/min. Demand dose was 4 microg/kg and lockout time was 3 min. Donors were randomized to receive either alkalinized (n = 19) or non-alkalinized (n=21) LA solution (lignocaine 1% with 1:100000 adrenaline). While post-operative nausea and vomiting were the only side-effects, all donors in both groups reported satisfactory pain scores during LA infiltration and satisfactory overall intra-operative comfort scores. They completed BMH using either regimen successfully, found this technique acceptable and would recommend this form of anaesthesia to others. Alkalinizing the LA solution did not significantly improve the pain scores during LA infiltration in the presence of EMLA. In conclusion, BMH can be performed safely using EMLA, LA and PCA-A without major complications.

Adolescent↗

The Local Public Health System Assessment of MAPP/The National Public Health Performance Standards Local Tool: a community-based, public health practice and academic collaborative approach to implementation.

The Local Public Health System Assessment (LPHSA) in Mobilizing for Action through Planning and Partnerships (MAPP), and the Local Tool of the National Public Health Performance Standards Program (LT/NPHPSP)--which are one in the same-attempt to assess the capacity to provide the essential public health services. Both tools have been utilized in various public health practice settings; however, users have been challenged with the complexity of the tools and time and human resource investment necessary to complete them. The recent Journal of Public Health Management and Practice issue focus on MAPP provided several examples of LPHSA implementation, both as a component of MAPP and as a stand-alone activity in the context of performance standards. The uniqueness in our approach involved a collaborative between a community-based organization, a public health academic program, and a governmental public health agency which conducted the LPHSA in a manner that did not require actual modification of the tool itself, was practical and feasible, and was of benefit and value to all partners.

Community Participation↗

Alterations in the pharmacokinetic properties of amide local anaesthetics following local anaesthetic induced convulsions.

The comparative pharmacokinetic properties of lidocaine, bupivacaine, etidocaine and mepivacaine were investigated in convulsing and non-convulsing dogs. The same dose of a given local anaesthetic was administered as either a 30-s intravenous (IV) bolus to produce convulsions or as a 15-min IV infusion producing no convulsions. Derived pharmacokinetic data were found to be different in convulsing and non-convulsing animals. Total body clearance was found to be significantly reduced for lidocaine (29%, P less than 0.05), bupivacaine (31%, P less than 0.05), etidocaine (60%, P less than 0.01) and mepivacaine (68%, P less than 0.01) in convulsing animals. Increases in elimination half-life only achieved statistical significance in mepivacaine-treated animals (non-convulsing 45.2 min, convulsing 105.4 min, P less than 0.01). Overall, the most profound effects of convulsions on pharmacokinetic data were seen with mepivacaine. Convulsions were associated with increases in heart rate ranging from 117% (lidocaine, P less than 0.05) to 129% (mepivacaine, P less than 0.05), increases in cardiac output ranging from 78% (mepivacaine) to 232% (bupivacaine, P less than 0.05) and increases in mean arterial pressure ranging from 45% (lidocaine, P less than 0.05) to 80% (bupivacaine, P less than 0.05). The results suggest that when local anaesthetic-induced seizures occur in man, it cannot be assumed that these drugs will be distributed and eliminated as predicted by intravenous infusion of non-toxic doses.

Anesthetics, Local↗

Radical prostatectomy for clinically localized prostate cancer: local tumor extension and prognosis.

BACKGROUND: This study was performed to evaluate the frequency of local tumor extension and its effect on disease progression after radical prostatectomy. METHODS: The study consisted of 66 consecutive men who underwent radical prostatectomy for clinically localized prostate cancer without any prior hormonal therapy. Cases were stratified according to pathologic findings. Sites of capsular penetration were also evaluated. RESULTS: The overall incidences of lymph node metastases, seminal vesicle invasion, capsular penetration, and positive surgical margin were, respectively, 23%, 32%, 55% and 35%. The disease progression rate in patients with positive lymph nodes differed significantly from that in those without nodal metastases (P < 0.0001). Although seminal vesicle invasion, capsular penetration, or positive surgical margin had an adverse effect on prognosis, the difference in progression missed statistical significance, when patients with positive lymph node metastases were excluded. The most common site of capsular penetration was posterolateral, in the area of the neurovascular bundle. CONCLUSIONS: Extraglandular tumor extension and positive surgical margins are common features of radical prostatectomy specimens. A nerve-sparing operation should be performed selectively and with great caution. The markedly adverse effect of lymph node involvement on progression must be accounted for when evaluating other variables relating to progression.

Aged↗

Do seminal or prostatic secretions play a role in local recurrence after radical prostatectomy for localized prostate cancer?

Neoplastic cellular contamination of the surgical bed may be responsible for late local failure after radical prostatectomy. Cytology analysis of the seminal and prostatic fluid collected intraoperatively was undertaken in 30 patients. Neoplastic cells were found in 2 patients both with seminal vesicle involvement. Although it is difficult to admit that tumor spillage during surgery would be a major cause of local recurrence, the presence of tumor cells in the ejaculate may be diagnostic of seminal vesicle invasion. All patients with pathologic stage T2 had a negative cytologic finding.

Body Fluids↗

Local dental anaesthesia and evidential breath testing: the effect of injection of local anaesthetic on lip seal.

The effect of local anaesthetic infiltration on the ability of subjects to provide adequate specimens of breath for analysis using an evidential breath testing device was assessed. The results showed that in ten out of the fourteen cases there was no impairment of the ability to provide the specimens of breath at any time. Within two hours of the administration of a local anaesthetic all subjects were able to provide the requisite samples.

Adult↗

Local superficial hyperthermia in combination with low-dose radiation therapy for palliation of locally recurrent breast carcinoma.

From September 1984 through March 1987, 30 patients with locally recurrent breast carcinoma who had been heavily pretreated with conventional modes of therapy (radiation, chemotherapy, and hormonal therapy) were entered into a phase II study of hyperthermia and low-dose irradiation. The purpose of the study was to determine the feasibility, effectiveness, and morbidity of this treatment combination. Radiation therapy was administered twice weekly, 4 Gy per fraction, to a total dose of 32 Gy, with 6 or 9 MeV electrons depending on the thickness of the lesions. Hyperthermia generated by microwave frequencies of 200 to 700 MHz was administered immediately after radiation therapy, with a time and temperature aim of 60 minutes at 43 degrees C. Complete response (CR) was achieved in 17 patients (57%), and partial response (PR) in 11 patients (36%). Response was positively correlated with tumor size; lesions less than 5 cm in diameter achieved CR significantly more frequently than lesions greater than or equal to 5 cm (P less than .001). Eighty percent of the complete responders continued to experience sustained control of the treated site from 6 to 32 months but showed evidence of progressive systemic disease or locoregional progression to the adjacent untreated sites, reflecting the natural history of this disease and extensive dermal lymphatic permeation. True recurrence within the treated volume occurred in three patients. Nonhealing ulceration developed in nine patients and seven of those were associated with persistent tumor. This study confirms the palliative value of hyperthermia in combination with radiotherapy for previously irradiated recurrent chest wall tumors and sets the scene for its comparative clinical evaluation against radiation therapy alone as first line therapy for locally recurrent breast carcinoma.

Adult↗

The site of action of epidural fentanyl infusions in the presence of local anesthetics: a minimum local analgesic concentration infusion study in nulliparous labor.

UNLABELLED: We have previously demonstrated that continuous epidural infusions of fentanyl without local anesthetics elicit analgesia by a systemic mechanism. In this study, we examined the hypothesis that, in the presence of epidural bupivacaine, continuous infusions of epidural fentanyl elicit analgesia by a spinal mechanism. Forty-eight nulliparous women in active labor participated in this prospective, randomized, double-blinded study. Women received lumbar epidural analgesia with 20-30 mL bupivacaine 0.125% until pain free. Subjects were then randomized to either IV or epidural (EPI) fentanyl infusion groups. Each infusion delivered fentanyl 30 microg/h. All women received an epidural infusion of bupivacaine at a rate of 20 mL/h, the concentration of which was determined by the response of the previous woman in the same group to the analgesic regimen used. Unlike previous studies that assessed the minimum local analgesic concentration (MLAC) for bolus administration at the initiation of analgesia, this study assessed MLAC(infusion) for the maintenance of analgesia throughout the first stage of labor. MLAC(infusion) was determined using the up-down sequential analysis described by Dixon and Massey. The MLAC(infusion) of epidural bupivacaine was 0.063% (95% confidence interval, 0.058-0.068) and 0.019% (95% confidence interval, 0.000-0.038) in the IV and EPI groups respectively. A continuous infusion of fentanyl was more than three times as potent when administered by the epidural than by the IV route. This marked increase in potency for the epidural route is highly suggestive for a predominantly spinal mechanism of action for infused epidural fentanyl under the conditions of this study. IMPLICATIONS: This study determined the median effective concentration for epidural infusions of bupivacaine during labor analgesia. Coadministered epidural fentanyl infusions were more than three times more potent than IV fentanyl infusions, suggesting a predominantly spinal mechanism of opioid action under these study conditions.

Adolescent↗

Effective local control and long-term survival in patients with T4 locally advanced breast cancer treated with breast conservation therapy.

BACKGROUND: The presence of skin involvement has been accepted as a relative contraindication to breast preservation because it is believed to be associated with an increased local failure rate. This study was conducted to assess the outcome of a carefully selected group of patients who presented with breast cancer involving the skin and who had breast conservation therapy (BCT) following neoadjuvant chemotherapy. METHODS: Between 1987 and 1999, 33 patients with stage IIIB or IIIC breast cancer completed treatment consisting of four cycles of neoadjuvant chemotherapy, lumpectomy, radiation therapy, and consolidative chemotherapy. Clinicopathologic factors were analyzed and patients were followed for locoregional and distant recurrence. RESULTS: Initial median tumor size was 7 cm. All patients had skin involvement, defined as erythema, skin edema, direct skin invasion, ulceration, or peau d'orange. Following chemotherapy, median pathologic tumor size was 2 cm. Complete resolution of skin changes occurred in 29 patients (88%). At median follow-up time of 91 months in surviving patients, 26 patients (79%) were alive without evidence of disease. The 5-year, disease-free survival rate was 70%, and the 5-year overall survival rate was 78%. The actuarial ipsilateral breast cancer recurrence rate was 6% at 5 years. CONCLUSIONS: Patients who present with T4 breast cancer who experience tumor shrinkage and resolution of skin changes with neoadjuvant chemotherapy represent a select group of patients who can have BCT. These patients have favorable rates of long-term local control and survival. Mastectomy is not mandatory for all patients with breast cancer who present with skin involvement.

Adult↗